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Melatonin attenuates titanium particle-induced osteolysis via activation of Wnt/β-catenin signaling pathway

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Abstract

Statement of significance: Peri-prosthetic osteolysis, initiated by wear debris-induced inhibition of bone regeneration and extensive bone resorption, is the leading cause for implant failure and reason for revision surgery. In the current study, we demonstrated for the first time that melatonin can induce bone regeneration and reduce bone resorption at osteolytic sites caused by titanium-particle stimulation. These effects might be mediated by activating Wnt/β-catenin signaling pathway and enhancing osteogenic differentiation. Meanwhile, the ability of melatonin to modulate the balance between receptor activator of nuclear factor kappa-B ligand and osteoprotegerin mediated by Wnt/β-catenin signaling pathway, thereby suppressing osteoclastogenesis, may be implicated in the protective effects of melatonin on titanium-particle-induced bone resorption. These results suggested that melatonin can be considered as a promising therapeutic agent for the prevention and treatment of peri-prosthetic osteolysis.

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... In recent years, it has been reported that MEL can have a pivotal role in this process when age-related osteoporosis is manifested, possibly due to an imbalance in bone turnover related with decreased level of the circulating MEL hormone; thus MEL could act as an autacoid or a local growth factor for the bone cells [4,6,7,30,36]. Importantly, it has also been reported that the proliferation of osteoblasts and the expression of type I collagen and biochemical markers of bone turnover, including bone sialoprotein (BSP) are also promoted by MEL [7,9,17,25,26,35]. Despite promising results, however, very few studies have been conducted to investigate the effects of exogenous administration of MEL as an agent that promotes bone regeneration to date and there is still no consensus on which agent to be used in cranioplasty is better in reconstruction of the cranial defects in humans. ...
... Thus, promotion of bone healing by MEL could be related with one or more of the following possible mechanisms: the promotion of the osteoblast differentiation and/or activity, an increased expression of the osteoprotegerin by osteoblasts, resulting with a decreased differentiation of osteoclasts, and increased scavenging of free radicals which were generated by osteoclasts [31]. Further, and more specifically, it has been speculated that MEL interferes with bone healing in several ways: through modulation of oxidative stres [27,28,32], collagen fibril formation [19], differentiation of osteoblasts via PDGF/AKT signaling pathway [9,25,26,35,43], or activity of osteoblasts and osteoclasts via MEL-MT2 receptor pathway [9,34,41] or RANK/NF-κB signaling pathway [14,26] or Wnt/β-catenin signaling pathway [40,25,16,40]. Moreover, MEL has also been found to stimulate gene expression of BSP and other bone marker proteins including alkaline phosphate, secreted protein, osteocalcin and osteopontin [30]. ...
... Thus, promotion of bone healing by MEL could be related with one or more of the following possible mechanisms: the promotion of the osteoblast differentiation and/or activity, an increased expression of the osteoprotegerin by osteoblasts, resulting with a decreased differentiation of osteoclasts, and increased scavenging of free radicals which were generated by osteoclasts [31]. Further, and more specifically, it has been speculated that MEL interferes with bone healing in several ways: through modulation of oxidative stres [27,28,32], collagen fibril formation [19], differentiation of osteoblasts via PDGF/AKT signaling pathway [9,25,26,35,43], or activity of osteoblasts and osteoclasts via MEL-MT2 receptor pathway [9,34,41] or RANK/NF-κB signaling pathway [14,26] or Wnt/β-catenin signaling pathway [40,25,16,40]. Moreover, MEL has also been found to stimulate gene expression of BSP and other bone marker proteins including alkaline phosphate, secreted protein, osteocalcin and osteopontin [30]. ...
... ODN is able to mimic the microbial/viral DNA function (De Stefano 2011). In a preliminary study, the anti-inflammatory effects of NF-κB decoy ODN could successfully suppress the UHMWPE wear debris-triggered chemokine and cytokine production in primary macrophages and macrophage-like cell lines, including monocyte chemoattractant protein-1 (MCP-1), macrophage inflammatory protein 1-alpha (MIP1α), and TNF-α (Ping et al. 2017). In another study, suppression of NF-κB signaling by decoy ODN with high affinity to NF-κB was shown to mitigate UHMWPE wear particle-induced inflammatory response through regulating MCP-1, MIP1α, and TNF-α in the macrophage cell lines and BMDMs (Tzu-hua Lin et al. 2014). ...
... Additionally, siRNA targeting CXCR2 inhibited the formation of osteoclastic cells via both direct effects on osteoclasts and indirect effects through regulating the gene expression of RANKL and OPG in osteoblasts in vitro (Wang et al. 2016). Previously, it was demonstrated that melatonin attenuated wear particle-induced bone loss and enhanced bone formation (Ping et al. 2017). Melatonin also was proven to attenuate the number of osteoclasts (TRAP + cells) and regulate inflammatory responses via reducing the number of TNF-α-, IL-1β-, and IL-6-positive cells. ...
... In addition, melatonin could moderate the activation of NF-κB via downregulating the protein levels of p-IκBα, p65, and p-p65 in an animal model of Ti particle-triggered osteolysis. Moreover, melatonin dose-dependently reduced RANKL-osteoclastogenesis, osteoclastic resorption, and F-actin ring formation in BMDMs (Ping et al. 2017). In an animal study, the effects of melatonin on Ti nanoparticleinduced osteolysis were investigated. ...
Article
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Particulate wear debris can trigger pro-inflammatory bone resorption and result in aseptic loosening. This complication remains major postoperative discomforts and complications for patients who underwent total joint arthroplasty. Recent studies have indicated that wear debris-induced aseptic loosening is associated with the overproduction of pro-inflammatory cytokines. The activation of osteoclasts as a result of inflammatory responses is associated with osteolysis. Moreover, stimulation of inflammatory signaling pathways such as the NF-κB/NLRP3 axis results in the production of pro-inflammatory cytokines. In this review, we first summarized the potential inflammatory mechanisms of wear particle-induced peri-implant osteolysis. Then, the therapeutic approaches, e.g., biological inhibitors, herbal products, and stem cells or their derivatives, with the ability to suppress the inflammatory responses, mainly NF-κB/NLRP3 signaling pathways, were discussed. Based on the results, activation of macrophages following inflammatory stimuli, overproduction of pro-inflammatory cytokines, and subsequent differentiation of osteoclasts in the presence of wear particles lead to bone resorption. The activation of NF-κB/NLRP3 signaling pathways within the macrophages stimulates the production of pro-inflammatory cytokines, e.g., IL-1β, IL-6, and TNF-α. According to in vitro and in vivo studies, novel therapeutics significantly promoted osteogenesis, suppressed osteoclastogenesis, and diminished particle-mediated bone resorption. Conclusively, these findings offer that suppressing pro-inflammatory cytokines by regulating both NF-κB and NLRP3 inflammasome represents a novel approach to attenuate wear-particle-related osteolytic diseases.
... Concerning the relationship between Wnt/β-catenin signaling and melatonin, a positive relationship has been repeatedly documented [60,73,155,[164][165][166][167][168]. However, it is important to distinguish between synergistic actions and direct regulation of the Wnt pathway by melatonin. ...
... This agent inhibits tankyrases 1 and 2, which leads to the upregulation of the axin-GSK3β complex that promotes the degradation of β-catenin. The same reservation has to be made for application of the β-catenin inhibitor ICG-001 [164]. For logical reasons, downstream inhibitions do not tell us anything about Wnt protein activity. ...
... The osteogenic differentiation of MSCs, frequently studied in BMSCs, is most amply documented within the area of morphogenetic signaling by melatonin [22,60,122,[164][165][166][167]172,177,[195][196][197][198][199][200][201][202][203][204][205][206]. In one case, an osteogenic potential of BMSCs was reported to be rescued by melatonin from titanium-induced impairment via HIF-1α stabilization and SIRT1 signaling [204], but this may be explained by counteraction against the metal-promoted oxidative stress rather than by a primary promotion of osteogenesis. ...
Article
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Melatonin interacts with various types of stem cells, in multiple ways that comprise stimulation of proliferation, maintenance of stemness and self-renewal, protection of survival, and programming toward functionally different cell lineages. These various properties are frequently intertwined but may not be always jointly present. Melatonin typically stimulates proliferation and transition to the mature cell type. For all sufficiently studied stem or progenitor cells, melatonin’s signaling pathways leading to expression of respective morphogenetic factors are discussed. The focus of this article will be laid on the aspect of programming, particularly in pluripotent cells. This is especially but not exclusively the case in neural stem cells (NSCs) and mesenchymal stem cells (MSCs). Concerning developmental bifurcations, decisions are not exclusively made by melatonin alone. In MSCs, melatonin promotes adipogenesis in a Wnt (Wingless-Integration-1)-independent mode, but chondrogenesis and osteogenesis Wnt-dependently. Melatonin upregulates Wnt, but not in the adipogenic lineage. This decision seems to depend on microenvironment and epigenetic memory. The decision for chondrogenesis instead of osteogenesis, both being Wnt-dependent, seems to involve fibroblast growth factor receptor 3. Stem cell-specific differences in melatonin and Wnt receptors, and contributions of transcription factors and noncoding RNAs are outlined, as well as possibilities and the medical importance of re-programming for transdifferentiation.
... The GSK-3β/Wnt/β-catenin signaling pathway is a mediator of Ti particle-induced osteolysis in vivo. Melatonin, icariin, and ghrelin, which activate Wnt/β-catenin signaling, have been shown to rescue Ti particle-impaired cellular function in MSCs and MC3T3-E1 cells in vitro, and to attenuate particle-induced osteolysis in animal models Ping et al., 2017;Lian et al., 2018;Qu et al., 2019). Furthermore, inhibiting GSK-3β activity with LiCl increased downstream β-catenin expression and mitigated Ti particle-induced suppression of osteogenesis, both in vitro and in vivo (Geng et al., 2015;Gu et al., 2017). ...
... In addition, a potential role of the BMP signaling pathway should not be neglected Quade et al., 2020). Wang et al., 2016;Yu and He, 2016;Gu et al., 2017;Ping et al., 2017;Geng et al., 2018c;Lian et al., 2018;Qu et al., 2019 Statins ( Statins, a class of cholesterol-lowering drugs used clinically to reduce the risk of cardiovascular diseases, have been documented to have a beneficial effect on bone metabolism (Zhang et al., 2014). The use of statins is associated with a substantially lower risk of developing femoral osteolysis, and lower revision risk following primary total hip arthroplasty (Thillemann et al., 2010;Lübbeke et al., 2013). ...
Article
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Aseptic loosening subsequent to periprosthetic osteolysis is the leading cause for the revision of arthroplasty failure. The biological response of macrophages to wear debris has been well established, however, the equilibrium of bone remodeling is not only dictated by osteoclastic bone resorption but also by osteoblast-mediated bone formation. Increasing evidence shows that wear debris significantly impair osteoblastic physiology and subsequent bone formation. In the present review, we update the current state of knowledge regarding the effect of biomaterial implant wear debris on osteoblasts. The interaction of osteoblasts with osteoclasts and macrophages under wear debris challenge, and potential treatment options targeting osteoblasts are also presented.
... In addition, in vitro and in vivo studies provide evidence that melatonin treatment contributes to the prevention of bone loss [6]. Specifically, it regulates the balance of osteoclasts and osteoblasts through signaling transduction, including the Wnt, NFκB, and MAPK pathways, to improve bone quality [7][8][9]. Older people tend to have decreased melatonin secretion, which is of interest to researchers studying osteoporosis because it is associated with an increased risk of osteoporosis [1,6]. Accordingly, melatonin intake may be an alternative therapy for improving bone health [10]. ...
... It is inferred that p38 and JNK among MAPKs were targets of melatonin, which suppressed their expression, followed by suppression of other osteoclastogenic factors. However, the study of Ping et al. [8] found that the osteoclast differentiation inhibitory effect of melatonin occurred through the abolition of the NF-kB signaling pathway, but that the MAPK and PI3 K/AKT signaling pathways did not show significant changes. ...
Article
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Melatonin is a hormone secreted by the pineal gland that is involved in the biorhythm of reproductive activities. The present study investigated the inhibitory effects of melatonin on osteoclastogenesis in RAW 264.7 cells according to changes in V-ATPase and the corresponding inhibition of the MAPK and NFATc1 signaling processes. Methods: the cytotoxic effect of melatonin was investigated by MTT assay. Osteoclast differentiation and gene expression of osteoclast-related factors were confirmed via TRAP staining, pit formation assay, immunofluorescence imaging, western blot, and real-time PCR. Results: melatonin was found to inactivate the p38 and JNK of MAP kinase in RAW264.7 cells treated with RANKL and treated with a combination RANKL and melatonin for 1, 3, and 5 days. The melatonin treatment group showed a reduction in osteoclastogenesis transcription factors and ATP6v0d2 gene expression. Conclusions: melatonin inhibits osteoclast differentiation and cell fusion by inhibiting the expression of Atp6v0d2 through the inactivation of MAPK and NFATc1 signaling in RANKL-stimulated RAW264.7 macrophages. The findings of the present study suggest that melatonin could be a suitable therapy for bone loss and imply a potential role of melatonin in bone health.
... 22 It has been shown that melatonin can activate Wnt/β-catenin signalling in neuron cells 23,24 and osteoblasts. 25 The ancient and evolutionarily conserved Wnt signalling pathway plays multiple roles in animal embryonic development as well as adult tissue homeostasis and regeneration, 26 and loss of function may contribute to neurodegenerative diseases such as Alzheimer's disease. 27 Wnt ligands are post-translationally modified by a palmitoleate moiety attached to a serine, 28 while the recently discovered Wnt deacylase Notum can remove this moiety and acts as a secreted feedback antagonist. ...
... Our observation that melatonin directly binds to Notum and inhibits its activity suggests a molecular mechanism for previous reports that melatonin can activate Wnt/β-catenin signalling in neuron cells and osteoblasts. [23][24][25]47 We report here a structural similarity between melatonin and the Notum inhibitor HWH identified from an X-ray crystallographic-based fragment screen. This observation suggested that melatonin could target Notum. ...
Article
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The hormone melatonin, secreted from the pineal gland, mediates multiple physiological effects including modulation of Wnt/β‐catenin signalling. The Wnt palmitoleate lipid modification is essential for its signalling activity, while the carboxylesterase Notum can remove the lipid from Wnt and inactivate it. Notum enzyme inhibition can therefore upregulate Wnt signalling. While searching for Notum inhibitors by crystallographic fragment screening, a hit compound N‐[2‐(5‐fluoro‐1H‐indol‐3‐yl)ethyl]acetamide that is structurally similar to melatonin, came to our attention. We then soaked melatonin and its precursor N‐acetylserotonin into Notum crystals and obtained high resolution structures (≤ 1.5 Å) of their complexes. In each of the structures, two compound molecules bind with Notum: one at the enzyme’s catalytic pocket, overlapping the space occupied by the acyl tail of the Wnt palmitoleate lipid; and the other at the edge of the pocket opposite the substrate entrance. Although the inhibitory activity of melatonin shown by in vitro enzyme assays is low (IC50 75 µM), the structural information reported here provides a basis for the design of potent and brain accessible drugs for neurodegenerative diseases such as Alzheimer’s disease, in which up‐regulation of Wnt signalling may be beneficial.
