- Abstract: Urokinase-type plasminogen activator (u-PA) plays an important role in tissue remodelling through the activation of plasminogen in the liver, but its mechanisms are less well known. Here, we investigated the involvement of u-PA in the accumulation and phenotypic heterogeneity of macrophages at the damaged site during liver repair. After induction of liver injury by photochemical reaction in mice, the subsequent pathological responses and expression of phenotypic markers in activated... Show More
- Abstract: To study spatiotemporal differences in vascular permeability, we histologically analysed tracer extravasation, neovessels and reactive astrocytes in a mouse ischaemic brain damage model. On day 1 after damage induction, the extravasation was not associated with the distribution of neovessels or reactive astrocytes. On day 7, the extravasation was limited within the infarct region in which neovessels, but not reactive astrocytes, were observed. However, the extravasation was not observed at... Show More
- Abstract: Fibrinolytic system impairment contributes to the development of thrombotic disease such as cardiovascular disease and stroke. Therefore, an agent that increases fibrinolytic activity may be useful for the prevention of these diseases. In this study, to explore novel profibrinolytic agents, we examined the profibrinolytic effect of Enzamin, an extract of metabolic products from Bacillus subtilis AK and Lactobacillus in vitro and in vivo. Enzamin directly enhanced plasmin activity generated... Show More
- Abstract: Urokinase-type plasminogen activator (u-PA) and plasminogen play a primary role in liver repair through the accumulation of macrophages and alteration of their phenotype. However, it is still unclear whether u-PA and plasminogen mediate the activation of macrophage phagocytosis during liver repair. Herein, we investigated the morphological changes in macrophages that accumulated at the edge of damaged tissue induced by a photochemical reaction or hepatic ischaemia-reperfusion in mice with... Show More
- Abstract: The transforming growth factor (TGF)-β family members, bone morphogenetic protein (BMP)-2 and TGF-β that signal via the receptor-regulated Smads (R-Smads) induce bone formation in vivo. The inhibitory Smads (I-Smads), Smad6 and Smad7, negatively regulate TGF-β family ligand signaling by competing with R-Smads for binding to activated type I receptors, and preventing R-Smad activation, Hence, the I-Smads potentially act as suppressors of bone formation although their effects on phenotypic... Show More
- Abstract: In diabetic patients, the risk of fracture is high because of impaired bone formation. However, the details of the mechanisms in the development of diabetic osteoporosis remain unclear. In the present study, we investigated the role of plasminogen activator inhibitor-1 (PAI-1) in the pathogenesis of type 1 diabetic osteoporosis by using PAI-1-deficient mice. Quantitative computed tomography analysis showed that PAI-1 deficiency protected against streptozotocin-induced bone loss in female... Show More
- Abstract: Aims: We investigated the pathophysiological changes in mice lacking α2-antiplasmin (α2-AP) and plasminogen activator inhibitor type-1 (PAI-1) genes, and elucidated the involvement of these inhibitors for fibrinolysis in immune response. Main methods: The pathophysiological changes induced by a lack of both α2-AP and PAI-1 were investigated using double knockout (KO) mice. The lung, liver, kidney and spleen tissues from α2-AP/PAI-1-double KO mice were compared with those from wild-type... Show More
- Abstract: The further development in research of bone regeneration is necessary to meet the clinical demand for bone reconstruction. Plasminogen is a critical factor of the tissue fibrinolytic system, which mediates tissue repair in the skin and liver. However, the role of the fibrinolytic system in bone regeneration remains unknown. Herein, we investigated bone repair and ectopic bone formation using plasminogen deficient (Plg-/- ) mice. Bone repair of the femur is delayed in Plg-/- mice, unlike that... Show More
- Abstract: Fibrodysplasia ossificans progressiva (FOP) is a skeletal disorder with progressive heterotopic ossification in skeletal muscle. A mutation causing constitutive activation in a bone morphogenetic protein (BMP) type 1 receptor [ALK2(R206H)] is found in most patients with FOP. However, the details in the heterotopic ossification of muscle in FOP and the role of matrix metalloproteinase-10 (MMP-10) in bone remain to be fully elucidated. In the present study, we investigated the role of MMP-10... Show More
