Pei Hu’s research while affiliated with West China Hospital of Stomatology and other places

Adiponectin receptor signaling represents a promising therapeutic target for age‐related conditions such as osteoporosis and diabetes. However, the literature presents conflicting evidence regarding the role of adiponectin signaling in bone homeostasis and fracture repair across different health states, ages, and disease conditions. These inconsistencies may arise from the complex endocrine and paracrine feedback mechanisms regulating adiponectin, as well as the variability in adiponectin isoforms and receptor expressions. In this study, we observed differential expression of adiponectin receptors in the bone marrow (BM) of aged mice, characterized by elevated levels of adiponectin receptor 2 and reduced levels of receptor 1, as corroborated by both single‐cell sequencing and in vivo staining. Additionally, circulating levels of adiponectin and its local expression were significantly higher in aged mice compared to younger counterparts. Treatment with adiponectin receptor agonist, AdipoRon, enhanced bone regeneration and repair in young mice by promoting osteogenesis and reducing osteoclastogenesis. Conversely, in aged mice, AdipoRon treatment led to cellular senescence, delayed bone repair, and inhibited osteogenic activity. Notably, the adiponectin receptor 1‐Wnt and adiponectin receptor 2‐MAPK and mTOR signaling pathways were differentially activated in AdipoRon‐treated BM mesenchymal stem cells from young and aged mice. Additionally, the NF‐κB, and AKT pathways were consistently downregulated in BM macrophages of both age groups following AdipoRon administration. In conclusion, aging significantly modulates the impact of adiponectin receptor signaling on BM mesenchymal stem cells. This modulation is potentially attributable to changes in receptor transcription and distribution, as well as differential activation of downstream signaling pathways.

Advanced glycation end products (AGEs) are a diverse range of compounds that are formed when free amino groups of proteins, lipids, and nucleic acids are carbonylated by reactive carbonyl species or glycosylated by reducing sugars. Hyperglycemia in patients with diabetes can cause an overabundance of AGEs. Excess AGEs are generally acknowledged as major contributing factors to the development of diabetic complications because of their ability to break down the extracellular matrix directly and initiate intracellular signaling pathways by binding to the receptor for advanced glycation end products (RAGE). Inflammation and oxidative stress are the two most well-defined pathophysiological states induced by the AGE–RAGE interaction. In addition to oxidative stress, AGEs can also inhibit antioxidative systems and disturb iron homeostasis, all of which may induce ferroptosis. Ferroptosis is a newly identified contributor to diabetic complications. This review outlines the formation of AGEs in individuals with diabetes, explores the oxidative damage resulting from downstream reactions of the AGE-RAGE axis, and proposes a novel connection between AGEs and the ferroptosis pathway. This study introduces the concept of a vicious cycle involving AGEs, oxidative stress, and ferroptosis in the development of diabetic complications.

The Hippo signaling pathway inhibits cell growth, and its components and functions are highly conserved in mammals. LATS1 is a core component of the Hippo signaling pathway associated with lymphatic invasion, astrogliosis, apoptosis, and autophagy. Nevertheless, the role of Hippo/LATS1 in osteogenesis remains unclear. Here, we used ribonucleic acid (RNA) lentiviruses to inhibit the expression of Lats1 in bone marrow-derived stem cells (BMSCs) and distraction osteogenic regions in rats. Increased osteogenic, proliferative, and migratory abilities of BMSCs were observed in Lats1-inhibited BMSCs, while these phenotypes were partially reversed by YAP1 inhibition. In vivo, we found that the LATS1/YAP1 axis promoted osteogenesis during distraction osteogenesis (DO). β-catenin was positively correlated with YAP1 expression in vivo and in vitro. When YAP1 was strongly positive in the nucleus, β-catenin expression was upregulated; when YAP1 expression was inhibited by verteporfin, β-catenin was not expressed in the nucleus. These findings suggest that the LATS1/YAP1 signaling axis promotes DO by activating the Wnt/β-catenin signaling pathway. This study provides insights into osteogenesis's molecular mechanism and a potential therapeutic strategy for bone regeneration in DO by associating with LATS1/YAP1-β-catenin.