... Melatonin exerts its physiological regulation mainly through receptors distributed in the hypothalamus (PT) and suprachiasmatic (SCN), and peripheral tissues, such as the nervous system, retina, immunity system, reproductive system and endocrine system tissues, also show a distribution of these receptors. Studies have shown that melatonin may have a regulatory effect on bone metabolism: promoting the osteogenic differentiation of BMSCs while inhibiting adipogenic differentiation [16,17]; inhibiting osteoclast formation and activation, thereby inhibiting bone resorption [18]; and activating the antioxidant defence system to maintain the self-renewal and differentiation of BMSCs after long-term passage [19]. Additionally, the expression of melatonin receptors was also found in MSCs. ...
... The interaction of melatonin with ECM deposited by natural cells can protect the osteogenic differentiation ability of MSCs [40]. Therefore, melatonin may provide a new option for the treatment of osteoporosis and fracture [19]. ...
Article
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Background: Mesenchymal stem cells (MSCs) play a crucial role in maintaining the dynamic balance of bone metabolism. Melatonin may have a regulatory effect on bone metabolism by regulating the lineage commitment and differentiation signalling pathways of MSCs. Among the BMP families, the osteogenesis of BMP9 is considered to be one of the strongest in MSCs. Here, we explored whether melatonin and BMP9 act synergistically on MSC osteogenic differentiation. Methods: The C3H10T1/2 osteogenic differentiation function induced by melatonin synergizes with BMP9, as detected by the expression of osteogenic markers at different periods. The result was further confirmed by foetal limb explant culture and in vivo stem cell implantation experiments. The effects of the AMPK/β-catenin pathway on the osteogenic differentiation of C3H10T1/2 cells were evaluated by Western blotting. Results: Melatonin combined with BMP9 significantly enhanced the expression of osteogenic markers at different periods in C3H10T1/2 cells, effectively enhancing BMP9-induced bone formation in cultured foetal explants and ectopic bone formation in vivo in stem cell transplantation experiments. Melatonin increases the expression of BMP9 in C3H10T1/2 cells and induces Smad1/5/8 translocation from the cytoplasm to the nucleus. In addition, melatonin and BMP9 synergistically promote AMPK and β-catenin phosphorylation, which can be largely eliminated by AMPK siRNA pretreatment. Conclusions: Melatonin and BMP9 in C3H10T1/2 cells synergistically promote osteogenic differentiation at least in part by activating the AMPK/β-catenin signalling pathway.
... However, researchers have found that total joint replacement surgery can also lead to increased rates of surgical error and implant fracture, as well as wear-debris-induced osteolysis caused by loosening of the prosthesis, which may affect the longevity of the implant and patient quality of life [3,4]. Among these side effects, weardebris-induced osteolysis remains the most usual-seen side effect after total joint replacement [5,6]. A chronic inflammatory response to wear debris is now considered to be a main reason of wear-debris-induced osteolysis, which is caused by polyethylene, poly(methyl methacrylate), cobalt, chromium, and titanium (Ti) emerged at the surface of prostheses [7,8]. ...
... Furthermore, Wnt proteins can bind to receptors located on the cell membrane through an autocrine or paracrine action, which activates a number of intracellular signaling pathways, including β-catenin, and thus regulates the differentiation and maturation of osteoblasts [27]. Reports have shown that the Wnt/β-catenin signaling pathway can exert an effect in wear-debris-induced osteolysis [5], and ghrelin can protect against many inflammatory diseases by activating the Wnt/β-catenin signaling pathway [28]. ...
Article
Full-text available
Aseptic loosening is a major complication of prosthetic joint surgery, in which exaggerated inflammation and impaired osteoblastogenesis are detected. Ghrelin is a recently discovered neuropeptide that is closely associated with inflammatory conditions and bone regeneration. Here, we report that titanium particles inhibited ghrelin expression in MC3T3-E1 cells. Furthermore, exogenous ghrelin effectively inhibited titanium particle-induced inflammation in vitro by interacting with its receptor GHSR1a; as an inhibitor of GHSR1a, Dlys repressed the function of ghrelin. Moreover, ghrelin attenuated the impairment of osteoblastogenesis and the exaggeration of osteolysis induced by titanium particles. Furthermore, the protective role of ghrelin in aseptic loosening might be associated with the Wnt/β-catenin signaling pathway. Collectively, these findings suggest that ghrelin might be a potential therapeutic target for wear-debris-induced inflammation and osteolysis.
... The conversion of L-Trp (precursor) to melatonin not only promotes antioxidant and anti-inflammatory effects; this hormone also induces bone formation and resorption through several mechanisms [35][36][37][38]. Although melatonin levels were not evaluated in the present study, we would expect decreased melatonin concentrations to be concomitant to L-Trp reductions in patients with long-term dental titanium implants and amalgams. ...
... Vidal et al. reported that mice without IDO activity are osteopenic; this feature suggests that elevations in kynurenine levels might indirectly reflect osteogenesis in A + I patients. Since melatonin attenuates titanium particle-induced osteolysis [36] and also stimulates dental implant osseointegration [37,40], this indirect evidence supports a role for kynurenine in osseointegration in patients with long-term dental titanium implants and amalgams. ...
Article
Full-text available
Titanium is the mean biocompatible metal found in dental titanium alloys (Ti-6Al-4V). The safety of certain dental biomaterial amalgams has been questioned in patients. The levels of several systemic cytokines (interleukin (IL)-1 beta, IL-4: pg/mL) and chemokines (monocyte chemoattractant protein-1 (MCP-1), soluble fractalkine (CX3CL1: pg/mL) were determined using ELISA and compared between these study groups. The study included 30 controls without dental materials (cont), 57 patients with long-term titanium dental implants plus amalgams (A + I group) as well as 55 patients with long-term dental amalgam alone (A group). All patients (except controls) have had dental titanium implants (Ti-6Al-4V) and/or amalgams for at least 10 years (average: 15 years). We evaluated whether systemic levels of cytokines/chemokines, kyn/L-trp ratio and aromatic amino acid levels (HPLC: mM/L, Phe, L-Trp, His, Treo) could be altered in patients with long-term dental titanium and/or amalgams. These systemic markers were evaluated in 142 patients. The A + I group had higher L-Kynurenine/L-Tryptophan ratios than patients with long-term dental amalgam fillings alone (A). In addition, levels of IL-1 Beta cytokine, CX3CL1 and MCP-1 chemokines were higher in the A + I group than in the A group (A). The increased L-kyn/L-trp ratio and MCP-1 and fractalkine receptor (CX3CR1) elevations could suggest enhanced chemotactic responses by these chemokines in the A + I group.
... Since a decrease in new bone formation is one of the main pathological changes of wear particles-induced osteolysis, 26 we determined whether inhibition of miR-106b has the ability to promote osteogenesis around the loosening implant. ...
... 41 In PPO, bone regeneration was weakened, and bone resorption was strengthened. 26 In this study, we systematically investigated the effect of miR-106b on PPO in rats. Our results showed that miR-106b regulated the balance of osteoclasts and osteoblasts through the PTEN/Akt and NF-κB signalling pathway, as well as by regulating macrophage polarization. ...
Article
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Aseptic loosening caused by periprosthetic osteolysis (PPO) is the main reason for the primary artificial joint replacement. Inhibition of inflammatory osteolysis has become the main target of drug therapy for prosthesis loosening. MiR‐106b is a newly discovered miRNA that plays an important role in tumour biology, inflammation and the regulation of bone mass. In this study, we analysed the in vivo effect of miR‐106b on wear debris‐induced PPO. A rat implant loosening model was established. The rats were then administrated a lentivirus‐mediated miR‐106b inhibitor, miR‐106b mimics or an equivalent volume of PBS by tail vein injection. The expression levels of miR‐106b were analysed by real‐time PCR. Morphological changes in the distal femurs were assessed via micro‐CT and histopathological analysis, and cytokine expression levels were examined via immunohistochemical staining and ELISA. The results showed that treatment with the miR‐106b inhibitor markedly suppressed the expression of miR‐106b in distal femur and alleviated titanium particle‐induced osteolysis and bone loss. Moreover, the miR‐106b inhibitor decreased TRAP‐positive cell numbers and suppressed osteoclast formation, in addition to promoting the activity of osteoblasts and increasing bone formation. MiR‐106b inhibition also significantly regulated macrophage polarization and decreased the inflammatory response as compared to the control group. Furthermore, miR‐106b inhibition blocked the activation of the PTEN/PI3K/AKT and NF‐κB signalling pathways. Our findings indicated that miR‐106b inhibition suppresses wear particles‐induced osteolysis and bone destruction and thus may serve as a potential therapy for PPO and aseptic loosening.
... In our previous works, we observed that Ang II, the main component of RAS, inhibited osteogenic differentiation of isolated fibroblast-like synovial cells by increasing DKK-1, a potent inhibitor of the canonical Wnt/β-catenin signaling , and activation of RAS in the synovium promoted periarticular osteopenia by increasing bone resorption and decreasing bone formation through regulating the RANKL/RANK/TRAF6 and Wnt/β-catenin signaling pathways (Wang et al., 2018). Moreover, studies on wear-particle-induced PPOL suggest that the inhibition of bone formation induced by wear particles is regulated by the Wnt/β-catenin signaling pathway (Wang et al., 2016;Ping et al., 2017;Wang et al., 2021). ...
... In this study, we found that the mRNA and protein expressions of RANKL, TRAF6, C-FOS, and NFATC1 in mouse calvarial tissues increased significantly with the presence of Ti particles, and such increase was evidently mitigated/reversed by the treatment of perindopril to inhibit ACE. Moreover, activation of the Wnt/β-catenin signaling is important to osteoblastogenesis and bone formation, and many studies have indicated that Ti particles inhibit bone formation by downregulating the Wnt/β-catenin signaling pathway (Wang et al., 2016;Ping et al., 2017). In line with these exisiting findings, the present study revealed down-regulated mRNA and protein expressions of β-catenin with the treatment of Ti particles, while such effects were abrogated by perindopril. ...
Article
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Wear particles may induce osteoclast formation and osteoblast inhibition that lead to periprosthetic osteolysis (PPOL) and subsequent aseptic loosening, which is the primary reason for total joint arthroplasty failure. Local bone renin-angiotensin system (RAS) has been found to participate in the pathogenic process of various bone-related diseases via promoting bone resorption and inhibiting bone formation. However, it remains unclear whether and how local bone RAS participates in wear-particle-induced PPOL. In this study, we investigated the potential role of RAS in titanium (Ti) particle-induced osteolysis in vivo and osteoclast and osteoblast differentiation in vitro. We found that the expressions of AT1R, AT2R and ACE in the interface membrane from patients with PPOL and in calvarial tissues from a murine model of Ti-particle-induced osteolysis were up-regulated, but the increase of ACE in the calvarial tissues was abrogated by perindopril. Moreover, perindopril mitigated the Ti-particle-induced osteolysis in the murine model by suppressing bone resorption and increasing bone formation. We also observed in RAW264.7 macrophages that Ang II promoted but perindopril suppressed Ti-particle-induced osteoclastogenesis, osteoclast-mediated bone resorption and expression of osteoclast-related genes. Meanwhile, Ang II enhanced but perindopril repressed Ti-particle-induced suppression of osteogenic differentiation and expression of osteoblast-specific genes in mouse bone marrow mesenchymal stem cells (BMSCs). In addition, local bone RAS promoted Ti-particle-induced osteolysis by increasing bone resorption and decreasing bone formation through modulating the RANKL/RANK and Wnt/β-catenin pathways. Taken together, we suggest that inhibition of RAS may be a potential approach to the treatment of wear-particle-induced PPOL.
... In recent years, the therapeutic approaches simultaneously inhibiting bone destruction and promoting bone regeneration have received increasing attention for prevention and treatment of osteolytic diseases [12,13]. Hh pathway, an evolutionarily conserved signaling pathway, plays critical roles in skeletal development and homeostasis, and is regarded as a promising anabolic pathway for treating osteoporosis and promoting bone regeneration [14,15]. ...
Article
Rationale: Wear particle-induced periprosthetic osteolysis (PPO) is a common long-term complication of total joint arthroplasty, and represents the major cause of aseptic loosening and subsequent implant failure. Previous studies have identified the central role of osteoclast-mediated bone resorption in the pathogenesis of PPO. Thus, therapeutic approaches of inhibiting osteoclast formation and activity are considered to be of great potential to prevent and treat this osteolytic disease. Hedgehog (Hh) signaling has been shown to play an important role in promoting osteoblast differentiation and bone formation. While Hh signaling is also implicated in regulating osteoclastogenesis, whether it can directly inhibit osteoclast differentiation and bone resorption remains controversial. Moreover, its potential therapeutic effects on PPO have never been assessed. In this study, we explored the cell-autonomous role of Hh signaling in regulating osteoclastogenesis and its therapeutic potential in preventing wear particle-induced osteolysis. Methods: Hh signaling was activated in macrophages by genetically ablating Sufu in these cells using LysM-Cre or by treating them with purmorphamine (PM), a pharmacological activator of Smoothened (Smo). In vitro cell-autonomous effects of Hh pathway activation on RANKL-induced osteoclast differentiation and activity were evaluated by TRAP staining, phalloidin staining, qPCR analyses, and bone resorption assays. In vivo evaluation of its therapeutic efficacy against PPO was performed in a murine calvarial model of titanium particle-induced osteolysis by μCT and histological analyses. Mechanistic details were explored in RANKL-treated macrophages through Western blot analyses. Results: We found that Sufu deletion or PM treatment potently activated Hh signaling in macrophages, and strongly inhibited RANKL-induced TRAP+ osteoclast production, F-actin ring formation, osteoclast-specific gene expression, and osteoclast activity in vitro. Furthermore, we found that Sufu deletion or PM administration significantly attenuated titanium particle-induced osteoclast formation and bone loss in vivo. Our mechanistic study revealed that activation of Hh signaling suppressed RANKL-induced activation of JNK pathway and downregulated protein levels of two key osteoclastic transcriptional factors, c-Fos and its downstream target NFATc1. Conclusions: Both genetic and pharmacological activation of Hh signaling can cell-autonomously inhibit RANKL-induced osteoclast differentiation and activity in vitro and protect against titanium particle-induced osteolysis in vivo. Mechanistically, Hh signaling hinders osteoclastogenesis partly through suppressing the JNK/c-Fos-NFATc1 cascade. Thus, Hh signaling may serve as a promising therapeutic target for the prevention and treatment of PPO and other osteolytic diseases.