- Abstract: Previous studies have suggested some interactions between muscle tissues and bone metabolism. The constitutively activating mutation (R206H) of the BMP type I receptor, activin-like-kinase 2 (ALK2), causes fibrodysplasia ossificans progressiva (FOP), which is characterized by extensive ossifications within muscle tissues. In the present study, we revealed that Tmem176b mRNA levels were upregulated by stable transfection of ALK2 (R206H) in mouse myoblastic C2C12 cells. Transient Tmem176b... Show More
- Abstract: The effects of Enzamin on obesity-related metabolic disorders in obese db/db mice were examined to explore a novel agent for the prevention of insulin resistance. Db/db mice were treated with water containing Enzamin (0·1 and 1·0 %) for 8 weeks from 6 weeks of age. Enzamin treatment at 1·0 %, but not at 0·1 %, significantly decreased the fasting plasma glucose, serum total cholesterol and TAG levels in db/db mice, without affecting body weight gain and body fat composition. Furthermore,... Show More
- Abstract: Type 1 diabetes is associated with an increased fracture risk, an impaired fracture healing, and an increased Vitamin D insufficiency. However, the role of vitamin D in diabetic bone repair process remains unclear. We therefore examined the effects of vitamin D deficiency on the impaired bone repair in streptozotocin (STZ)-induced diabetes using female mice. Diabetes was induced by STZ injection into female mice after feeding with normal or vitamin D-deficient diet for 6 weeks from the age... Show More
- Abstract: We previously demonstrated that plasminogen activator inhibitor-1 (PAI-1), an inhibitor of fibrinolysis, is involved in type 1 diabetic bone loss in female mice. PAI-1 is well known as an adipogenic factor induced by obesity. We therefore examined the effects of PAI-1 deficiency on bone, glucose and lipid metabolism in high fat and high sucrose diet (HF/HSD)-induced obese female mice. Female wild-type (WT) and PAI-1-deficient (KO) mice were fed with HF/HSD or normal diet for 20 weeks from 10... Show More
- Abstract: Previous studies suggest that fracture healing is impaired in diabetes; however, the underlying mechanism remains unclear. Here, we investigated the roles of plasminogen activator inhibitor-1 (PAI-1) in the impaired bone repair process by using streptozotocin (STZ)-induced diabetic female wild-type (PAI-1+/+) and PAI-1-deficient (PAI-1-/-) mice. Bone repair and the number of alkaline phosphatase (ALP)-positive cells at the site of a femoral bone damage were comparable in PAI-1+/+ and... Show More
- Abstract: Fibrodysplasia ossificans progressiva (FOP) is characterized by extensive ossification within muscle tissues, and its molecular pathogenesis is responsible for the constitutively activating mutation (R206H) of the bone morphogenetic protein (BMP) type 1 receptor, activin-like kinase 2 (ALK2). In the present study, we investigated the effects of implanting ALK2 (R206H)-transfected myoblastic C2C12 cells into nude mice on osteoclast formation during heterotopic ossification in muscle and... Show More
- Abstract: Further development in research of bone regeneration is necessary to meet the clinical demand for bone reconstruction. We recently reported that plasminogen is crucial for bone repair through enhancement of vessel formation. However, the details in role of tissue-type plasminogen activator (tPA) and urokinase-type PA (uPA) in the bone repair process still remain unknown. Herein, we examined the effects of PAs on bone repair after a femoral bone defect using tPA-deficient (tPA(-/-)) and... Show More
- Abstract: Long-term use of glucocorticoids (GCs) causes numerous adverse effects, including glucose/lipid abnormalities, osteoporosis, and muscle wasting. The pathogenic mechanism, however, is not completely understood. In this study, we used PAI-1-deficient mice to explore the role of plasminogen activator inhibitor 1 (PAI-1) in GC-induced glucose/lipid abnormalities, osteoporosis, and muscle wasting. Corticosterone markedly increased the levels of circulating PAI-1 and the PAI-1 mRNA level in the... Show More
- Abstract: Macrophages play crucial roles in repair process of various tissues. However, the details in the role of macrophages during bone repair still remains unknown. Herein, we examined the contribution of the tissue fibrinolytic system to the macrophage functions in bone repair after femoral bone defect by using male mice deficient in plasminogen (Plg-/-), urokinase-type plasminogen activator (uPA-/-) or tissue-type plasminogen activator (tPA-/-) genes and their wild-type littermates. Bone repair... Show More