Senile osteoporotic fracture has aroused increasing attention due to high morbidity and mortality. However, to date, there is no effective therapeutic approach available. Senile osteoporosis is characterized by impaired osteogenesis and angiogenesis, osteoporotic fracture repair could also be promoted by enhancing osteogenesis and angiogenesis. Tetrahedral framework nucleic acids (tFNAs) are a multifunctional nanomaterial that have recently been extensively used in biomedical fields, which could enhance osteogenesis and angiogenesis in vitro. Therefore, we applied tFNAs to intact and femoral fractural senile osteoporotic mice, respectively, to evaluate the effects of tFNAs on senile osteoporosis and osteoporotic fracture repair regarding the osteogenesis and angiogenesis of the callus at the early healing stages and to initially explore the potential mechanism. The outcomes showed that tFNAs had no significant effects on the osteogenesis and angiogenesis of the femur and mandible in intact senile osteoporotic mice within 3 weeks after tFNA treatment, while tFNAs could promote osteogenesis and angiogenesis of callus in osteoporotic fracture repair, which may be regulated by a FoxO1-related SIRT1 pathway. In conclusion, tFNAs could promote senile osteoporotic fracture repair by enhancing osteogenesis and angiogenesis, offering a new strategy for the treatment of senile osteoporotic fracture.

Introduction: Osteoporosis invariably manifests as loss of bone, which is replaced by adipose tissue; this can easily lead to fractures, accompanied by delayed and poor healing. Adiponectin (APN) balances osteogenesis and adipogenesis in bone marrow mesenchymal stem cells (BMSCs). Therefore, this study explored whether adiponectin promotes bone fracture healing by regulating the balance between osteogenesis and adipogenesis. Materials and methods: We used adenovirus overexpression vectors carrying APN (Ad-APN-GFP) to treat ovariectomized (OVX) mouse BMSCs and osteoporotic bone fractures to investigate the role of APN in bone microenvironment metabolism in osteoporotic fractures. We subsequently established an OVX mice and bone fracture model using Ad-APN-GFP treatment to investigate whether APN could promote bone fracture healing in osteoporotic mice. Results: The experimental results showed that APN is a critical molecule in diverse differentiation directions in OVX mouse BMSCs, with pro-osteogenesis and anti-adipogenesis properties. Importantly, our study revealed that Ad-APN-GFP treatment facilitates bone generation and healing around the osteoporotic fracture ends. Moreover, we identified that Sirt1 and Wnt signaling were closely related to the pro-osteogenesis and anti-adipogenesis commitment of APN in OVX mouse BMSCs and femoral tissues. Conclusion: We demonstrated that APN overexpression facilitates bone fracture healing in osteoporosis. Furthermore, APN overexpression promoted bone formation in OVX mouse BMSCs and bone fracture ends by regulating the balance between osteogenesis and adipogenesis both in vitro and in vivo.

The cover image is based on the Original Article An adiponectin receptor agonist promote osteogenesis via regulating bone-fat balance by Hanghang Liu et al., https://doi.org/10.1111/cpr.13035.