... The delivery of melatonin in animal studies is traditionally through oral administration or intraperitoneal injection. Daily oral administration of melatonin (100 mg/kg body weight/day) has been reported to prevent ovariectomyinduced bone degeneration by increasing bone formation in mice [38], while intraperitoneal melatonin injections were proven to effectively alleviate titanium particle-induced inflammatory osteolysis in a murine calvarial model [39]. However, considering that chondrocytes uptake nutrients mainly from the synovial fluid, intra-articular injection is an effective way to administer melatonin into the articular cavity in DMM-induced OA mice. ...
Article
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Osteoarthritis (OA) is characterized by the progressive destruction of articular cartilage, which is involved in the imbalance between extracellular matrix (ECM) synthesis and degradation. MicroRNA-140-5p (miR-140) is specifically expressed in cartilage and plays an important role in OA-induced matrix degradation. The aim of this study was to investigate (1) whether intra-articular injection of melatonin could ameliorate surgically induced OA in mice and (2) whether melatonin could regulate matrix-degrading enzymes at the posttranscriptional level by targeting miR-140. In an in vitro OA environment induced by interleukin-1 beta (IL-1β), melatonin treatment improved cell proliferation of human chondrocytes, promoted the expression of cartilage ECM proteins (e.g., type II collagen and aggrecan), and inhibited the levels of IL-1β-induced proteinases, such as matrix metalloproteinase 9 (MMP9), MMP13, ADAMTS4 (a disintegrin and metalloproteinase with thrombospondin motifs 4), and ADAMTS5. Both the microarray and polymerase chain reaction (PCR) experiments revealed that miR-140 was a melatonin-responsive microRNA and melatonin upregulated miR-140 expression, which was suppressed by IL-1β stimulation. In vivo experiments demonstrated that intra-articular injection of melatonin prevented disruptions of cartilage matrix homeostasis and successfully alleviated the progression of surgery-induced OA in mice. Transfection of miR-140 antagomir completely counteracted the antiarthritic effects of melatonin by promoting matrix destruction. Our findings demonstrate that melatonin protects the articular cartilage from OA-induced degradation by targeting miR-140, and intra-articular administration of melatonin may benefit patients suffering from OA.
... This flavonoid also inhibits the formation and activation of osteoclasts. Other medications such as melatonin have shown similar results [172,173]. Strontium ranelate is another potential treatment for particle-induced osteolysis. This drug is currently approved for the treatment of post-menopausal osteoporosis. ...
Article
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Clinical studies, as well as in vitro and in vivo experiments have demonstrated that byproducts from joint replacements induce an inflammatory reaction that can result in periprosthetic osteolysis (PPOL) and aseptic loosening (AL). Particle-stimulated macrophages and other cells release cytokines, chemokines, and other pro-inflammatory substances that perpetuate chronic inflammation, induce osteoclastic bone resorption and suppress bone formation. Differentiation, maturation, activation, and survival of osteoclasts at the bone–implant interface are under the control of the receptor activator of nuclear factor kappa-Β ligand (RANKL)-dependent pathways, and the transcription factors like nuclear factor κB (NF-κB) and activator protein-1 (AP-1). Mechanical factors such as prosthetic micromotion and oscillations in fluid pressures also contribute to PPOL. The treatment for progressive PPOL is only surgical. In order to mitigate ongoing loss of host bone, a number of non-operative approaches have been proposed. However, except for the use of bisphosphonates in selected cases, none are evidence based. To date, the most successful and effective approach to preventing PPOL is usage of wear-resistant bearing couples in combination with advanced implant designs, reducing the load of metallic and polymer particles. These innovations have significantly decreased the revision rate due to AL and PPOL in the last decade.
... All animals were treated according to the Institutional Animal Care and Use Committee of Ningxia Medical University. The Ti particle-irritated calvarial model was established as previously described [12]. In brief, eighty C57BL/6J female mice were randomly assigned to four groups: Sham control (PBS treatment), Vehicle (Ti/ PBS treatment), Low-LBP (Ti/50 mg kg -1 day -1 LBP (Sigma, St. Louis, MO, USA), and High-LBP (Ti/100 mg kg -1 day -1 LBP). ...
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Objective. To investigate the effect of Lycium barbarum polysaccharide (LBP) in a mouse calvarial osteolysis model and to explore the potential mechanisms involved. Methods. Eighty C57BL/6J mice were randomly assigned to four groups: Sham control (PBS treatment), Vehicle (titanium/PBS treatment), Low-LBP (titanium/50 mg kg-1 day-1 LBP), and High-LBP (titanium/100 mg kg-1 day-1 LBP). After 2 weeks, mouse calvariae were collected for microcomputed tomography (micro-CT) and histomorphometry analysis. The levels of tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and IL-6 were measured by enzyme-linked immunosorbent assay (ELISA). Results. LBP significantly reduced titanium-particle-induced osteolysis compared with the Vehicle group as confirmed by micro-CT and histomorphometry data. Additionally, high osteoprotegerin (OPG) and low receptor activator of nuclear factor kappa-Β ligand (RANKL), TNF-α, IL-1β and IL-6 were noted in LBP treatment groups. Conclusion. LBP inhibited wear particle-induced osteolysis in mice and suppressed the expression of inflammation-related factors; this inhibitory effect of LBP may be achieved with the regulation of OPG/RANKL pathway and inhibition of inflammatory factor production.
... In contrast, a recent study demonstrated that a high dose of melatonin by oral administration (100 mg/kg body weight/day) was able to cure ovariectomy-induced bone loss by improving the biomechanical properties of bones [35]. Intraperitoneal injection of melatonin is another commonly used administration method which was proven to promote mouse cortical bone formation [36] and alleviate titanium particle-induced inflammatory osteolysis in a murine calvarial model by inhibiting osteoclast formation [37]. In this study, we chose to inject melatonin via the tail vein into OVX rats; from a therapeutic point of view, this method was similar to intravenous injection in clinical practice. ...
Article
Postmenopausal osteoporosis (OP) is one of the most common bone diseases that affects millions of aging women. Reduced osteogenesis and increased oxidative stress have been implicated in bone marrow mesenchymal stem cells (BMMSCs) derived from OP patients. Melatonin has shown positive effects on osteoblast differentiation and bone formation; however, it was unknown whether melatonin could restore OP-impaired osteogenic potential of BMMSCs and what the underlying mechanisms entailed. The objective of this study is to investigate (1) whether melatonin can restore the impaired osteogenic potential of OP BMMSCs by preserving their antioxidant functions, and if so, (2) whether intravenous administration of melatonin can prevent OP-induced bone loss in ovariectomized (OVX) rats. Ovariectomies were performed in female rats and BMMSCs were isolated from the osteoporotic rats 3 months later. In vitro treatment with melatonin successfully improved the osteogenic differentiation of OP BMMSCs, as evidenced by increased levels of matrix mineralization and osteoblast-specific genes. In melatonin-treated OP BMMSCs, intracellular oxidative stress was significantly attenuated, while levels of intracellular antioxidant enzymes were noticeably up-regulated - particularly superoxide dismutase 2 (SOD2) and glutathione peroxidase 1 (GPX1). Silent information regulator type 1 (SIRT1) was involved in the melatonin-mediated recovery of osteogenesis and antioxidant functions. Meanwhile, in vivo injections of melatonin via the tail vein successfully ameliorated the bone micro-architecture in ovariectomized rat femurs. Further experiments confirmed that BMMSCs derived from melatonin-treated OVX rats exerted well-preserved antioxidant properties and osteogenic potential. Our findings demonstrate that the administration of melatonin is a promising strategy for treating patients with postmenopausal OP by preserving the antioxidant properties and osteogenic potential of their BMMSCs.
... Studies have verified the primary effect exerted by osteoclasts in inflammatory osteolysis and subsequent aseptic loosening (Hotokezaka et al., 2007;Ping et al., 2017a). This work initially confirmed that puerarin could suppress wear particle-stimulated bone destruction in a calvarial osteolysis model. ...
Article
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Wear particle-stimulated inflammatory bone destruction and the consequent aseptic loosening remain major postoperative problems for artificial joints. Studies have indicated that puerarin promotes osteogenesis and alleviates lipopolysaccharide-induced osteoclastogenesis in vitro. However, the underlying molecular mechanism by which puerarin interacts with receptor activator of nuclear factor kappa-B ligand (RANKL)-mediated osteoclast formation in vitro and wear particle-stimulated osteolysis in vivo has not been reported. In this work, the protective effects exerted by puerarin on titanium particle-stimulated bone destruction in vivo and on RANKL-induced osteoclast activation in osteoclastic precursor cells in vitro were investigated. As expected, puerarin significantly inhibited wear particle-mediated bone resorption and proinflammatory cytokine productions in a calvarial resorption model. Additionally, puerarin inhibited RANKL-induced osteoclast activation, bone resorption ability, and F-actin ring formation in vitro as puerarin concentration increased. Furthermore, mechanistic investigation indicated that reduced RANKL-stimulated MEK/ERK/NFATc1 signaling cascades might regulate the protective effect of puerarin. Conclusively, these results indicate that puerarin, a type of polyphenol, might serve as a protective agent to prevent osteoclast-related osteolytic diseases.
... When taking only the diaphysis for analysis, it was found that β-catenin activation was more powerful than PTH in accelerating diaphyseal fracture healing, which consistent with the findings of Agholme 18 and Sandberg et al. 19 And they promoted diaphysis fracture healing better than wild group, and promoted the expression levels of OCN, RUNX2, LEF-1 in the defect, as others report. [36][37][38] In rat, a low dose of PTH enhanced metaphyseal repair, whereas the Scl-ab had mainly cortical bone effects with less influence on metaphyseal healing. Therefore, new clinical studies of PTH treatment for accelerating corticocancellous fracture repair are warranted. ...
Article
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Parathyroid hormone (PTH) and agents related to the manipulation of Wnt/β‐catenin signaling are two promising anabolic anti‐osteoporotic therapies that have been shown to promote the healing of bone fractures. Now, it is widely accepted that cortical bone and trabecular bone are two different compartments, and should be treated as separate compartments in pathological processes, such as fracture healing. It is currently unknown whether PTH and the activation of β‐catenin signaling would demonstrate different effects on cortical bone and trabecular bone healing. In the current study, single 0.6‐mm cortex holes were made in the femur metaphysis and diaphysis of mice, and then PTH application and β‐catenin activation were used to observe the promoting effect on bone healing. The effects of β‐catenin and PTH signaling on fracture healing were observed by X‐ray and CT at 3, 6, and 14 days after fracture, and the levels of β‐catenin were detected by RT‐PCR assay,and The number of specific antigen‐positive cells of BRDU, OCN,RUNX2 was counted by Immunohistochemical staining. While β‐catenin activation and PTH were found to demonstrate similar effects on accelerating metaphyseal bone healing, activation of β‐catenin showed a more striking effect than PTH on promoting diaphyseal bone healing. These findings might be helpful for selecting proper medication to accelerate fracture healing of different bone compartments. This article is protected by copyright. All rights reserved.
... Xiao et al. demonstrated the targeted overexpression of low molecular weight (LMV) fibroblast growth factor-2 (FGF-2) isoform in osteoblast precursors enhanced bone defect healing by increased osteoblast activity along with increased canonical Wnt signalling [23]. Ping et al. demonstrated in two separate studies that melatonin can induce bone regeneration and enhancing osteogenic differentiation at osteolytic sites by activating Wnt/b-catenin signalling pathway [24,25]. In addition, they introduced icariin as inducer osteogenic differentiation of MSCs which promote new bone formation at a titanium-particle-induced osteolytic site through the activated Wnt/b-catenin signalling pathway [25]. ...
Article
There are several signal pathways involved in bone regeneration that can be triggered by several factors including mechanical, physical and chemical factors. Chemical growth factors are commonly used in differentiation induction to stem cells, while have side effects. In this study, inorganic poly-phosphate (poly-P) as a natural-based molecule was used to induce Wnt/β-catenin signalling in adipose-derived mesenchymal stem cells (AT-MSCs) while cultured on 2D and 3D culture systems. Common osteogenic markers were investigated to detect the influence of Wnt/β-catenin signalling induction on osteogenic differentiation of AT-MSCs and signalling genes up regulation was also evaluated by its related gene expression measurement. Results were shown that Cyclin-D1 and β-catenin gene expression was significantly increased in those cells treated by poly-P. Osteogenic differentiation of those stem cells with higher Cyclin-D1 and β-catenin gene expression was significantly higher than other groups except those stem cells cultured under osteogenic medium. According to the results, inorganic poly-P can trigger osteogenic differentiation in stem cells through Wnt/β-catenin signalling and this potential is almost close to common osteogenic growth factors and this could be used as natural-based molecules in bone regeneration, apart from concerns about the use of chemical factors.
... Consistent with this result, we found that OVX significantly reduced active β-catenin expression in the induced osteoblasts (Fig. 5a, b). Park et al. demonstrated that melatonin enhances osteoblastic differentiation that is related to β-catenin activation [21]. Melatonin attenuates titanium particle-induced osteolysis by activating the Wnt/βcatenin pathway [36]. GSK3β, a cytoplasmic serine/threonine protein kinase, plays critical roles in multiple biological processes [37]. ...
Article
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Postmenopausal osteoporosis induced by estrogen deficiency causes inadequate new bone formation and affects millions of women worldwide. Melatonin can improve bone mineral density at the femoral neck in postmenopausal women with osteopenia. This study aimed to investigate the mechanism of melatonin in estrogen deficiency-induced osteoporosis by focusing on osteoblast differentiation. 12-week-old female C57BL/6J mice were ovariectomized (OVX) and intraperitoneally injected with 10 or 50 mg/kg of melatonin for 8 weeks. Micro-computerized tomography scanning demonstrated that melatonin alleviated OVX-induced bone loss in a dose-dependent manner. Serum levels of ALP and osteocalcin (OCN) were further increased, whereas tartrate-resistant acid phosphatase level was decreased by melatonin in OVX-treated mice. Melatonin promoted osteoblast differentiation in primary bone marrow mesenchymal stem cells from OVX mice. It also inhibited activation of NLRP3 inflammasome in femoral bone protein and in induced osteoblasts stimulated by OVX. Knockdown of NLRP3 attenuated OVX-induced repression of osteogenic differentiation. The NLRP3 inflammasome activator monosodium urate partly abrogated the effect of melatonin on the expression of osteoblastogenic markers, including Runx2 and OCN. Additionally, the results showed that melatonin suppressed NLRP3 inflammasome activation by regulating Wnt/β-catenin signaling, which was confirmed by the Wnt/β-catenin inhibitor recombinant DKK1. These results indicated that melatonin ameliorates estrogen deficiency-induced osteoporosis and impaired osteogenic differentiation potential by suppressing activation of the NLRP3 inflammasome via mediating the Wnt/β-catenin pathway.