- Abstract: The mechanism of postmenopausal osteoporosis is not fully understood. α2-Antiplasmin (α2-AP) is the primary inhibitor of plasmin in the fibrinolytic system, but is known to have activities beyond fibrinolysis. However, its role in bone metabolism and the pathogenesis of osteoporosis remains unknown. In the current study, we therefore examined the effects of α2-AP deficiency on ovariectomy (OVX)-induced bone loss by using wild-type and α2-AP-deficient mice. Quantitative computed tomography... Show More
- Abstract: Fibrodysplasia ossificans progressiva (FOP) is a disorder of skeletal malformations and progressive heterotopic ossification. The constitutively activating mutation (R206H) of the bone morphogenetic protein type 1 receptor, activin-like kinase 2 (ALK2), is responsible for the pathogenesis of FOP. Although transfection of the causal mutation of FOP into myoblasts enhances osteoclast formation by transforming growth factor-β (TGF-β), the role of osteoclasts in heterotopic ossification is... Show More
Publications citing this author (161)
[Show abstract] [Hide abstract] ABSTRACT: Background Reduced physical activity and increased intake of calorically-dense diets are the main risk factors for obesity, glucose intolerance, and type 2 diabetes. Chronic overnutrition and hyperglycemia can alter gene expression, contributing to long-term obesity complications. While caloric restriction can reduce obesity and glucose intolerance, it is currently unknown whether it can effectively reprogram transcriptome to a pre-obesity level. The present study addressed this question by the preliminary examination of the transcriptional dynamics in skeletal muscle after exposure to overnutrition and following caloric restriction. Results Six male rhesus macaques of 12–13 years of age consumed a high-fat western-style diet for 6 months and then were calorically restricted for 4 months without exercise. Skeletal muscle biopsies were subjected to longitudinal gene expression analysis using next-generation whole-genome RNA sequencing. In spite of significant weight loss and normalized insulin sensitivity, the majority of WSD-induced (n = 457) and WSD-suppressed (n = 47) genes remained significantly dysregulated after caloric restriction (FDR ≤0.05). The MetacoreTM pathway analysis reveals that western-style diet induced the sustained activation of the transforming growth factor-β gene network, associated with extracellular matrix remodeling, and the downregulation of genes involved in muscle structure development and nutritional processes. Conclusions Western-style diet, in the absence of exercise, induced skeletal muscle transcriptional programing, which persisted even after insulin resistance and glucose intolerance were completely reversed with caloric restriction. Electronic supplementary material The online version of this article (doi:10.1186/s12864-017-3799-y) contains supplementary material, which is available to authorized users.
- MIF and PAI-1: Circulating MIF and PAI-1 levels were elevated during WSD and CR, although the significance of these changes remains unclear. MIF has been shown to promote fibroblast survival and collagen synthesis in SM, while PAI-1 levels are increased after long-term glucocorticoid use, which contributed to muscle wasting and IR in miceand is thought to be responsible for SM fibrosis.
[Show abstract] [Hide abstract] ABSTRACT: Gravity changes concurrently affect muscle and bone as well as induce alterations in vestibular signals. However, the role of vestibular signals in the changes in muscle and bone induced by gravity changes remains unknown. We therefore investigated the effects of vestibular lesions (VL) on the changes in muscle and bone induced by 3 g hypergravity for 4 weeks in C57BL/6J mice. Quantitative computed tomography analysis revealed that hypergravity increased muscle mass surrounding the tibia and trabecular bone mineral content, adjusting for body weight in mice. Hypergravity did not affect cortical bone and fat masses surrounding the tibia. Vestibular lesions blunted the increases in muscle and bone masses induced by hypergravity. Histological analysis showed that hypergravity elevated the cross-sectional area of myofiber in the soleus muscle. The mRNA levels of myogenic genes such as MyoD, Myf6, and myogenin in the soleus muscle were elevated in mice exposed to hypergravity. Vestibular lesions attenuated myofiber size and the mRNA levels of myogenic differentiation markers enhanced by hypergravity in the soleus muscle. Propranolol, a β-blocker, antagonized the changes in muscle induced by hypergravity. In conclusion, this study is the first to demonstrate that gravity changes affect muscle and bone through vestibular signals and subsequent sympathetic outflow in mice.
