Association between SMAD3 gene polymorphisms and osteoarthritis risk: a systematic review and meta-analysis.

OBJECTIVE: Several studies have been performed to investigate the association between SMAD3 gene polymorphism and osteoarthritis (OA), but the results were inconclusive. This study aims to determine whether SMAD3 polymorphism is associated with risk of OA. METHOD: A comprehensive literature search in PubMed, Embase, and ISI Web of Science for relevant studies was performed. After extracting data from eligible studies, we chose the fixed or random effect model according to the heterogeneity test. Estimation of publication bias and sensitivity analysis were conducted to confirm the stability of this meta-analysis. RESULTS: In total, 10 studies from 6 articles with 5093 OA patients and 5699 controls were enrolled in this meta-analysis. The combined results revealed significant association between SMAD3 rs12901499 polymorphism and the risk of OA (allele model: OR 1.21, 95% CI 1.07-1.38). Subgroup analysis revealed that G allele increased the risk of OA in Caucasians, but not in Asians (allele model: Caucasians: OR 1.31, 95% CI 1.18-1.44; Asians: OR 1.24, 95% CI 0.95-1.61). And the pooled results revealed significant association between SMAD3 rs12901499 polymorphism and both knee and hip OA (knee OA: OR 1.18, 95% CI 1.04-1.34; hip OA: OR 1.31, 95% CI 1.18-1.44). CONCLUSION: The current meta-analysis revealed that the G variant of SMAD3 rs12901499 polymorphism increased the risk of OA in Caucasians. Further well-designed studies with larger sample size in different ethnic populations are required to confirm these results.

A novel anti-osteoporotic agent that protects against postmenopausal bone loss by regulating bone formation and bone resorption.

AIMS: Postmenopausal osteoporosis is a bone metabolism disease that is caused by an imbalance between bone-resorbing osteoclast and bone-forming osteoblast actions. Herein, we describe the role of troxerutin (TRX), a trihydroxyethylated derivative of rutin, in ovariectomy (OVX)-induced osteoporosis and its effects on the regulation of osteoclasts and osteoblasts. MAIN METHODS: In vivo, OVX female mice were intraperitoneally injected with either saline, 50 mg/kg TRX, or 150 mg/kg TRX for 6 weeks and then sacrificed for micro-computed tomography analyses, histological analyses, and biomechanical testing. In vitro, RAW264.7 cell-derived osteoclasts and MC3T3-E1 cell-derived osteoblasts were treated with different concentrations of TRX to examine the effect of TRX on osteoclastogenesis and bone resorption, as well as on osteogenesis and mineralization. KEY FINDINGS: In this study, we demonstrated that TRX prevented cortical and trabecular bone loss in ovariectomized mice by reducing osteoclastogenesis and promoting osteogenesis in vivo. In vitro, TRX inhibited the formation and activity of RAW264.7-derived osteoclasts and the expression of nuclear factor of activated T-cells 1 and cathepsin K. Meanwhile, TRX improved the osteogenesis and mineralization of MC3T3-E1 by enhancing the expression of Runt-related transcription factor 2, Osterix, and collagen type 1 alpha 1. SIGNIFICANCE: Our data demonstrated that TRX could prevent OVX-induced osteoporosis and be used in a novel treatment for postmenopausal osteoporosis.

Cepharanthine Prevents Estrogen Deficiency-Induced Bone Loss by Inhibiting Bone Resorption.

Osteoporosis is a common health problem worldwide caused by an imbalance of bone formation vs. bone resorption. However, current therapeutic approaches aimed at enhancing bone formation or suppressing bone resorption still have some limitations. In this study, we demonstrated for the first time that cepharanthine (CEP, derived from Stephania cepharantha Hayata) exerted a protective effect on estrogen deficiency-induced bone loss. This protective effect was confirmed to be achieved through inhibition of bone resorption in vivo, rather than through enhancement of bone formation in vivo. Furthermore, the in vitro study revealed that CEP attenuated receptor activator of nuclear factor κB ligand (RANKL)-induced osteoclast formation, and suppressed bone resorption by impairing the c-Jun N-terminal kinase (JNK) and phosphatidylinositol 3-kinase (PI3K)-AKT signaling pathways. The inhibitory effect of CEP could be partly reversed by treatment with anisomycin (a JNK and p38 agonist) and/or SC79 (an AKT agonist) in vitro. Our results thus indicated that CEP could prevent estrogen deficiency-induced bone loss by inhibiting osteoclastogenesis. Hence, CEP might be a novel therapeutic agent for anti-osteoporosis therapy.

Sophocarpine attenuates wear particle-induced implant loosening by inhibiting osteoclastogenesis and bone resorption via suppression of the NF-κB signalling pathway in a rat model.

BACKGROUND AND PURPOSE: Aseptic prosthesis loosening, caused by wear particles, is one of the most common causes of arthroplasty failure. Extensive and over-activated osteoclast formation and physiological functioning are regarded as the mechanism of prosthesis loosening. Therapeutic modalities based on inhibiting osteoclast formation and bone resorption have been confirmed to be an effective way of preventing aseptic prosthesis loosening. In this study, we have investigated the effects of sophocarpine (SPC, derived from Sophora flavescens) on preventing implant loosening and further explored the underlying mechanisms. EXPERIMENTAL APPROACH: The effects of SPC in inhibiting osteoclastogenesis and bone resorption were evaluated in osteoclast formation, induced in vitro by the receptor activator of NF-κB ligand (RANKL). A rat femoral particle-induced peri-implant osteolysis model was established. Subsequently, micro-CT, histology, mechanical testing and bone turnover were used to assess the effects of SPC in preventing implant loosening. KEY RESULTS: In vitro, we found that SPC suppressed osteoclast formation, bone resorption, F-actin ring formation and osteoclast-associated gene expression by inhibiting NF-κB signalling, specifically by targeting IκB kinases. Our in vivo study showed that SPC prevented particle-induced prosthesis loosening by inhibiting osteoclast formation, resulting in reduced periprosthetic bone loss, diminished pseudomembrane formation, improved bone-implant contact, reduced bone resorption-related turnover and enhanced stability of implants. Inhibition of NF-κB signalling by SPC was confirmed in vivo. CONCLUSION AND IMPLICATIONS: SPC can prevent implant loosening through inhibiting osteoclast formation and bone resorption. Thus, SPC might be a novel therapeutic agent to prevent prosthesis loosening and for osteolytic diseases.