... Proximal metaphyseal part of tibia Calvarial defects Mice Titanium particle 5 mg/kg or 50 mg/kg Melatonin inhibited titanium particle-induced osteolysis and increased bone formation at osteolytic sites. Ping et al. (2017) Osteoclast numbers decreased dramatically in the low-and high-melatonin administration mice. ...
Article
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Melatonin research has been experiencing hyper growth in the last two decades; this relates to its numerous physiological functions including anti-inflammation, oncostasis, circadian and endocrine rhythm regulation, and its potent antioxidant activity. Recently, a large number of studies have focused on the role of melatonin in the regeneration of cells or tissues after their partial loss. In this review, we discuss the recent findings on the molecular involvement of melatonin in the regeneration of various tissues including the nervous system, liver, bone, kidney, bladder, skin, and muscle, among others.
... Moreover, the ALP, RUNX2, COL1, OPG, and osterix signaling cascades can be activated by the Wnt pathway, thereby controlling bone regeneration. 69,70 In the present study, the increased expression of ALP, RUNX2, OPG, and osterix as well as Alp, Col1, Opg, and Runx2 indicated that the Wnt signaling pathway may have been activated by ZIF-8@AHT-1/8; this requires further investigation. ...
... Based on this, anti-bone resorption compounds have been studied over the years to treat PPO and bone loss [6,7]. Disappointingly, single downregulation of osteoclasts cannot repair bone quantity, indicating osteoblastic bone formation is significantly reduced in osteolytic disease [8]. Osteoblasts are derived from pluripotent mesenchymal stem cells (MSCs), with programmed regulation by many specific bone-forming genes and signals, such as bone morphogenetic proteins (BMPs), osteocalcin (OCN), alkaline phosphatase (ALP), Runt-related transcription factor 2 (Runx2), Osterix and particularly the Wnt/b-catenin signaling pathway, which was thought to be essential in the early procedure of osteoblastogenesis [9,10]. ...
Article
Peri-prosthetic osteolysis (PPO) often generates after total joint arthroplasty, which can bring implant failure and following revision surgery. Wear debris shed from prostheses strongly enhances bone resorption and attenuates bone formation in osteolytic process. We previously proved that suppression of protein phosphatase 2A (PP2A), a major serine-threonine phosphatase, inhibited wear-debris-induced osteoclastogenesis and alleviated local osteolysis. Whether PP2A inhibition facilitates osteoblastogenesis and bone formation in the osteolytic sites remains unclear. Here, we observed that PP2A inhibition with a selective inhibitor attenuated particle-induced bone destruction by accelerating osteoblast differentiation and promoting bone regeneration. Meanwhile, we proved inhibition of PP2A alleviated the inhibition of osteogenic differentiation by titanium particles in MC3T3-E1 cells. In addition, PP2A inhibition increased β-catenin expression and enhanced β-catenin nuclear translocation, compared with that in the vehicle group. ICG-001, a specific inhibitor of β-catenin, was further applied and was found to weaken the effect of PP2A inhibition on β-catenin expression and nuclear translocation. Therefore, we demonstrated PP2A inhibition exerts protective effects on osteogenic differentiation mainly by activating Wnt/β-catenin signaling pathway. Thus, all the results further revealed PP2A could be a promising target for treating PPO and other bone related diseases.
... Some research showed that it inhibited OCs differentiation both in vivo and vitro, although necessary for proliferation of OCs progenitors [27][28][29]. Thus, Wnt signaling agonist could be used to treat osteolytic lesion by inhibiting OCs formation [30,31]. Some other literature indicated that constitutive activation of β catenin also facilitated osteoclastogenesis [32]. ...
Article
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Periodontitis thereby the alveolar bone loss induced by inflammation, is a wide-spread phenomenon around the world. It is an ongoing challenge faced by clinicians worldwide. This study aimed to identify the effects of lipopolysaccharide (LPS) on osteoclasts (OCs) differentiation in vitro and to investigate its molecular mechanism. For bone marrow derived macrophages (considered as Pro-OCs), LPS impaired their differentiation into OCs in a dose-dependent manner. In contrast, it promoted Pre-OCs (referred to receptor activator of nuclear factor-κB ligand (RANKL) pretreated Pro-OCs) and differentiated to OCs with increased maximum diameter, quantity, the covering area and the fusion index in vitro. It also facilitated OCs proliferation, bone resorption and OCs related genes expression. Furthermore, it was revealed that LPS enhanced OCs genesis from Pre-OCs via activating autophagy pathway consequently elevated the accumulation of TRAP, Cts K and NFATC1, specific genes of OCs. The members of Wnt signaling were expressed as at lower states during the LPS induced OCs formation, but they could be rescued in the presence of autophagy inhibitor. The most promising observation was the direct interaction of LC3B and Dvl2, indicating that the crosstalk between above pathways existed in OCs. Taken together, we consider that LPS activates autophagy which negatively regulates Wnt signaling via autophagic degradation of Dvl2 is significant for osteoclastogenesis from Pre-OCs in vitro. Our study sheds light on the fact that autophagy inhibitors will become a new, potentially applicable therapeutic option in the treatment of periodontal bone loss.
... Many studies have showed that melatonin plays an important role in many physiological processes such as regulating sleeping quality, heart rate, body temperature and immunity [21][22][23][24]. Besides, it is also reported that melatonin can regulate bone formation, mineralization and bone reconstruction [25][26][27]. However, the underlying mechanism that melatonin protects BMSCs against iron overload-induced dysfunction remains unclear. ...
Article
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Iron overload induces severe damage to several vital organs such as the liver, heart and bone, and thus contributes to the dysfunction of these organs. The aim of this study is to investigate whether iron overload causes the apoptosis and necrosis of bone marrow mesenchymal stem cells (BMSCs) and melatonin may prevent its toxicity. Perls' Prussion blue staining showed that exposure to increased concentrations of ferric ammonium citrate (FAC) induced a gradual increase of intracellular iron level in BMSCs. Trypan blue staining demonstrated that FAC decreased the viability of BMSCs in a concentration-dependent manner. Notably, melatonin protected BMSCs against apoptosis and necrosis induced by FAC and it was vertified by Live/Dead, TUNEL and PI/Hoechst stainings. Furthermore, melatonin pretreatment suppressed FAC-induced reactive oxygen species accumulation. Western blot showed that exposure to FAC resulted in the decrease of anti-apoptotic protein Bcl-2 and the increase of pro-apoptotic protein Bax and Cleaved Caspase-3, and necrosis-related proteins RIP1 and RIP3, which were significantly inhibited by melatonin treatment. At last, melatonin receptor blocker luzindole failed to block the protection of BMSCs apoptosis and necrosis by melatonin. Taken together, melatonin protected BMSCs from iron overload induced apoptosis and necrosis by regulating Bcl-2, Bax, Cleaved Caspase-3, RIP1 and RIP3 pathways.
... 23,24 Multiple intracellular pathways, such as BDNF and Hippo signaling, have been demonstrated to be responsive to melatonin stimulation and mediate the effects of melatonin. [25][26][27] Therefore, it is of great interest to test whether melatonin could be protective for neonatal Sev anesthesia. ...
Article
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Sevoflurane (Sev) is one of the most widely used pediatric anesthetics. The major concern of neonatal repeated application of Sev is its potential long term impairment of cognition and learning/memory, for which there still lacks effective treatment. At the cellular level, Sev exerts toxic effects in multiple aspects, making it difficult for effective interference. Melatonin is a pineal hormone regulated by and feedbacks to biological rhythm at physiological condition. Recent studies have revealed significant neuroprotective effects of exogenous melatonin or its agonists under various pathological conditions. Whether melatonin could prevent the long term toxicity of Sev remains elusive. Here, we report that neonatal repeated Sev exposure up‐regulated MT1 receptor in hippocampal neurons and oligodendrocytes. Pretreatment with melatonin significantly alleviated Sev‐induced synaptic deficiency, dysmyelination, and long term learning impairment. Both MT1 shRNA and MT1 knockout effectively blocked the protective effects of melatonin on synaptic development, myelination and behavior performance. Interestingly, long‐lasting suppression of Wnt signaling, instead of cAMP/PKA signaling, was observed in hippocampal neurons and oligodendrocytes after neonatal Sev exposure. Pharmacologically activating Wnt signaling rescued both the long term synaptic deficits and dysmyelination induced by Sev. Further analysis showed that MT1 receptor co‐expressed well with β‐catenin and Axin2, and bound to β‐catenin by its C‐terminal. Melatonin pretreatment effectively rescued Sev‐induced Wnt suppression. Wnt signaling inhibitor XAV939 significantly compromised the protective effects of melatonin. Taken together, our data demonstrated a beneficial effect of melatonin pretreatment on the long term synaptic impairment and dysmyelination induced by neonatal Sev exposure, and a novel MT1 receptor‐mediated interaction between melatonin and canonical Wnt signaling, indicating that melatonin may be clinically applied for improving the safety of pediatric Sev anesthesia.
... can inhibit osteoclast formation and/or bone resorption are ideal therapeutic agents for preventing and ameliorating wear particleinduced osteolysis (Ping et al., 2017). ...
Article
Osteolysis is a common medical condition characterized by excessive activity of osteoclasts and bone resorption, leading to severe poor quality of life. It is essential to identify the medications that can effectively suppress the excessive differentiation and function of osteoclasts to prevent and reduce the osteolytic conditions. It has been reported that Carnosol (Car), isolated from rosemary and salvia, has anti‐inflammatory, antioxidative, and anticancer effects, but its activity on osteolysis has not been determined. In this study, we found that Car has a strong inhibitory effect on the receptor activator of nuclear factor‐κB ligand (RANKL)‐induced osteoclast differentiation dose‐dependently without any observable cytotoxicity. Moreover, Car can inhibit the RANKL‐induced osteoclastogenesis and resorptive function via suppressing NFATc1, which is a result of affecting MAPK, NF‐κB and Ca²⁺ signaling pathways. Moreover, the particle‐induced osteolysis mouse model confirmed that Car could be effective for the treatment of bone loss in vivo. Taken together, by suppressing the formation and function of RANKL‐induced osteoclast, Car, may be a therapeutic supplementary in the prevention or the treatment of osteolysis.
... The study is of review type using the keywords: mesenchymal cells implant surface, differentiation, and their combination with the aim of finding logical connections between the activity of mesenchymal cells and possible and different modifications of the implant surface. The search was conducted in several attempts to find articles, (Esfahanian et al. 2012) where gradually from 259 articles it was narrowed the list at 73 articles and after the elimination of articles in accordance with the criteria of non-inclusion and during the reading and analysis phase of abstracts, at the end of the electronic search, was a total of 36 articles, available for further and detailed analysis, in accordance with the purpose of the study (Omar et al. 2011;Wang et al. 2014 Yang et al. 2015;Hao et al. 2016;He et al. 2016;Zhou et al. 2017;Ping et al. 2017;Li et al. 2017;Zheng et al. 2017;Tsuchiya et al. 2018;Shao et al. 2018;Chen et al. 2018;Deng et al. 2018;An et al. 2018;Karthik et al. 2013;Adell et al. 1981;Heta and Robo 2018;Bouri et al. 2008;Banche et al. 2007;Klokkevold and Han 2007;Koldsland et al. 2009;Robo et al. 2017;Alsaadi et al. 2007;Olate et al. 2010;Baqain et al. 2012;Jacobi-Gresser et al. 2013;Brånemark et al. 1999;Branemark et al. 2001;Vendramini et al. 2021). ...
Article
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Background The process of osteointegration, as key point has the activation of mesenchymal cells at implant-bone interspace, their differentiation into osteoblasts and connection between the implant surface and the surrounding bone. Main text Implant surfaces composed by biocompatible, organism-friendly materials require changes in content and surface morphology; changes that may further stimulate mesenchymal cell activation. The way the implant surfaces are affected with advantages and disadvantages, that typically bring each methodology, is also the purpose of this study. The study is of review type, based on finding articles about implant surface modification, with the aim of promoting the mesenchymal cell activation, utilizing keyword combination. Conclusions Implant success beyond the human element of the practicioner and the protocol element of implant treatment, also relies on the application of the right type of implant, at the right implant site, in accordance with oral and individual health status of the patient. Implant success does not depend on type of "coating" material of the implants. Based at this physiological process, the success or implant failure is not a process depending on the type of selected implant, because types of synthetic or natural materials that promote osteointegration are relatively in large number.
... Inhibiting GSK-3β activity with drugs such as melatonin, icariin, ghrelin, and LiCl increased downstream β-catenin expression, and mitigated Ti particle-induced suppression of osteogenesis, both in vitro and in vivo. [68][69][70][71][72] Unfortunately, to date, the involvement of GSK-3β/Wnt/β-catenin signaling pathway in nano-sized Ti particle-induced osteolysis has never been studied. More studies are needed to elucidate this aspect. ...
Article
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Over the last decades, joint arthroplasty has become a successful treatment for joint disease. Nowadays, with a growing demand and increasingly younger and active patients accepting these approaches, orthopedic surgeons are seeking implants with improved mechanical behavior and longer life span. However, aseptic loosening as a result of wear debris from implants is considered to be the main cause of long-term implant failure. Previous studies have neatly illustrated the role of micrometric wear particles in the pathological mechanisms underlying aseptic loosening. Recent osteoimmunologic insights into aseptic loosening highlight the important and heretofore underrepresented contribution of nanometric orthopedic wear particles. The present review updates the characteristics of metallic and ceramic nanoparticles generated after prosthesis implantation and summarizes the current understanding of their hazardous effects on peri-prosthetic cells.
... Osteoclasts (OCs) are multinucleated, terminally differentiated cells derived from haemopoietic progenitor cells of the monocyte/macrophage lineage that exist around the implant and degrade mineralized bone matrix [45]. Studies over the past few decades have strongly indicated osteoclasts as the major cause of the osteolysis leading to implant failure [46][47][48]. ...