- Quantitative computed tomography (QCT) analysis was performed according to our previous study (Tamura et al. 2014) and the guidelines of the American Society for Bone and Mineral Research (Bouxsein et al. 2010). Briefly, after the mice were euthanized with excess isoflurane , hind limbs of mice were scanned using an X-ray CT system in vivo (Latheta LCT-200; Hitachi Aloka Medical, Tokyo, Japan).
[Show abstract] [Hide abstract] ABSTRACT: Wnt signaling pathways are essential for bone formation. Previous studies showed that Wnt signaling pathways were regulated by miR-375. Thus, we aim to explore whether miR-375 could affect osteogenesis. In the present study, we investigated the roles of miR-375 and its downstream targets. Firstly, we revealed that miR-375-3p negatively modulated osteogenesis by suppressing positive regulators of osteogenesis and promoting negative regulators of osteogenesis. In addition, the results of TUNEL cell apoptosis assay showed that miR-375-3p induced MC3T3-E1 cell apoptosis. Secondly, miR-375-3p targeted low-density lipoprotein receptor-related protein 5 (LRP5), a co-receptor of the Wnt signaling pathways, and β-catenin as determined by luciferase activity assay, and it decreased the expression levels of LRP5 and β-catenin. Thirdly, the decline of protein levels of β-catenin was determined by immunocytochemistry and immunofluorescence. Finally, silence of LRP5 in osteoblast precursor cells resulted in diminished cell viability and cell proliferation as detected by WST-1-based colorimetric assay. Additionally, all the parameters including the relative bone volume from μCT measurement suggested that LRP5 knockout in mice resulted in a looser and worse-connected trabeculae. The mRNA levels of important negative modulators relating to osteogenesis increased after the functions of LRP5 were blocked in mice. Last but not least, the expression levels of LRP5 increased during the osteogenesis of MC3T3-E1, while the levels of β-catenin decreased in bone tissues from osteoporotic patients with vertebral compression fractures. In conclusion, we revealed miR-375-3p negatively regulated osteogenesis by targeting LRP5 and β-catenin. In addition, loss of functions of LRP5 damaged bone formation in vivo. Clinically, miR-375-3p and its targets might be used as diagnostic biomarkers for osteoporosis and might be also as novel therapeutic agents in osteoporosis treatment. The relevant products of miR-375-3p might be developed into molecular drugs in the future. These molecules could be used in translational medicine.
- Mothers against decapentaplegic homolog 7 (SMAD7) binds to Pellino-1 and then inhibits NF-κB activity. SMAD7 blocks the differentiation of osteoblastic cells . All the aforementioned molecules could be used as the indicator of osteogenesis.
[Show abstract] [Hide abstract] ABSTRACT: The hope of selectively targeting cancer cells by therapy and eradicating definitively malignancies is based on the identification of pathways or metabolisms that clearly distinguish "normal" from "transformed" phenotypes. Some tyrosine kinase activities, specifically unregulated and potently activated in malignant cells, might represent important targets of therapy. Consequently, tyrosine kinase inhibitors (TKIs) might be thought as the "vanguard" of molecularly targeted therapy for human neoplasias. Imatinib and the successive generations of inhibitors of Bcr-Abl1 kinase, represent the major successful examples of TKI use in cancer treatment. Other tyrosine kinases have been selected as targets of therapy, but the efficacy of their inhibition, although evident, is less definite. Two major negative effects exist in this therapeutic strategy and are linked to the specificity of the drugs and to the role of the targeted kinase in non-malignant cells. In this review, we will discuss the data available on the TKIs effects on the metabolism and functions of mesenchymal stromal cells (MSCs). MSCs are widely distributed in human tissues and play key physiological roles; nevertheless, they might be responsible for important pathologies. At present, bone marrow (BM) MSCs have been studied in greater detail, for both embryological origins and functions. The available data are evocative of an unexpected degree of complexity and heterogeneity of BM-MSCs. It is conceivable that this grade of intricacy occurs also in MSCs of other organs. Therefore, in perspective, the negative effects of TKIs on MSCs might represent a critical problem in long-term cancer therapies based on such inhibitors.