Objectives Adiponectin signalling has been considered to be a promising target to treat diabetes‐related osteoporosis. However, contradictory results regarding bone formation were observed due to the various isoforms of adiponectin. Therefore, it would be necessary to investigate the effect of adiponectin receptor signals in regulating bone‐fat balance. Materials and Methods We primarily applied a newly found specific activator for adiponectin receptor, AdipoRon, to treat bone metabolism‐related cells to investigate the role of Adiponectin receptor signals on bone‐fat balance. We then established femur defect mouse model and treated them with AdipoRon to see whether adiponectin receptor activation could promote bone regeneration. Results We found that AdipoRon could slightly inhibit the proliferation of pre‐osteoblast and pre‐osteoclast, but AdipoRon showed no effect on the viability of mesenchymal stromal cells. AdipoRon could remarkably promote cell migration of mesenchymal stromal cells. Additionally, AdipoRon promoted osteogenesis in both pre‐osteoblasts and mesenchymal cells. Besides, AdipoRon significantly inhibited osteoclastogenesis via its direct impact on pre‐osteoclast and its indirect inhibition of RANKL in osteoblast. Moreover, mesenchymal stromal stems cells showed obviously decreased adipogenesis when treated with AdipoRon. Consistently, AdipoRon‐treated mice showed faster bone regeneration and repressed adipogenesis. Conclusions Our study demonstrated a pro‐osteogenic, anti‐adipogenic and anti‐osteoclastogenic effect of adiponectin receptor activation in young mice, which suggested adiponectin receptor signalling was involved in bone regeneration and bone‐fat balance regulation.

Facial asymmetry is a common maxillofacial deformity which requires surgery to recover the 3-dimensional relationship of bones. The computer-aided design and computer-aided manufacturing (CAD/CAM) has been developed and applied to improve orthognathic analysis and surgery design. How to accurately realize the preoperative design of orthognathic surgery with CAD/CAM occlusal splints during operation remains a big problem. In this study, 24 consecutive patients with facial asymmetry were recruited and assigned to 2 groups. For Group A, CAD/CAM was applied to designing and producing not only the occlusal splints, but also the drilling guiding templates and pre-bent titanium plates, and for Group B CAD/CAM was applied for occlusal splints only. Postoperative clinical examinations, symmetry evaluation through 3D cephalometric analysis, accuracy comparison using color distance maps and quantitative accuracy analysis were performed. Symmetry evaluation showed that patients of both groups achieved improved facial symmetry after surgery. The color distance maps and quantitative accuracy analysis together demonstrated significantly less difference found between virtual simulated surgery and postoperative CT scan data in Group A than in Group B. In conclusion, by navigation with the drilling guiding templates and pre-bent titanium plates, the facial symmetry for patients with facial asymmetry was successfully restored after orthognathic surgery, same as applying CAD/CAM occlusal splints only. However, the drilling guiding templates and pre-bent titanium plates would provide a more accurate performance according to preoperative simulation, especially for proximal mandibular segments.

Background/purpose: Mechanical stretch plays a key role in promoting proliferation and differentiation of bone marrow mesenchymal stem cells (BMSCs) in distraction osteogenesis (DO). A better understanding of how the extracellular biomechanical stimulation is transferred to intracellular signal expression will benefit DO. Focal adhesion kinase (FAK) is a key factor in integrin signaling pathway. However, little is known about the effect of integrin-FAK signaling during the process of stretch induced osteogenic differentiation of BMSCs. Materials and methods: A specific short hairpin RNAs (shRNAs) lentiviral expression vector was used to silence Fak gene and a well-established in vitro uniaxial dynamic stretching device was applied to stimulate DO. Fak silencing was confirmed by fluorescence microscopy and the detection of Fak mRNA and FAK, p-FAK protein expression. Alkaline phosphatase (ALP) activity, expression of osteogenic differentiation markers - runt-related transcription factor 2 (RUNX2/Runx2) and alkaline phosphatase (Alp) together with integrin upstream signal transduction molecules integrin beta-1 (ITGB1/Itgb1) and downstream signal transduction molecules integrin-linked kinase (ILK) were detected after the stretch. Results: The results showed that mechanical stretch in control groups significantly induced the osteogenic differentiation of BMSCs with increased ALP activity, expression of RUNX2/Runx2 and Alp, together with upregulated ITGB1/Itgb1 and ILK, which all vanished in Fak silencing group. Conclusion: Silencing of the Fak gene inhibited the osteogenic differentiation of rat BMSCs induced by in vitro mechanical stretch through integrin signaling pathway.