Article
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With the massive use of medical implants (e.g., metals, polymers and ceramics) in orthopedic and cardiovascular surgery, surface biomodification of these exogenous biomaterials has caused growing concern, for the purpose of improving their functions and avoiding surgical failure. Mussel-inspired chemistry (i.e., dopamine self-polymerization) based on covalent and noncovalent catechol-mediated molecular adhesion exhibits versatility in surface biomodification. However, the inevitable consumption of amino and thiol groups in the bioactive molecules still make this robust surface chemistry in a dilemma. Taking this biomimetic strategy one step further, synthetic peptides with multiple DOPA (3,4-Dihydroxy-L-phenylalanine) units were recently extensively studied. Since the catecholic DOPA unit is abundant in the main component of mussel foot protein, these peptides are able to adhere onto various substrates. In addition, these mussel-inspired peptides could be flexibly linked with bioactive or attachable molecules, which can bypass the consumption of active groups in the second-step biomodification of poly(dopamine) method. Owing to these superiorities, mussel adhesive peptides mimics with diversified bioactivity are widely used for surface modification of medical implants to regulate different cell responses. The purpose of this review is to provide a brief overview of the latest developments in the surface bioengineering of medical implants using these mussel adhesive peptides mimics as a medium. We anticipate that the stepwise discussions from peptide mimicking and synthesis to surface bioactivity adaptation in different implants may also encourage researchers to innovate current mussel-inspired peptides at molecular level and expand their applications in the field of biomaterial engineering.
... Although several studies have revealed the benefits of melatonin on osteolysis [25][26][27][28], whether melatonin plays the anti-osteolysis effects indirectly through gut microbiota reprogramming is still unknown. The role of SCFAs in the course of osteolysis is also undiscovered. ...
Article
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Background Inflammatory osteolysis after total joint replacement (TJR) may cause implant failure, periprosthetic fractures, and be a severe threat to global public health. Our previous studies demonstrated that melatonin had a therapeutic effect on wear-particles induced osteolysis. Gut microbiota is closely related to bone homeostasis, and has been proven to be affected by melatonin. However, whether melatonin could play its anti-osteolysis effects through reprogramming gut microbiota remains elusive. Results Here, we demonstrated that melatonin could alleviate Ti-particles induced osteolysis, while this therapeutic effect was blocked by antibiotic cocktail treatment. Interestingly, transplantation of fecal microbiota from mice treated with melatonin reappeared the same beneficial effect. Analysis of the 16S rRNA revealed that melatonin could reverse dysbacteriosis triggered by osteolysis, and elevate the relative abundance of some short chain fatty acid (SCFA) producing bacteria. Moreover, butyrate was enriched by exogenous melatonin administration, while acetate and propionate did not show an evident difference. This was consistent with the results of the metagenomic approach (PICRUSt2) analysis, which revealed a general increase in the synthetic enzymes of butyrate. More importantly, direct supplementation of butyrate could also recapitulate the anti-osteolysis effect of melatonin. Further analysis identified that butyrate alleviated osteolysis via activating its receptor GPR109A, and thus to suppress the activation of NLRP3 inflammasome triggered by Ti-particles. Conclusions Taken together, our results suggested that the benefits of melatonin mainly depend on the ability of modulating gut microbiota and regulating butyrate production. Graphic Abstract
... However, this study has the following limitations. Bone metabolism includes two major processes: osteoblastmediated bone formation and osteoclast-mediated bone absorption, which are not independent and are regulated by the interaction and influence of osteoblasts and osteoclasts (Ping et al. 2017). Our study focused on the effect of changes in dopamine receptors on osteoblasts in the context of GC-induced bone loss. ...
Article
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Background The inhibition of osteogenic differentiation is a major factor in glucocorticoid-induced bone loss, but there is currently no effective treatment. Dopamine, a major neurotransmitter, transmits signals via five different seven-transmembrane G protein-coupled receptors termed D1 to D5. Although the relevance of the neuroendocrine system in bone metabolism has emerged, the precise effects of dopamine receptor signaling on osteoblastogenesis remain unknown. Methods In vitro, western blotting and immunofluorescence staining were used to observe the expression of dopamine receptors in MC3T3-E1 and BMSCs cells treated with dexamethasone (Dex). In addition, Alizarin red S (ARS) and alkaline phosphatase (ALP) staining and western blotting were used to evaluate the effect of D1R activation on osteogenic differentiation in Dex-induced MC3T3-E1 cells via the ERK1/2 signaling pathway. In vivo, micro-CT and hematoxylin and eosin (H&E), toluidine blue and immunohistochemical staining were used to determine the effect of D1R activation on Dex-induced bone loss. Results We demonstrated that the trend in D1R but not D2-5R was consistent with that of osteogenic markers in the presence of Dex. We also demonstrated that the activation of D1R promoted Dex-induced osteogenic differentiation by activating the ERK1/2 pathway in vitro. We further demonstrated that a D1R agonist could reduce Dex-induced bone loss, while pretreatment with a D1R inhibitor blocked the effect of a D1R agonist in vivo. Conclusions Activation of D1R promotes osteogenic differentiation and reduces Dex-induced bone loss by activating the ERK1/2 pathway. Hence, D1R could serve as a potential therapeutic target for glucocorticoid-induced osteoporosis.
... Notably, MT is implicated in the homeostasis of bone metabolism, and MT reduction is a key factor in bone loss and OP [13][14][15]. Moreover, MT enhances osteogenic differentiation of MSCs by regulating the Wnt/β-catenin, AMPK/βcatenin, and other signaling pathways [16,17]. The MT injection into rats induces the expression of osteogenesis-related genes in BMSCs, promotes osteoblast differentiation, and elevates the bone mineral density (BMD), bone volume fraction (BV/TV), and trabecular number (Tb.N) in the OP model [18]. ...
Article
Implant dentures become the first choice for denture restoration in patients with tooth loss. However, oral implants often fail in osteoporosis (OP) patients. Melatonin (MT) induces osteogenic differentiation of bone mesenchymal stem cells (BMSCs), suggesting its therapeutic potential in OP treatment. Long non-coding RNA H19 induces osteogenic differentiation of BMSCs, while its regulatory mechanism in MT-involved osteogenic and adipogenic differentiation of BMSCs remains elusive. Ovariectomized (OVX) rat was used to construct an OP model, and bone quality was assessed. Meanwhile, the expression of H19, miR-541-3p, MT and adiponectin (APN) was examined by quantitative reverse transcription-PCR (qRT-PCR) or ELISA. The adipogenic and osteogenic differentiation of BMSCs were determined by oil red O staining and alizarin red S staining, respectively. The targeting relationships between H19, miR-541-3p and APN mRNA were predicted by bioinformatics and confirmed by RNA immunoprecipitation and dual-luciferase reporter assay. The results showed that MT, H19 and APN were down-regulated, while miR-541-3p was up-regulated in the OVX rat model. At the cellular level, MT reduced adipogenic differentiation, heightened osteogenic differentiation of BMSCs, and activated Wnt/β-catenin pathway, which were reversed by the MT2 selective inhibitor 4-P-PDOT. Overexpressing H19 facilitated the osteogenic differentiation and inhibited the adipogenic differentiation of BMSCs mediated by MT, while H19 knockdown or overexpressing miR-541-3p had the opposite effect. Moreover, H19 functioned as a competitive endogenous RNA and sponged miR-541-3p, and miR-541-3p targeted APN. Overall, MT modulates the osteogenic and adipogenic differentiation of BMSCs by mediating H19/miR-541-3p/APN axis, providing a new reference for the targeted therapy of OP.
... Similarly, Bin Hu et al. showed that microbubble injection in bone canals enhances the inhibitory effect of low-intensity pulsed ultrasound (LIPUS) on debris-induced osteolysis and further strengthens the mechanical fixation of implants in an earlystage osteolysis model in vivo [82]. Other studies evaluated potential drug therapies to prevent periprosthetic osteolysis: metformin was shown to be able to attenuate osteolysis induced in mouse calvaria by the particles, inducing a reduction in osteoclast number and polarization of macrophages to an anti-inflammatory functional phenotype [83]. Melatonin can also be considered a promising therapeutic agent for the prevention and treatment of peri-prosthetic osteolysis. ...
Article
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The success of implant performance and arthroplasty is based on several factors, including oxidative stress-induced osteolysis. Oxidative stress is a key factor of the inflammatory response. Implant biomaterials can release wear particles which may elicit adverse reactions in patients, such as local inflammatory response leading to tissue damage, which eventually results in loosening of the implant. Wear debris undergo phagocytosis by macrophages, inducing a low-grade chronic inflammation and reactive oxygen species (ROS) production. In addition, ROS can also be directly produced by prosthetic biomaterial oxidation. Overall, ROS amplify the inflammatory response and stimulate both RANKL-induced osteoclastogenesis and osteoblast apoptosis, resulting in bone resorption, leading to periprosthetic osteolysis. Therefore, a growing understanding of the mechanism of oxidative stress-induced periprosthetic osteolysis and anti-oxidant strategies of implant design as well as the addition of anti-oxidant agents will help to improve implants’ performances and therapeutic approaches.
... However, the role of melatonin in regulating other ocular stem cells, such as corneal epithelial stem cells, and the assessment of their effect in treating ocular diseases in animal models are still unknown. Furthermore, melatonin also exhibits regulating ability for exogenous stem cells such as mesenchymal stem cells (MSCs) in viability, proliferation, differentiation, paracrine, and apoptosis through certain signaling pathways like Wnt and MAPK and acts as antioxidant agents to reduce the oxidative stress-induced apoptosis and enhance activity of stem cells (Ping et al., 2017;Chatterji et al., 2018;Lee et al., 2018;Majidinia et al., 2018;Fan et al., 2020;Giannaccare et al., 2020). Such properties of melatonin have been successfully applied in various disease therapies, including chronic kidney diseases, neurodegenerative diseases, and orthopedic disorders, through pretreatment or combining with scaffold, while its application is rare for ocular diseases (Ramezani et al., 2020;Yan et al., 2020;Yoon et al., 2020). ...
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Melatonin plays a critical role in the pathophysiological process including circadian rhythm, apoptosis, and oxidative stress. It can be synthesized in ocular tissues, and its receptors are also found in the eye, triggering more investigations concentrated on the role of melatonin in the eye. In the past decades, the protective and therapeutic potentials of melatonin for ocular diseases have been widely revealed in animal models. Herein, we construct a knowledge map of melatonin in treating ocular diseases through bibliometric analysis and review its current understanding and clinical evidence. The overall field could be divided into twelve topics through keywords co-occurrence analysis, in which the glaucoma, myopia, and retinal diseases were of greatest research interests according to the keywords burst detection. The existing clinical trials of melatonin in ocular diseases mainly focused on the glaucoma, and more research should be promoted, especially for various diseases and drug administration. We also discuss its bioavailability and further research topics including developing melatonin sensors for personalized medication, acting as stem cell therapy assistant drug, and consuming food-derived melatonin for facilitating its clinical transformation.
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Statement of significance: Wear debris-induced chronic inflammation, osteoclastic activation and osteoblastic inhibition have been identified as critical factors of peri-implant bone loss. We previously demonstrated that melatonin, a bioactive indolamine secreted mainly by the pineal gland, activates Wnt/β-catenin signaling pathway and enhances bone regeneration at osteolytic site in vivo. In the current study, we further demonstrated that melatonin significantly suppresses wear debris-induced bone resorption and inflammatory cytokine expression in vivo. In addition, melatonin inhibits receptor activator of nuclear factor kappa-B ligand induced osteoclast formation and osteoclastic bone resorption in vitro. Meanwhile, we found that melatonin mediates its anti-inflammation and anti-bone resorption effects by abrogating nuclear factor kappa-B activation. These results further support the protective effects of melatonin on wear debris-induced peri-implant bone loss, and strongly suggest that melatonin could be considered as a potential candidate for the prevention and treatment of wear debris-induced osteolysis and subsequent aseptic loosening.
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Melatonin's therapeutic potential has been highly underestimated because its biological functional roles are diverse and relevant mechanisms are complicated. Among the numerous biological activities of melatonin, its regulatory effects on pluripotent mesenchymal stem cells (MSCs), which are found in bone marrow stem cells (BMSCs) and adipose tissue (AD-MSC), have been recently proposed, which has received increasingly more attention in recent studies. Moreover, receptor-dependent and receptor-independent responses to melatonin are identified to occur in these cells by regulating signaling pathways, which drive the commitment and differentiation of MSCs into osteogenic, chondrogenic, or adipogenic lineages. Therefore, the aim of our current review is to summarize the evidence related to the utility of melatonin as a regulatory agent by focusing on its relationship with the differentiation of MSCs. In particular, we aimed to review its roles in promoting osteogenic and chondrogenic differentiation and the relevant signaling cascades involved. Also, the roles that melatonin and, particularly, its receptors play in these processes are highlighted.
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Melatonin is a signal molecule that modulates the biological circadian rhythms of vertebrates. Melatonin deficiency is thought to be associated with several disorders, including insomnia, cancer, and cardiovascular and neurodegenerative diseases. Accumulating evidence has also indicated that melatonin may be involved in the homeostasis of bone metabolism. Age‐related reductions in melatonin are considered to be critical factors in bone loss and osteoporosis with aging. Thus, serum melatonin levels might serve as a biomarker for the early detection and prevention of osteoporosis. Compared to conventional antiosteoporosis medicines, which primarily inhibit bone loss, melatonin both suppresses bone loss and promotes new bone formation. Mechanistically, by activating melatonin receptor 2 (MT2), melatonin upregulates the gene expression of alkaline phosphatase (ALP), bone morphogenetic protein 2 (BMP2), BMP6, osteocalcin and osteoprotegerin to promote osteogenesis while inhibiting the receptor activator of NF‐kB ligand (RANKL) pathway to suppress osteolysis. In view of the distinct actions of melatonin on bone metabolism, we hypothesize that melatonin may be a novel remedy for the prevention and clinical treatment of osteoporosis. This article is protected by copyright. All rights reserved.