- BM-MSC subpopulations expressing different patterns of these proteins have been putatively identified, making tremendously complicated a straightforward MSC characterization. SCF and CXCL12 are soluble factors produced by BM mesenchymal sub-population required for HSC maintenance in the hematopoietic niche, while Prx1 is a DNA-interacting protein whose expression occurs only in the mesoderm during embryonic development and only in mesenchymal tissues in adult mice [68, 70]. An additional consideration should be made before discussing further the heterogeneity of BM-MSCs.
[Show abstract] [Hide abstract] ABSTRACT: Aim: Cellular and molecular immunoinflammatory changes in gingival tissues drive alveolar bone loss in periodontitis. Since aging is a risk factor for periodontitis, we sought to identify age-related gingival transcriptome changes associated with bone metabolism in both healthy and in naturally-occurring periodontitis. Materials and methods: Adult (12-16 years) and aged (18-23 years) non-human primates (M. mulatta) (n=24) were grouped into healthy and periodontitis. Gingival tissue samples were obtained and subjected to microarray analysis using the Gene Chip Macaque Genome Array. Gene expression profiles involved in osteoclast/osteoblast proliferation, adhesion, and function were evaluated and compared across and between the age groups. QPCR was also performed on selected genes to validate microarray data. Results: Healthy aged tissues showed a gene profile expression that suggest enhancement of osteoclastic adhesion, proliferation/survival and function (SPP1, TLR4, MMP8, and TFEC) and impaired osteoblastic activity (SMEK3P and SMAD5). The gingival transcriptome in both adult and aged animals with naturally-occurring periodontitis (FOS, IL6, TLR4, MMP9, MMP10 and SPP1 genes) was consistent with a local inflammatory response driving towards bone/connective tissue destruction. Conclusion: A pro-osteoclastogenic gingival transcriptome is associated with periodontitis irrespective of age; however; a greater bone-destructive molecular environment is associated with aging in healthy tissues. This article is protected by copyright. All rights reserved.
- Consistently, aged periodontitis tissues exhibited significantly higher levels of MMP10 and PTK2B than adult diseased tissues. MMP10, besides being a regulator of matrix modelling, plays a role in osteoblast differentiation through BMP signalling (Mao et al. 2013). PTK2B (Protein tyrosine kinase 2 beta/ PYK2) is a calcium dependent tyrosine kinase that regulates reorganization of cytoskeleton, migration, adhesion and bone remodelling (Lakkakorpi et al. 2003 ).
[Show abstract] [Hide abstract] ABSTRACT: Background Systemic sclerosis (SSc) is a connective tissues disease of unknown origin characterized by vascular damage and extensive fibrosis. Recently, we demonstrated that α2-antiplasmin (α2AP) is associated with the development of fibrosis in SSc. We herein investigate the roles of α2AP in vascular dysfunction in SSc. Methods Vascular damage in mice was determined by the levels of blood vessels and blood flow. Vascular functions in vascular endothelial cells (ECs) were determined by the levels of tube formation, cell proliferation, and endothelial junction-associated protein (VE-cadherin and PECAM1) production. ResultsThe administration of α2AP induced vascular damage in mice. Conversely, the α2AP neutralization improved vascular damage in a bleomycin-induced mouse model of SSc. Additionally, we showed that the SSc fibroblast-conditioned media induced the reduction of tube formation, cell proliferation, and endothelial junction-associated protein production in ECs, and that α2AP neutralization improved them. We also examined the mechanisms underlying the effects of α2AP on vascular alteration in SSc and found that α2AP attenuated vascular endothelial growth factor-induced tube formation, cell proliferation, and endothelial junction-associated protein production through the adipose triglyceride lipase/tyrosine phosphatase SHP2 axis in ECs. Conclusion Our findings demonstrate that α2AP is associated with vascular alteration, and that the blocking of α2AP improves vascular dysfunction in SSc.