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Vitamin E-blended ultra-high molecular weight polyethylene (VE-UHMWPE) is a newly introduced material for prosthetic components that has proven a better mechanical performance with lesser adverse cellular responses than conventional polyethylene in experimental animal models. However, the mechanisms by which VE-UHMWPE particles trigger a reduced osteolytic activity are unclear and remain to be investigated. Therefore, the current study aims at exploring a possible anti-osteolytic mechanism associated with VE-UHMWPE particles. Transcriptional profiling and bioinformatic analyses of human macrophages stimulated by VE-UHMWPE particles revealed a distinct transcriptional program from macrophages stimulated with UHMWPE particles. Out of the up-regulated genes, IL-27 was found to be significantly elevated in macrophages cultured with VE-UHMWPE particles as compared to these with UHMWPE particles (p = 0.0084). Furthermore, we studied the potential anti-osteolytic function of IL-27 in osteolysis murine model. Interestingly, administration of recombinant IL-27 onto calvariae significantly alleviated osteolytic lesions triggered by UHMWPE particles (p = 0.0002). Likewise, IL-27 inhibited differentiation of osteoclasts (p = 0.0116) and reduced inflammatory response (p < 0.0001) elicited by conventional UHMWPE particles in vitro. This is the first study demonstrating the involvement of IL-27 in macrophage response to VE-UHMWPE particles and its regulatory role in osteolysis. Our data highlight a novel therapeutic agent for treatment of inflammatory osteolysis induced by polyethylene debris. Statement of Significance Aseptic loosening due to inflammatory osteolysis remains the major cause of arthroplasty failure and represents a substantial economic burden worldwide. Ideal approach to prevent this failure should be directed to minimize inflammatory response triggered by wear particles at the site of implant. Understanding the mechanism by which VE-UHMWPE particles triggers lesser cellular responses and reduced osteolysis as compared to conventional UHMWPE particles may aid in discovery of regulatory factors. In the current study, we reported that IL-27 is a potent regulator of inflammatory osteolysis involved in the reduced biologic activities and osteolytic potentials associated with VE-UHMWPE particles. Initiating the production IL-27 in vivo after total joint arthroplasties might be a novel strategy to prolong the life-spam of implant.
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Melatonin (MLT) is widely known for regulating the circadian cycles and has been studied for its role in bone regeneration and inflammation. Its application as a coating for dental implants can condition the local microenvironment, affecting protein deposition on its surface and the cellular and tissue response. Using sol-gel coatings as a release vehicle for MLT, the aim of this work was to assess the potential of this molecule in improving the osseointegration and inflammatory responses of a titanium substrate. The materials obtained were physicochemically characterized (scanning electron microscopy, contact angle, roughness, Fourier-transform infrared spectroscopy, nuclear magnetic resonance, Si release, MLT liberation, and degradation) and studied in vitro with MC3T3-E1 osteoblastic cells and RAW264.7 macrophage cells. Although MLT application led to an increased gene expression of RUNX2 and BMP2 in 10MTL, it did not improve ALP activity. On the other hand, MLT-enriched sol-gel materials presented potential effects in the adsorption of proteins related to inflammation, coagulation and angiogenesis pathways depending on the dosage used. Using LC-MS/MS, protein adsorption patterns were studied after incubation with human serum. Proteins related to the complement systems (CO7, IC1, CO5, CO8A, and CO9) were less adsorbed in materials with MLT; on the other hand, proteins with functions in the coagulation and angiogenesis pathways, such as A2GL and PLMN, showed a significant adsorption pattern.
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Wear particle-induced periprosthetic osteolysis is the primary complication of the total joint replacement; however, no conservative treatment except for reversal surgery is available for this disease. During the past decade, Chinese herbal medicines have been widely investigated to inhibit osteoclast differentiation, which may exhibit the potential to treat wear particle-induced periprosthetic osteolysis. The present study was aimed at the investigation of the effects of forsythiaside on osteocytes. The current data revealed that the forsythiaside treatment notably inhibited the titanium (Ti) particle-induced inflammation through impaired NF-κB signaling, thereby inhibiting TNF-α and IL-1β. In addition, the in vitro study demonstrated that forsythiaside effectively prevented the RANKL-induced differentiation of osteoclasts and inhibited the expression of osteoclast-specific genes in osteoclasts via inhibition of the JNK signaling pathway. The in vivo study of Ti particle-induced implant-associated osteolysis indicated that forsythiaside could also inhibit osteoclastogenesis. In summary, forsythiaside could inhibit osteoclastogenesis and particle-induced inflammation, resulting in decreased secretion of inflammatory cytokines such as TNF-α and IL-1β. On the other hand, forsythiaside could inhibit RANKL-induced osteoclastogenesis and Ti particle-induced periprosthetic osteolysis via JNK, ERK and p38 signaling pathways. Both the abovementioned biofunctions of forsythiaside contributed to the implant-associated particle-induced osteolysis. Thus, forsythiaside can act as a candidate drug for the precaution of implant-associated particle-induced osteolysis.
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Pulsed electromagnetic field (PEMF) therapy and melatonin (MEL) supplementation are expected to be important strategies for the treatment of osteoporosis. The aim of the current study was to investigate the efficacy of PEMF therapy, MEL supplementation, a combination of PEMF therapy, and MEL supplementation (PEMF + MEL) in mice with bilateral ovariectomy (OVX)‐induced osteoporosis. Forty 12‐week‐old female C57/BL mice were randomly assigned to five groups (n = 8/group): OVX, PEMF, MEL, PEMF + MEL, and sham‐operation (sham) groups. All mice in the first four groups were subjected to OVX. The mice in the PEMF and PEMF + MEL groups were exposed to PEMF (75 Hz, 1.6 mT, 1 h/day for 12 weeks), while those in the MEL and PEMF + MEL groups were administered MEL (50 mg/kg, i.p.). Body mass, micro‐computed tomography, histology, immunohistochemistry, and real‐time polymerase chain reaction were performed. PEMF + MEL treatment enhanced bone volume fraction (BV/TV) 2.2‐fold over OVX control (P < 0.001) and increased expression levels of collagen type I (COL1) 1.9‐fold and bone morphogenetic protein 2 (BMP2) 2.5‐fold. PEMF + MEL also reduced the ratio of bone surface/bone volume (BS/BV) by 40% (P < 0.05) and appeared to reduce the number of osteoclasts in the metaphysis area. Preservation of bone value and bone microarchitecture in the combined therapy group were found to be superior to those in the single treatment groups. However, there were no apparent differences between the PEMF and MEL groups. The use of a combination of PEMF therapy and MEL supplementation may be an effective method to treat osteoporosis.
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Periprosthetic osteolysis (PIO) caused by wear particles is the main cause of implant failure, which is regulated by nuclear factor κ B receptor activator ligand (RANKL)/osteoprotegerin (OPG) system. At present, there is a lack of effective drugs to prevent or treat PIO. Previous studies have confirmed that DNA methylation is closely related to postmenopausal osteoporosis and can affect the expression of OPG and RANKL. However, the relationship between DNA methylation and PIO is not clear. In this study, we investigated the inhibitory effect of 5-Aza-2-deoxycytidine (AzadC) on osteolysis induced by titanium particles in a mouse model. This inhibition mechanism is achieved by changing the ratio of RANKL/OPG in the osteolysis model. In conclusion, there is a relationship between DNA methylation and PIO. AzadC has a certain inhibitory effect on osteolysis induced by titanium particles. Regulating DNA methylation may be a new way to treat PIO. Our findings lay a foundation for epigenetic understanding and intervention of osteolysis.
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Purpose: Titanium particle-induced osteolysis is one of the important causes of aseptic loosening of artificial joints. Previous studies have shown the potential of natural compounds in preventing Ti particle-induced bone resorption. In this study, we observed the effects of magnesium lithospermate B (MLB) on titanium particle-induced osteoclast activity in vitro. Materials and Methods: RAW264.7 cells were treated with titanium particles (0.1 mg/mL) in the presence or absence of MLB (200 nmol/L). We evaluated the osteoclast formation, bone pits formation and tartrate-resistant acid phosphatase 5b (Tracp5b) levels. Reverse transcription polymerase chain reaction (RT-PCR) and Western blot were used to evaluate osteoclast differentiation-related genes (TRAF6, NFATc1, and c-fos) and protein expression. Results: The number of osteoclasts, pit formation and Tracp5b levels were all the group treated with titanium particles compared to the control group (all p < 0.05). Titanium particles also promoted the expression of the TRAF6, NFATc1 and c-fos genes and protein expression. MLB significantly abolished the titanium particle-enhanced osteoclast and pits formation, and Traf6, NFATc1, and c-fos expression. Conclusions: Our data demonstrated that MLB can suppress titanium-induced osteoclast activity via inhibiting c-fos and NFATc1 expression.
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Excessive osteoclast recruitment and activation is the chief cause of periprosthetic osteolysis and subsequent aseptic loosening, so blocking osteolysis may be useful for protecting against osteoclastic bone resorption. We studied the effect of aspirin on titanium (Ti)‐particle‐induced osteolysis in vivo and in vitro using male C57BL/6J mice randomized to sham (sham surgery), Ti (Ti particles), low‐dose aspirin (Ti/5 mg·kg−1·d−1 aspirin), and high‐dose aspirin (Ti/30 mg·kg−1·d−1 aspirin). After 2 weeks, a three‐dimensional reconstruction evaluation using micro‐computed tomography and histomorphology assessment were performed on murine calvariae. Murine hematopoietic macrophages and RAW264.7 lineage cells were studied to investigate osteoclast formation and function. Aspirin attenuated Ti‐particle‐induced bone erosion and reduced osteoclasts. In vitro, aspirin suppressed osteoclast formation, osteoclastic‐related gene expression, and osteoclastic bone erosion in a dose‐dependent manner. Mechanically, aspirin reduced osteoclast formation by suppressing receptor activator of nuclear factor kappa‐B ligand‐induced activation of extracellular signal‐related kinase, p‐38 mitogen‐activated protein kinase, and c‐Jun N‐terminal kinase. Thus, aspirin may be a promising option for preventing and curing osteoclastic bone destruction, including peri‐implant osteolysis. Aspirin blocks receptor activator of nuclear factor kappa‐B ligand‐induced mitogen‐activated protein kinase activation and osteoclast formation, and subsequently attenuates wear‐debris‐induced osteolysis. Thus, aspirin might be an appropriate reagent for treating osteoclastic bone loss, including peri‐implant osteolysis.
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Peri-implantitis, which is characterized by peri-implant mucositis and alveolar bone resorption, significantly shortens the service life of dental implants. Melatonin is well-known for its anti-inflammatory and osteoprotective activities. Nevertheless, the effects and mechanisms of melatonin to prevent peri-implantitis remain unknown. In this study, the lipopolysaccharide-induced peri-implantitis model was established after the titanium implants were osseointegrated, and the rats received daily administrations of melatonin. The gingival fibroblasts and osteoclasts/osteoblasts were also co-cultured to simulate the inflammatory environment in vitro. We found that prophylactic administration of melatonin decreased proinflammatory cytokine levels and osteoclast numbers, attenuated alveolar bone resorption, and reduced the incidence of peri-implantitis in vivo. Furthermore, melatonin suppressed osteoclastic formation and function in the inflammatory co-culture environment, while melatonin promoted osteoblastic differentiation and function in the in vitro model. Mechanistically, melatonin reduced TLR4 protein levels, and inhibited activation of NF-κB to downregulate the levels of TNF, IL-1β, and IL-6. These data showed that melatonin was a potent agent to prevent peri-implantitis through inhibiting TLR4/NF-κB signaling. Our findings provide a novel strategy to prevent peri-implantitis, and expand the applications of melatonin. Statement of significance : Dental implants have become the first choice for restoring partial and full edentulism, but its service life is seriously affected by peri-implantitis. Exploration of novel and effective approaches to prevent peri-implantitis is an important and urgent need. In the present study, we have reported for the first time that prophylactic administration of melatonin delayed the occurrence and reduced the incidence of peri-implantitis by decreasing proinflammatory cytokine levels, inhibiting osteoclastogenesis, and promoting osteogenesis. The study is expected to have an important significance on the prevention of peri-implantitis.
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Wear debris-induced osteoclast accumulation around implants plays a crucial role during the progression of periprosthetic osteolysis (PPO). We have confirmed that acetyl-11-keto-β-boswellic acid (AKBA) promotes bone formation and protects against particle-induced bone destruction in vivo. However, the effect of AKBA on titanium-induced bone resorption is unknown. In this study, we detected the inhibitory effect of AKBA on titanium-induced bone erosion in vivo and used RAW264.7 cells and bone marrow macrophages (BMMs) to investigate the effect and underlying mechanism of AKBA on the differentiation and resorptive function of osteoclasts. Our findings revealed that AKBA inhibited particle-induced bone loss and osteoclast formation in vivo. Furthermore, AKBA exerted inhibitory effects on RANKL-induced osteoclastogenesis, osteoclastic ring-dependent resorption and the expression of osteoclast marker genes via the ERK signaling pathway in vitro. Our data further established the protective effect of AKBA on titanium particle-induced bone erosion from a new perspective of bone erosion prevention, strongly confirming that AKBA is an appropriate agent for protection against PPO.
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Background and purpose: Melatonin is a neurohormone involved in many biological activities, especially bone homeostasis. However, how melatonin directs bone remodelling and the role of bone marrow mesenchymal stem cells (BMMSCs) in the regulating melatonin-mediated bone formation-resorption balance remain undefined. Experimental approach: Osteoporosis models were established, and bone tissue and serum were collected to test the effects of melatonin on bone homeostasis. Melatonin receptors (MT receptors) were knocked down, the NF-κB signalling pathway and receptor activator of nuclear factor-κB ligand (RANKL) expression were investigated, and communication between BMMSCs and osteoclasts was detected with direct-contact or indirect-contact system. Key results: Bone loss and microstructure disorder in mice were profoundly reversed after melatonin treatment, as an integrated result of anabolic and anti-resorptive effects. In vitro, a low physiological melatonin concentration selectively promoted the BMMSCs' osteogenic lineage commitment and extracellular mineralization, but had no impact on extracellular matrix synthesis. After MT knockdown, especially MT2 knockdown, the positive effects of melatonin on osteogenesis were attenuated. The canonical NF-κB signalling pathway was the first discovered downstream signalling pathway after MT receptor activation and was found to be downregulated by melatonin during osteogenesis. Melatonin suppressed BMMSC-mediated osteoclastogenesis by inhibiting RANKL production in BMMSCs, and this effect only occurred when BMMSCs and osteoclast precursors were co-cultured in an indirect-contact manner. Conclusion and implications: Our work suggests that melatonin plays a crucial role in bone balance, significantly accelerates the osteogenic differentiation of BMMSCs by suppressing the MT2-dependent NF-κB signalling pathway, and downregulates osteoclastogenesis via RANKL paracrine secretion.
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Growing evidence shows that the inhibitory effect of inflammatory cytokines on new bone formation by osteogenic precursor cells is a critical cause of net bone-density reduction. Melatonin has been proven to be a potential therapeutic candidate for osteoporosis. However, whether it is capable of antagonizing the suppressing effect of inflammatory cytokines on osteogenic precursor cells is so far elusive. In this study, using the cell culture system of human bone marrow stromal cells and MC3T3-E1 preosteoblasts, we recorded the following vital observations that provided insights of melatonin-induced bone formation: 1) melatonin induced bone formation in both normal and inflammatory conditions; 2) Wnt4 was essential for melatonin-induced bone formation in inflammatory stimulation; 3) melatonin- and Wnt4-induced bone formation occurred via activation of β-catenin and p38-JNK MAPK pathways by interaction with a distinct frizzled LDL receptor-related protein complex; 4) melatonin suppressed the inhibitory effect of NF-κB on osteogenesis in a Wnt4-dependent manner; and 5) melatonin induced Wnt4 expression through the ERK1/2-Pax2-Egr1 pathway. In summary, we showed a novel mechanism of melatonin-induced bone formation in an inflammatory environment. Melatonin-induced Wnt4 expression is essential for its osteoinductive effect and the inhibitory effect of NF-κB on bone formation. Our novel findings may provide useful information for its potential translational application.-Li, X., Li, Z., Wang, J., Li, Z., Cui, H., Dai, G., Chen, S., Zhang, M., Zheng, Z., Zhan, Z., Liu, H. Wnt4 signaling mediates protective effects of melatonin on new bone formation in an inflammatory environment.
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Wear-debris-induced periprosthetic osteolysis (PIO) is a common clinical condition following total joint arthroplasty, which can cause implant instability and failure. The host response to wear debris promotes bone resorption and impairs bone formation. We previously demonstrated that icariin suppressed wear-debris-induced osteoclastogenesis and attenuated particle-induced osteolysis in vivo. Whether icariin promotes bone formation in a wear-debris-induced osteolytic site remains unclear. Here, we demonstrated that icariin significantly attenuated titanium-particle inhibition of osteogenic differentiation of mesenchymal stem cells (MSCs). Additionally, icariin increased bone mass and decreased bone loss in titanium-particle-induced osteolytic sites. Mechanistically, icariin inhibited decreased β-catenin stability induced by titanium particles in vivo and in vitro. To confirm icariin mediated its bone-protective effects via the Wnt/β-catenin signaling pathway, we demonstrated that ICG-001, a selective Wnt/β-catenin inhibitor, attenuated the effects of icariin on MSC mineralization in vitro and bone formation in vivo. Therefore, icariin could induce osteogenic differentiation of MSCs and promote new bone formation at a titanium-particle-induced osteolytic site via activation of the Wnt/β-catenin signaling pathway. These results further support the protective effects of icariin on particle-induced bone loss and provide novel mechanistic insights into the recognized bone-anabolic effects of icariin and an evidence-based rationale for its use in PIO treatment.
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We examined the effects of triptolide on receptor activator of nuclear factor-κB ligand (RANKL)-induced osteoclast differentiation and on titanium (Ti) particle-induced osteolysis. To examine the effect of triptolide on osteoclast differentiation, bone marrow macrophages (BMMs) were treated with 100 ng/mL of RANKL and 30 ng/mL of macrophage-colony stimulating factor, or co-cultured with osteoblasts stimulated with 10 nM vitamin D3 and 1 μM prostaglandin E2 in the presence or absence of triptolide (2.8-14 nM). Osteoclast differentiation and activation were assessed using tartrate-resistant acid phosphatase staining, reverse transcriptase-polymerase chain reaction analysis to determine differentiation marker gene expression and pit formation assays. To examine the effect of triptolide on wear debris-induced osteolysis, titanium (Ti) particles were injected into the calvaria of ICR mice. Then, the mice were divided into three groups and were orally administered vehicle, or 16 or 32 μg/kg/day triptolide for ten days, followed by histomorphometric analysis. Triptolide suppressed RANKL-mediated osteoclast differentiation of BMMs in a dose-dependent manner. In a co-culture system, osteoblasts treated with triptolide could not induce osteoclast differentiation of BMMs, which was accompanied by down-regulation of RANKL and up-regulation of osteoprotegrin. Moreover, triptolide significantly inhibited bone resorption, and expression of the bone resorption marker genes. RANKL-induced activation of p38, ERK, and JNK was substantially inhibited by triptolide. Further, in a Ti-induced mouse calvarial erosion model, mice perorally administrated with triptolide showed significant attenuation of Ti-mediated osteolysis. Our data indicated that triptolide had an anti-osteoclastic effect and significantly suppressed wear debris-induced osteolysis in mice.
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Introduction: Previous studies have shown that melatonin, an anti-oxidant molecule secreted from the pineal gland, is a positive regulator of bone mass. However, the potential effects of melatonin on bone mass have never been investigated in an old population. The aim of this study was to assess the effects of dietary melatonin supplementation on mass accrual and biomechanical properties of old rat femora. Methods: Twenty 22-month-old male Wistar rats were divided into two randomly assigned groups. The first group was treated for 10 weeks with melatonin, whereas the second group was untreated (control). Rat femurs were collected, and their phenotypes and biomechanical properties were investigated by micro-computed tomography, histomorphometry, and a three-point-bending test. Statistical analyses were performed by the Student two-tailed unpaired t-test. In all experiments, a value of p<0.05 was considered significant. Results: Rats treated with melatonin had higher bone volume, bone trabecular number, trabecular thickness, and cortical thickness in comparison to the control group. Histomorphometric analyses confirmed the increase of bone volume in melatonin-treated rats. In agreement with these findings, melatonin-treated rats showed higher bone stiffness, flexural modulus, and ultimate load compared to controls. Conclusion: These compelling results are the first evidence indicating that dietary melatonin supplementation is able to exert beneficial effects against age-related bone loss in old rats, improving the microstructure and biomechanical properties of aged bones.
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Monoblock acetabular components used in uncemented total hip arthroplasty (THA) have certain mechanical characteristics that potentially reduce acetabular osteolysis and polyethylene wear. However, the degree to which they achieve this goal is not well documented. The purpose of this study was to use a systematic review of controlled trials to test the hypothesis that monoblock cups have superior (1) polyethylene wear rate; (2) frequency of cup migration; (3) frequency of acetabular osteolysis; and (4) frequency of aseptic loosening compared with modular components used in uncemented THA. A systematic search was conducted in the Medline, Embase, and Cochrane electronic databases to assemble all controlled trials comparing monoblock with modular uncemented acetabular components in primary THA. Included studies were considered "best evidence" if the quality score was either ≥ 50% on the Cochrane Back Review Group checklist or ≥ 75% the Newcastle-Ottawa quality assessment scale. A total of seven publications met our inclusion criteria. Best evidence analysis showed no difference in polyethylene wear rate, the frequency of cup migration, and aseptic loosening between monoblock and modular acetabular components. No convincing evidence was found for the claim that lower frequencies of acetabular osteolysis are observed with the use of monoblock cups compared with modular uncemented cups. The purported benefits of monoblock cups were not substantiated by this systematic review of controlled studies in that polyethylene wear rates and frequencies of cup failure and acetabular osteolysis were similar to those observed with modular implants. Other factors should therefore drive implant selection in cementless THA. Level III, therapeutic study. See the Guidelines for Authors for a complete description of levels of evidence.
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Wear debris-induced osteolysis in periprosthetic tissue with aseptic loosening is a serious problem after total joint arthroplasty. Matrix metalloproteinase-9 (MMP-9) is expressed in osteoclast cells that surround loosening peri-implant tissue, but the molecular mechanism of MMP-9 action in wear debris-induced osteolysis remains ambiguous. We used a murine osteolysis model to examine the hypothesis that administration of an MMP-9 inhibitor reduces the expression of receptor activator of nuclear factor-κB (RANK) and nuclear factor-κB ligand (RANKL) and, thereby, suppressesdebris-induced inflammatory osteolysis. Experiments were performed in 3 groups of 15 mice: a control, a titanium (Ti) and a Ti plus tetracycline group. To provoke inflammatory osteolysis, calvarial bone was implanted from syngeneic littermates, followed by injection of Ti particles into established air pouches for all groups except the control. Tetracycline was administered daily by intraperitoneal (i.p.) injection, and PBS was administered by i.p. injection to the control and Ti groups. Mice were sacrificed 14 days after bone-Ti implantation. Pouch membranes with the intact bone implants were collected for histological and molecular analysis. Tetracycline had minimum effect on the expression of MMP-9 and tumor necrosis factor-α (TNF-α) but it decreased gene activation and inhibited the expression of RANK and RANKL, thereby inhibiting Ti-particle-induced inflammatory osteolysis. Tetracycline decreased the number of tartrate-resistant acid phosphatase (TRAP)-positive cells in the pouch tissues. Our results in the murine osteolysis model suggest that through the downregulation of RANK/RANKL, tetracycline significantly inhibits debris-induced inflammatory osteolysis. Its use in clinical practice may help prevent complications experienced by patients who have undergone total joint arthroplasty.
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The objective of this paper was to analyze the data supporting the possible role of melatonin on bone metabolism and its repercussion in the etiology and treatment of bone pathologies such as the osteoporosis and the adolescent idiopathic scoliosis (AIS). Melatonin may prevent bone degradation and promote bone formation through mechanisms involving both melatonin receptor-mediated and receptor-independent actions. The three principal mechanisms of melatonin effects on bone function could be: (a) the promotion of the osteoblast differentiation and activity; (b) an increase in the osteoprotegerin expression by osteoblasts, thereby preventing the differentiation of osteoclasts; (c) scavenging of free radicals generated by osteoclast activity and responsible for bone resorption. A variety of in vitro and in vivo experimental studies, although with some controversial results, point toward a possible role of melatonin deficits in the etiology of osteoporosis and AIS and open a new field related to the possible therapeutic use of melatonin in these bone diseases.
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Melatonin is synthesized and secreted by the pineal gland and other organs. The pattern of melatonin secretion is controlled by an endogenous circadian timing system and conveys information about the light-dark cycle to the organism, thereby organizing its seasonal and circadian rhythms. Melatonin has powerful antioxidant effects, functions in an immunomodulatory role, may protect against certain cancers, delays some age-related processes, stimulates the synthesis of type I collagen fibers, and promotes bone formation. An extensive review was made (e.g., using PubMed, Science Direct, and Web of Knowledge) of the literature. Melatonin, which is released into the saliva, may have important implications for dental disorders, especially in periodontal disease. Diseases of the periodontium are known to be aggravated by free radicals and by alterations in the immune response to microorganisms that are present in plaque. In response to periodontal inflammation, the blood and salivary levels of melatonin may increase. Melatonin may play a role in protecting the oral cavity from tissue damage that is due to oxidative stress, and it may contribute to the regeneration of alveolar bone through the stimulation of type I collagen fiber production and the modulation of osteoblastic and osteoclastic activity.
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The immune system modulates many key biological processes in humans. However, the exact role of the immune system in particle-associated periprosthetic osteolysis is controversial. Human tissue retrieval studies, in vivo and in vitro experiments suggest that the immune response to polymer particles is non-specific and macrophage-mediated. Lymphocytes may modulate this response. However direct lymphocyte activation by polymer particle-protein complexes seems unlikely. However, metallic byproducts may complex with serum proteins and lead to a Type IV, lymphocyte-mediated immune reaction. In predisposed individuals, this reaction may rarely lead to persistent painful joint effusions, necessitating debridement and excision of the bearing surfaces of the prosthesis. In these patients, retrieved periprosthetic tissues exhibit histological evidence of perivascular lymphocytic cuffing. These findings are worrisome, given the fact that increasing numbers of metal-on-metal joint implants are being implanted in younger more active individuals worldwide.
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Small-animal models are useful for the in vivo study of particle-induced osteolysis, the most frequent cause of aseptic loosening after total joint replacement. Microstructural changes associated with particle-induced osteolysis have been extensively explored using two-dimensional (2D) techniques. However, relatively little is known regarding the 3D dynamic microstructure of particle-induced osteolysis. Therefore, we tested micro-computed tomography (micro-CT) as a novel tool for 3D analysis of wear debris-mediated osteolysis in a small-animal model of particle-induced osteolysis. The murine calvarial model based on polyethylene particles was utilized in 14 C57BL/J6 mice randomly divided into two groups. Group 1 received sham surgery, and group 2 was treated with polyethylene particles. We performed 3D micro-CT analysis and histological assessment. Various bone morphometric parameters were assessed. Regression was used to examine the relation between the results achieved by the two methods. Micro-CT analysis provides a fully automated means to quantify bone destruction in a mouse model of particle-induced osteolysis. This method revealed that the osteolytic lesions in calvaria in the experimental group were affected irregularly compared to the rather even distribution of osteolysis in the control group. This is an observation which would have been missed if histomorphometric analysis only had been performed, leading to false assessment of the actual situation. These irregularities seen by micro-CT analysis provide new insight into individual bone changes which might otherwise be overlooked by histological analysis and can be used as baseline information on which future studies can be designed.
Article
Melatonin is remarkably functionally-diverse with actions as a free radical scavenger and antioxidant, circadian rhythm regulator, anti-inflammatory and immuno-regulating molecule and as an oncostatic agent. We hypothesize that the initial and primary function of melatonin in photosynthetic cyanobacteria, which appeared on Earth 3.5-3.2 billion years ago, was as an antioxidant. The evolution of melatonin as an antioxidant by this organism was necessary since photosynthesis is associated with the generation of toxic free radicals. The other secondary functions of melatonin came about much later in evolution. We also surmise that mitochondria and chloroplasts may be primary sites of melatonin synthesis in all eukaryotic cells that possess these organelles. This prediction is made on the basis that mitochondria and chloroplasts of eukaryotes developed from purple non-sulfur bacteria (which also produce melatonin) and cyanobacteria when they were engulfed by early eukaryotes. Thus, we speculate that the melatonin-synthesizing actions of the engulfed bacteria were retained when these organelles became mitochondria and chloroplasts, respectively. That mitochondria are likely sites of melatonin formation is supported by the observation that this organelle contains high levels of melatonin that are not impacted by blood melatonin concentrations. Melatonin has a remarkable array of means by which it thwarts oxidative damage. It, as well as its metabolites, is differentially effective in scavenging a variety of reactive oxygen and reactive nitrogen species. Moreover, melatonin and its metabolites modulate a large number of antioxidative and pro-oxidative enzymes, leading to a reduction in oxidative damage. The actions of melatonin on radical metabolizing/producing enzymes may be mediated by the Keap1-Nrf2-ARE pathway. Beyond its direct free radical scavenging and indirect antioxidant effects, melatonin has a variety of physiological and metabolic advantages that may enhance its ability to limit oxidative stress. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
Article
Aseptic loosening is associated with the development of wear debris-induced peri-implant osteolytic bone disease caused by an increased osteoclastic bone resorption and decreased osteoblastic bone formation. However, no effective measures for the prevention and treatment of peri-implant osteolysis currently exist. The aim of this study was to determine whether lithium chloride (LiCl), a selective inhibitor of glycogen synthetase kinase 3 beta (GSK-3β), mitigates wear debris-induced osteolysis in a murine calvarial model of osteolysis. GSK-3β is activated by titanium (Ti) particles, and implantation of Ti particles on the calvarial surface in C57BL/6 mice resulted in osteolysis caused by an increase in the number of osteoclasts and a decrease in the number of osteoblasts. Mice implanted with Ti particles were gavage-fed LiCl (50 or 200 mg kg(-1)d(-1)), 6 days per week for 2 weeks. The LiCl treatment significantly inhibited GSK-3β activity and increased β-catenin and axin-2 expression in a dose-dependent manner, dramatically mitigating the Ti particle-induced suppression of osteoblast numbers and the expression of bone formation markers. Finally, we demonstrated that inhibition of GSK-3β suppresses osteoclast differentiation and reduces the severity of Ti particle-induced osteolysis. The results of this study indicate that Ti particle-induced osteolysis is partly dependent on GSK-3β and, therefore, the canonical Wnt signaling pathway. This suggests that selective inhibitors of GSK-3β such as LiCl may help prevent and treat wear debris-induced osteolysis. Copyright © 2015 Elsevier Ltd. All rights reserved.