- Recently, we showed that α2AP is associated with the development of fibrosis in SSc  10]. α2AP is also associated with angiogenesis  , vascular re- modeling , the production of IgG, IgM, and IgE [14, 15], and the recruitment of lymphocytes and neutrophils . These observations suggest that α2AP may be a critical regulator in the pathogenesis of SSc.
[Show abstract] [Hide abstract] ABSTRACT: Bone loss occurs in obesity and cancer-associated complications including wasting. This study determined whether a high-fat diet and a deficiency in monocyte chemotactic protein-1 (MCP-1) altered bone structural defects in male C57BL/6 mice with Lewis lung carcinoma (LLC) metastases in lungs. Compared to non-tumor-bearing mice, LLC reduced bone volume fraction, connectivity density, trabecular number, trabecular thickness and bone mineral density and increased trabecular separation in femurs. Similar changes occurred in vertebrae. The high-fat diet compared to the AIN93G diet exacerbated LLC-induced detrimental structural changes; the exacerbation was greater in femurs than in vertebrae. Mice deficient in MCP-1 compared to wild-type mice exhibited increases in bone volume fraction, connectivity density, trabecular number and decreases in trabecular separation in both femurs and vertebrae, and increases in trabecular thickness and bone mineral density and a decrease in structure model index in vertebrae. Lewis lung carcinoma significantly decreased osteocalcin but increased tartrate-resistant acid phosphatase 5b (TRAP 5b) in plasma. In LLC-bearing mice, the high-fat diet increased and MCP-1 deficiency decreased plasma TRAP 5b; neither the high-fat diet nor MCP-1 deficiency resulted in significant changes in plasma concentration of osteocalcin. In conclusion, pulmonary metastasis of LLC is accompanied by detrimental bone structural changes; MCP-1 deficiency attenuates and high-fat diet exacerbates the metastasis-associated bone wasting.
- In the present study, the high-fat diet increased body adiposity and plasma concentrations of all proinflammatory cytokines quantified including MCP-1 (not in MCP-1-/-mice), PAI-1, TNF-? and leptin. As aforementioned, these cytokines participate in bone metabolism, and their elevations often result in bone loss35]and osteoclastogenesis[30,31]. Thus, elevations of these cytokines likely contributed to the high-fat diet exacerbating bone loss in LLC-bearing mice. Bone remodeling is a highly coordinated process of bone formation and bone resorption.
[Show abstract] [Hide abstract] ABSTRACT: Macrophages play crucial roles in repair process of various tissues. However, the details in the role of macrophages during bone repair still remains unknown. Herein, we examined the contribution of the tissue fibrinolytic system to the macrophage functions in bone repair after femoral bone defect by using male mice deficient in plasminogen (Plg-/-), urokinase-type plasminogen activator (uPA-/-) or tissue-type plasminogen activator (tPA-/-) genes and their wild-type littermates. Bone repair of the femur was delayed in uPA-/- mice until day 6, compared with wild-type (uPA+/+) mice. Number of Osterix-positive cells and vessel formation were decreased in uPA-/- mice at the bone injury site on day 4, compared with those in uPA+/+ mice. Number of macrophages and their phagocytosis at the bone injury site were reduced in uPA-/- and Plg-/-, but not in tPA-/- mice on day 4. Although uPA or plasminogen deficiency did not affect the levels of cytokines, including TNF-α, IL-1β, IL-6, IL-4 and IFN-γ mRNA in the damaged femur, the elevation in CCL3 mRNA levels was suppressed in uPA-/- and Plg-/-, but not in tPA-/- mice. Neutralization of CCL3 antagonized macrophage recruitment to the site of bone injury and delayed bone repair in uPA+/+, but not in uPA-/- mice. Our results provide novel evidence that the tissue fibrinolytic system contributes to the induction of macrophage recruitment and CCL3 at the bone injury site, thereby, leading to the enhancement of the repair process.
- We therefore speculated that uPA might contribute to the regulation of CCL3 levels through IL-13 expression in the damaged femur during bone repair. Macrophages recruited to the site of tissue injury show functional phenotypes regulated by the balance of cytokines, including IFN-γ, TNF-α, IL-4 and IL-13, in the tissue microenviron- ment [4,10,42]. We revealed that macrophage phagocytosis was reduced in uPA-deficient and plasminogen-deficient mice at the damaged site, suggesting that uPA or plasminogen deficiency suppresses the activation of the recruited macrophages at the damaged site of the femur.