Article
Melatonin is known for its regulation of circadian rhythm. Recently, studies have shown that melatonin may have a positive effect on the skeleton. By increasing age, the melatonin levels decrease, which may lead to a further imbalanced bone remodeling. We aimed to investigate whether treatment with melatonin could improve bone mass and integrity in humans. In a double-blind RCT, we randomized 81 post-menopausal osteopenic women to one-year daily treatment with melatonin 1mg (N=20), or 3mg (N=20), or placebo (N=41). At baseline and after one-year treatment, we measured BMD by DXA, quantitative computed tomography (QCT), and high resolution peripheral QCT (HR-pQCT), and determined calcitropic hormones and bone markers. Mean age of the study subjects was 63 (range 56-73) years. Compared to placebo, femoral neck BMD increased by 1.4% in response to melatonin (p<0.05) in a dose-dependent manner (p<0.01), as BMD increased by 0.5% in the 1mg/d group (p=0.55) and by 2.3% (p<0.01) in the 3mg/d group. In the melatonin group, trabecular thickness in tibia increased by 2.2% (p=0.04), and vBMD in the spine by 3.6% (p=0.04) in the 3mg/d. Treatment did not significantly affect BMD at other sites or levels of bone turnover markers, however, 24h urinary calcium was decreased in response to melatonin by 12.2% (p=0.02). In conclusion, one-year treatment with melatonin increased BMD at femoral neck in a dose-dependent manner, while high dose melatonin increased vBMD in the spine. Further studies are needed to assess the mechanisms of action and whether the positive effect of night-time melatonin will protect against fractures. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
Article
Periprosthetic osteolysis and subsequent aseptic loosening are common in implant failure, a complication with revision surgery being the only established treatment. Wear particle-induced inflammation and extensive osteoclastogenesis play critical roles in periprosthetic osteolysis. A recent approach in limiting osteolysis is therefore focused on inhibiting osteoclastic bone resorption. This study aimed to investigate the potential impact of icariin, the major ingredient of Epimedium, on titanium particle-induced osteolysis in a mouse calvarial model. Eighty-four male C57BL/J6 mice were divided randomly into four groups. Mice in the sham group underwent sham surgery only, whereas animals in the vehicle, low- and high-concentration icariin groups received titanium particles. Mice in the low- and high-concentration icariin groups were gavage-fed with icariin at 0.1 or 0.3 mg/g/day, respectively, until sacrifice. Mice in the sham and vehicle groups received phosphate-buffered saline daily. After 2 weeks, mouse calvariae were collected for micro-computed tomography, histomorphometry and molecular analysis. Icariin significantly reduced particle-induced bone resorption compared with the vehicle group. Icariin also prevented an increase in receptor activator of nuclear factor kappa B ligand/osteoprotegerin ratio and subsequently suppressed osteoclast formation in titanium particle-charged calvariae. In addition, immunohistochemical analysis and enzyme-linked immunosorbent assay showed icariin significantly reduced expression and secretion of tumor necrosis factor-α, interleukin-1β and interleukin-6 in the calvariae of titanium-stimulated mice. Collectively, these results suggest that icariin represents a potential treatment for titanium particle-induced osteolysis and could be developed as a new therapeutic candidate for the prevention and treatment of aseptic loosening. Copyright © 2015 Elsevier Ltd. All rights reserved.
Article
WNTs are extracellular proteins that activate different cell surface receptors linked to canonical and non-canonical WNT signalling pathways. The Wnt genes were originally discovered as important for embryonic development of fruit flies and malignant transformation of mouse mammary cancers. More recently, WNTs have been implicated in a wide spectrum of biological phenomena and diseases. During the last decade, several lines of clinical and preclinical evidence have indicated that WNT signalling is critical for trabecular and cortical bone mass and this pathway is currently an attractive target for drug development. Based on detailed knowledge of the different WNT signalling pathways, it appears that it might be possible to develop drugs that specifically target cortical and trabecular bone. Neutralization of a bone-specific WNT inhibitor is now being evaluated as a promising anabolic treatment for patients with osteoporosis. Here, we provide the historical background to the discoveries of WNTs, describe the different WNT signalling pathways and summarize the current understanding of how these proteins regulate bone mass by affecting bone formation and resorption. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
Article
Wear-particle-induced osteolysis leads to prosthesis loosening, which is one of the most common causes of joint-implant failure, a problem that must be fixed using revision surgery. Thus, a potential treatment for prosthetic loosening is focused on inhibiting osteoclastic bone resorption, which prevents wear-particle-induced osteolysis. In this study, we synthesized a compound named OA-14 (N-(3- (dodecylcarbamoyl)phenyl)-1H-indole-2-carboxamide) and examined how OA-14 affects titanium (Ti)-particle-induced osteolysis and osteoclastogenesis. We report that OA-14 treatment protected against Ti-particle-induced osteolysis in a mouse calvarial model. Interestingly, the number of tartrate-resistant acid phosphatase-positive osteoclasts decreased after treatment with OA-14 in vivo, which suggested that OA-14 inhibits osteoclast formation. To test this hypothesis, we conducted in vitro studies, and our results revealed that OA-14 markedly diminished osteoclast differentiation and osteoclast-specific gene expression in a dose- and time-dependent manner. Moreover, OA-14 suppressed osteoclastic bone resorption and F-actin ring formation. Furthermore, we determined that OA-14 inhibited osteoclastogenesis by specifically blocking the p38-Mitf-c-fos-NFATc1 signaling cascade induced by RANKL (ligand of receptor activator of nuclear factor κB). Collectively, our results suggest that the compound OA-14 can be safely used for treating particle-induced peri-implant osteolysis and other diseases caused by excessive osteoclast formation and function.
Article
Objective The aim of this study was to evaluate the effect of the topical application of melatonin compared with collagenized porcine bone grafts to accelerate bone formation 2 months after their insertion in tibiae rabbits. Material and Methods Twenty New Zealand rabbits weighing 3,900–4,500 g were used. Twenty collagenized porcine bone (MP3) grafts, twenty melatonin-impregnated bone grafts, and twenty control areas were placed in the proximal metaphyseal area of both rear tibias. Four groups were formed according to the moment in which animal killing was carried out: Group I (15 days), Group II (30 days), Group III (45 days) and Group IV (60 days). Cortical width and cortical length of bone formation was measured. Following implantation, an anteroposterior and lateral radiological study was carried out. Samples were sectioned at 5 μm and stained using hematoxylin-Eeosin, Masson's trichromic, and Gordon-Switt reticulin stains. ResultsAfter 60 days of treatment period, melatonin increased the length of cortical bone formation 99.03 ± 0.61% like control 98.90 ± 3.82% compared with porcine bone 92.73 ± 1.08%. Related to perimeter of cortical bone of the tibiae melatonin new bone was 98.35 ± 1.14% like control 98.0 ± 1.43% more than porcine bone 92.05 ± 1.03%. Histomorphometric values related to porcine bone were connective tissue 49.16 ± 2.4%, graft material (MP3) 23.52 ± 2.3%, and new bone formation 27.32 ± 1.4% compared with test group with melatonin 24.5 ± 1.2%, connective tissue 45.1 ± 1.2%, and new bone formation of 30.4 ± 1.0%. Conclusion Melatonin has proven to regenerate the width and length of cortical bone in tibiae rabbits more quickly than collagenized porcine bone. Melatonin acts as a bone stimulator compared with porcine bone and control sites.
Article
An important role for melatonin in bone formation and restructuring has emerged and studies demonstrate the multiple mechanisms for these beneficial actions. Statistical analysis shows that even with existing osteoporotic therapies, bone-related disease and mortality are on the rise creating a huge financial burden for societies worldwide. These findings suggest that novel alternatives need to be developed to either prevent or reverse bone loss to combat osteoporosis-related fractures. The focus of this review describes melatonin's role in bone physiology and discusses how disruption of melatonin rhythms by light exposure at night, shift work and disease can adversely impact on bone. The signal transduction mechanisms underlying osteoblast and osteoclast differentiation and coupling with one another are discussed with a focus on how melatonin, through the regulation of RANKL and osteoprotegerin synthesis and release from osteoblasts, can induce osteoblastogenesis while inhibiting osteoclastogenesis. Also, melatonin's free radical scavenging and antioxidant properties of this indoleamine are discussed as yet an additional mechanism by which melatonin can maintain one's bone health, especially oral health. The clinical use for melatonin in bone grafting procedures, in reversing bone loss due to osteopenia and osteoporosis, and in managing periodontal disease are discussed. This article is protected by copyright. All rights reserved.
Article
Estrogen withdrawal following surgical ovariectomy was recently shown to mitigate particle-induced osteolysis in the murine calvarial model. Currently, we hypothesize that estrogen receptors (ERs) were involved in this paradoxical phenomenon. To test this hypothesis, we first evaluated polyethylene (PE) particle-induced osteolysis in the murine calvarial model, using wild type (WT) C57BL6J female mice, ERα deficient (ERαKO) mice, and WT mice either treated with 17β-estradiol (E2) or with the ER pan-antagonist ICI 182,780. According to micro-CT and histomorphometry, we showed that bone resorption was consistently altered in both ERαKO and ICI 182,780 treated mice as compared to WT and E2 groups. Then, we demonstrated that ER disruption consistently decreased both PE and polymethylmethacrylate (PMMA) particle-induced production of TNF-α by murine macrophages in vitro. Similar results were obtained following ER blockade using ICI 182,780 in RAW 264.7 and WT macrophages. ER disruption and pre treatment with ICI 182,780 resulted in a consistent down-regulation of particle-induced TNF-α mRNA expression relative to WT macrophages or untreated RAW cells. These results indicate that the response to wear particles involves estrogen receptors in female mice, as part of macrophage activation. Estrogen receptors may be considered as a future therapeutic target for particle-induced osteolysis.
Article
Sleep problems are known to be common in Angelman syndrome (AS), a neurodevelopmental disorder which is associated with an abnormality of chromosome 15q11-q13. However, the circadian aspect of sleep disorders in AS and an effective treatment for the disorder have yet to be established. We elucidated the sleep-wake patterns of AS patients and its relationship to the serum melatonin levels. The serum melatonin levels of 15 AS patients were measured every 4h for one day and the values were compared with those of age-matched controls. We also examined the effectiveness of the oral administration of melatonin on AS patients with circadian rhythm sleep disorders (CRSD). A total of eight of the 15 AS patients had CRSD (irregular sleep-wake type, n=4; free-running type n=2; delayed sleep phase type, n=2). The nighttime serum melatonin levels of the AS patients were significantly lower than those of the controls at the measured time points during the night. The nocturnal melatonin levels were comparably low both in AS patients with and without CRSD except for the cases with delayed sleep phase type, which showed normal but delayed peak melatonin level. Six out of eight CRSD cases were given a daily dose of 1mg of melatonin between 18:00 and 19:00 regularly for three months. After receiving the treatment, the sleep patterns improved in four cases. This study revealed a high prevalence of CRSD in AS patients, which may be related to abnormal serum melatonin profiles.
Article
Melatonin is a highly evolutionary conserved endogenous molecule that is mainly produced by the pineal gland, but also by other nonendocrine organs, of most mammals including man. In the recent years, a variety of anti-inflammatory and antioxidant effects have been observed when melatonin is applied exogenously under both in vivo and in vitro conditions. A number of studies suggest that this indole may exert its anti-inflammatory effects through the regulation of different molecular pathways. It has been documented that melatonin inhibits the expression of the isoforms of inducible nitric oxide synthase and cyclooxygenase and limits the production of excessive amounts of nitric oxide, prostanoids, and leukotrienes, as well as other mediators of the inflammatory process such as cytokines, chemokines, and adhesion molecules. Melatonin's anti-inflammatory effects are related to the modulation of a number of transcription factors such as nuclear factor kappa B, hypoxia-inducible factor, nuclear factor erythroid 2-related factor 2, and others. Melatonin's effects on the DNA-binding capacity of transcription factors may be regulated through the inhibition of protein kinases involved in signal transduction, such as mitogen-activated protein kinases. This review summarizes recent research data focusing on the modulation of the expression of different inflammatory mediators by melatonin and the effects on cell signaling pathways responsible for the indole's anti-inflammatory activity. Although there are a numerous published reports that have analyzed melatonin's anti-inflammatory properties, further studies are necessary to elucidate its complex regulatory mechanisms in different cellular types and tissues.
Article
Over 500,000 bone graft or bio-implant procedures are performed annually in the United States. It has been reported that osseous autograft procurement may result in donor site complications and bio-implant allografts have been associated with disease transmission. Ceramic scaffolds are only osteoconductive, limiting their clinical use. The objective of this study was to create a bone filler substitute with regenerating properties similar to natural bone. Therefore, melatonin and platelet-rich plasma (PRP) were utilized for their known osteoinductive properties. It was hypothesized that melatonin and/or PRP would enhance the osteoinductive and osteoconductive properties of calcium aluminate (CA) scaffolds to promote bone regeneration in a model of calvarial defects. The biocompatibility of CA and CA-Mel scaffolds was tested in vitro and in vivo. Data show that CA-Mel scaffolds, in comparison with CA scaffolds, enhanced the adhesion, viability, and proliferation of normal human osteoblasts cells but not that of NIH3T3 fibroblasts. Data also showed that human adult mesenchymal stem cells grown on CA or CA-Mel scaffolds showed a time-dependent induction into osteoblasts over 14days revealed through scanning electron microscopy and by alkaline phosphatase analyses. Implantation of CA-Mel scaffolds into critical size calvarial defects in female, ovariectomized rats showed that the CA-Mel scaffolds were biocompatible, allowed for tissue infiltration, and showed evidence of scaffold biodegradation by 3 and 6months. Bone regeneration, assessed using fluorochrome labeling at 3 and 6months, was greatest in animals implanted with the CA-Mel scaffold. Overall, results from this study show that CA-Mel scaffolds were osteoconductive and osteoinductive.