[Show abstract] [Hide abstract] ABSTRACT: Osteoporosis and osteoporotic fractures are strongly associated with mortality and morbidity, both in developing and developed countries. Menopause accelerates bone loss due to estrogen deficiency and age-related linear bone loss. We investigated plasminogen activator inhibitor-1 (PAI-1) gene polymorphisms in postmenopausal women with osteoporotic vertebral compression fractures (OVCFs). In this case-control study, 355 postmenopausal women were genotyped for the presence of PAI-1 gene polymorphisms −844A > G, −675 4G > 5G, 43G > A, 9785A > G, and 11053T > G. Genetic polymorphisms of PAI-1 were analyzed by the polymerization chain reaction restriction fragment length polymorphism assay, and their association with disease status and folate and homocysteine levels was determined in 158 OVCF patients and 197 control subjects. The PAI-1 −675 5G5G (adjusted odds ratio (AOR), 3.302; p = 0.017) and 43GA + AA (AOR, 2.087; p = 0.042) genotype frequencies showed significant association with the increased prevalence of OVCFs in postmenopausal women. In addition, we performed gene-environment interaction studies and demonstrated an association between PAI-1 gene polymorphisms and OVCF prevalence. Our novel finding is the identification of several PAI-1 genetic variants that increase susceptibility to OVCF. Our findings suggest that polymorphisms in PAI-1 may contribute to OVCF, and that they can be developed as biomarkers for evaluating OVCF risk.
- A recent study has shown that plasminogen is involved in bone recovery in mice , suggesting that fibrinolysis in tissue might be a crucial factor in bone fracture recovery . Many previous studies have investigated functional PAI-1 in osteoporosis patients [20,21,23]. However, none have reported on the association between PAI-1 polymorphisms and osteoporotic vertebral compression fractures (OVCFs) in postmenopausal women.
[Show abstract] [Hide abstract] ABSTRACT: Mesoporous calcium sulfate-based bone cements (m-CSBC) were prepared by introducing mesoporous magnesium-calcium silicate (m-MCS) with specific surface area (410.9 m2 g21) and pore volume (0.8 cm3 g21) into calcium sulfate hemihydrate (CSH). The setting time of the m-CSBC was longer with the increase of m-MCS content while compressive strength decreased. The degradation ratio of m-CSBC increased from 48.6 w% to 63.5 w% with an increase of m-MCS content after soaking in Tris-HCl solution for 84 days. Moreover, the m-CSBC containing m-MCS showed the ability to neutralize the acidic degradation products of calcium sulfate and prevent the pH from dropping. The apatite could be induced on m-CSBC surfaces after soaking in SBF for 7 days, indicating good bioactivity. The effects of the m-CSBC on vitamin D3 sustained release behaviours were investigated. It was found that the cumulative release ratio of vitamin D3 from the m-CSBC significantly increased with the increase of m-MCS content after soaking in PBS (pH = 7.4) for 25 days. The m-CSBC markedly improved the cell-positive responses, including the attachment, proliferation and differentiation of MC3T3-E1cells, suggesting good cytocompatibility. Briefly, m-CSBC with good bioactivity, degradability and cytocompatibility might be an excellent biocement for bone regeneration. © 2015 The Author(s) Published by the Royal Society. All rights reserved.
- Therefore, with the significantly improved bioactivity, the m-CSBC was expected to form stronger bone-bonding with the surrounding bone tissue by the apatite layer compared with the traditional calcium sulfate cement. Vitamin D 3 can turn into 1,25-(OH) 2 -VitD 3 (active form of vitamin D 3 ) after transformation in kidney and liver in vivo; vitamin D 3 is capable of conditioning the metabolism of Ca and P ions; inducing osteoblast differentiation; and regulating mRNA and protein expression. Animal experiments have proved that 1,25-(OH) 2 -VitD 3 had the ability to treat osteoporosis and repair articular cartilage defects by stimulating osteoblast growth in implants, which is a promising drug to help bone regeneration and accelerate the progress of bone construction. Figure 5. SEM images of apatite formation on CSBC (a, b), 20 m-CSBC (c,d ) and 40 m-CSBC (e,f ) after immersing in SBF for 7 days.
[Show abstract] [Hide abstract] ABSTRACT: LR8 gene was first reported in a subpopulation of cultured human lung fibroblasts expressing the receptor for C1q-globular domain, and it was not detectable in cultured endothelial cells and smooth muscle cells. LR8 mRNA levels were higher in fibrotic lungs. In this study we assessed LR8 production in human tissues and determined if the distribution of fibroblasts producing LR8 is affected in fibrosis. Normal and fibrotic tissue sections from human liver, lung and kidneys were immunostained with antibodies to LR8 and examined for the presence of fibroblasts staining positively and negatively. The cells were also examined for co-expression of α-smooth muscle actin (SMA), a marker for myofibroblasts. The results showed that LR8 was expressed by fibroblasts, smooth muscle cells, endothelial cells, bile duct cells, pulmonary alveolar cells and distal and proximal kidney tubule cells. Connective tissues of normal and fibrotic tissues contained fibroblasts staining positively and negatively with anti- LR8 antibody. The number of LR8-positive cells was higher in fibrotic tissues, but differences were not statistically significant. Fibroblasts producing both LR8 and SMA were present in higher numbers in fibrotic tissues as compared to normal tissues and the differences were statistically significant (p<0.05). Our results show that fibroblast subtypes differing in LR8 expression are present in human tissues, and that in fibrotic tissues cells co-expressing LR8 and SMA are present. Our results indicate that LR8 expressing cells may participate in the early stages of fibrotic diseases and that fibroblasts expressing LR8, not LR8 negative cells, have potential to become myofibroblasts in fibrotic tissues.
- Human LR8 gene is about 12 kb long and contains a 772 base pair long open reading frame. The LR8 protein belongs to the CD-20 superfamily (NCBI Conserved Domain Database), and it appears to be involved in the control of dendritic cell maturation, differentiation of myoblasts into an osteoblast lineage and regulation of immune cells[10,12,13]. LR8 expression is upregulated in human lungs with idiopathic pulmonary fibrosis and bleomycin-induced fibrotic mouse lungs.
[Show abstract] [Hide abstract] ABSTRACT: Fibrodysplasia ossificans progressiva is a rare genetic disorder characterized by progressive heterotopic ossification. FOP patients develop soft tissue lumps as a result of inflammation-induced flare-ups which leads to the irreversible replacement of skeletal muscle tissue with bone tissue. Classical FOP patients possess a mutation (c.617G > A; R206H) in the ACVR1-encoding gene which leads to dysregulated BMP signaling. Nonetheless, not all FOP patients with this mutation exhibit equal severity in symptom presentation or disease progression which indicates a strong contribution by environmental factors. Given the pro-inflammatory role of TGFβ, we studied the role of TGFβ in the progression of osteogenic differentiation in primary dermal fibroblasts from five classical FOP patients based on a novel method of platelet lysate-based osteogenic transdifferentiation. During the course of transdifferentiation the osteogenic properties of the cells were evaluated by the mRNA expression of Sp7/Osterix, Runx2, Alp, OC and the presence of mineralization. During transdifferentiation the expression of osteoblast markers Runx2 (p < 0.05) and Alp were higher in patient cells compared to healthy controls. All cell lines exhibited increase in mineralisation. FOP fibroblasts also expressed higher baseline Sp7/Osterix levels (p < 0.05) confirming their higher osteogenic potential. The pharmacological inhibition of TGFβ signaling during osteogenic transdifferentiation resulted in the attenuation of osteogenic transdifferentiation in all cell lines as shown by the decrease in the expression of Runx2 (p < 0.05), Alp and mineralization. We suggest that blocking of TGFβ signaling can decrease the osteogenic transdifferentiation of FOP fibroblasts.
- However, bone development is a multifactorial process in which angiogenesis and osteoclastogenesis are mutually involved. Angiogenesis is recognized as a feature of pre-osseous FOP lesionswhile recent developments reveal enhanced osteoclastogenesis in response to FOP-related ACVR1 signaling. Future efforts will be focused on the incorporation of these aspects of bone remodeling in this system.