Wenfeng Xiao

Autophagy in osteoarthritis

Degradation of the articular cartilage is at the centre of the pathogenesis of osteoarthritis (OA), for which age is the major risk factor. Maintaining the chondrocytes in a healthy condition appears to be an important factor for preservation of the entire cartilage and preventing its degeneration. Autophagy, which is an essential cellular homeostatic mechanism for the removal of dysfunctional cellular organelles and macromolecules, is increased by catabolic and nutritional stresses. Autophagy is increased in OA chondrocytes and cartilage, particularly during the initial degenerative phase, to regulate changes in OA-like gene expression through modulation of apoptosis and reactive oxygen species (ROS). In this way, autophagy acts as an adaptive response to protect chondrocytes from various environmental changes, while with gradual cartilage degradation, decreased autophagy is linked with cell death. Rapamycin, which is a specific inhibitor of the mTOR signaling pathway, enhances expression of autophagy regulators and prevents chondrocyte death. In the future, pharmacological activation of autophagy may be an effective therapeutic approach for OA.

MicroRNA-127-5p regulates osteopontin expression and osteopontin-mediated proliferation of human chondrocytes

The aim of this study was to determine the specific microRNA (miRNA) that regulates expression of osteopontin (OPN) in osteoarthritis (OA). The potential regulatory miRNAs for OPN messenger RNA (mRNA) were predicted by miRNA prediction programs. Among eight potential regulatory miRNAs, miR-220b, miR-513a-3p and miR-548n increased, while miR-181a, miR-181b, miR-181c, miR-181d and miR-127-5p decreased in OA patients. miRNA-127-5p mimics suppressed OPN production as well as the activity of a reporter construct containing the 3′-UTR of human OPN mRNA. In addition, mutation of miR-127-5p binding site in the 3′-UTR of OPN mRNA abolished miR-127-5p-mediated repression of reporter activity. Conversely, treatment with miR-127-5p inhibitor increased reporter activity and OPN production. Interestingly, miR-127-5p inhibited proliferation of chondrocytes through OPN. In conclusion, miRNA-127-5p is an important regulator of OPN in human chondrocytes and may contribute to the development of OA.

MALAT1 promotes osteosarcoma development by targeting TGFA via MIR376A

Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) is a long non-coding RNA (lncRNA) that contributes to the initiation and development of many solid tumors, including osteosarcoma (OS). Here, we showed that MALAT1 was increased in human OS cell lines and tissues and promoted OS cell growth, while MALAT1 knockdown suppressed OS cell growth. We also detected downregulation of MIR376A, a suppressor of OS growth, and upregulation of TGFA, a promoter of OS growth, in OS tissues. TGFA expression was positively correlated with MALAT1 expression, and both were negatively correlated with MIR376A expression. There was a direct interaction between MIR376A and MALAT1 via a putative MIR376A binding site within the MALAT1 3′-untranslated region (3′-UTR). There was also a direct interaction between MIR376A and the TGFA 3′-UTR. Thus, MALAT1 may promote OS cell growth through inhibition of MIR376A, leading to increased expression of TGFA. Our results suggest a MALAT1/MIR376A/TGFA axis mediates OS cell proliferation and tumor progression.

MicroRNA-200b acts as a tumor suppressor in osteosarcoma via targeting ZEB1

Osteosarcoma is the most common type of cancer that develops in bone, mainly arising from the metaphysis of the long bones. MicroRNA (miR)-200b has been found to generally act as a tumor suppressor in multiple types of human cancers. However, the detailed role of miR-200b in osteosarcoma still remains to be fully understood. This study aimed to investigate the exact role of miR-200b in the progression of osteosarcoma and the underlying mechanism. Real-time reverse transcription-polymerase chain reaction data showed that miR-200b was significantly downregulated in osteosarcoma tissues compared to their matched adjacent nontumor tissues. Low miR-200b level was associated with the advanced clinical stage and positive distant metastasis. Besides, it was also downregulated in osteosarcoma cell lines (U2OS, Saos2, HOS, and MG63) compared to normal osteoblast cell line NHOst. In vitro study showed that restoration of miR-200b led to a significant decrease in proliferation, migration, and invasion of osteosarcoma cells. Moreover, ZEB1 was identified as a target gene of miR-200b, and its expression levels were negatively mediated by miR-200b in osteosarcoma cells. In addition, ZEB1 was significantly upregulated in osteosarcoma cells compared to the normal osteoblast cell line NHOst, and inhibition of ZEB1 expression also suppressed the proliferation, migration, and invasion in osteosarcoma cells. Finally, we showed that ZEB1 was frequently upregulated in osteosarcoma tissues compared to their matched adjacent normal tissues, and its expression was reversely correlated to the miR-200b levels in osteosarcoma tissues. Based on these findings, our study suggests that miR-200b inhibits the proliferation, migration, and invasion of osteosarcoma cells, probably via the inhibition of ZEB1 expression. Therefore, miR-200b/ZEB1 may become a potential target for the treatment of osteosarcoma.

Comparison between 200 mg QD and 100 mg BID oral celecoxib in the treatment of knee or hip osteoarthritis

This network meta-analysis aimed to investigate the effectiveness and safety of 100 mg BID and 200 mg QD oral celecoxib in the treatment of OA of the knee or hip. PubMed, Embase and Cochrane Library were searched through from inception to August 2014. Bayesian network meta-analysis was used to combine direct and indirect evidences on treatment effectiveness and safety. A total of 24 RCTs covering 11696 patients were included. For the comparison in between the two dosage regimens, 100 mg BID oral celecoxib exhibited a greater probability to be the preferred one either in terms of pain intensity or function at the last follow-up time point. For total gastrointestinal (GI) adverse effects (AEs), both of the two dosage regimens demonstrated a higher incidence compared to the placebo group. Further analyses of GI AEs revealed that only 200 mg QD was associated with a significantly higher risk of abdominal pain when compared with placebo. Furthermore, 100 mg BID showed a significantly lower incidence of skin AEs when compared with 200 mg QD and placebo. Maybe 100 mg BID should be considered as the preferred dosage regimen in the treatment of knee or hip OA.

Effect of epimedium pubescen flavonoid on bone mineral status and bone turnover in male rats chronically exposed to cigarette smoke

BackgroundEpimedii herba is one of the most frequently used herbs in formulas that are prescribed for the treatment of osteoporosis in China and its main constituent is Epimedium pubescen flavonoid (EPF). However, it is unclear whether EPF during chronic exposure to cigarette smoke may have a protective influence on the skeleton. The present study investigated the effect of EPF on bone mineral status and bone turnover in a rat model of human relatively high exposure to cigarette smoke.MethodsFifty male Wistar rats were randomized into five groups: controls, passive smoking groups and passive smoking rats administered EPF at three dosage levels (75, 150 or 300 mg/kg/day) in drinking water for 4 months. A rat model of passive smoking was prepared by breeding male rats in a cigarette-smoking box. Bone mineral content (BMC), bone mineral density (BMD), bone turnover markers, bone histomorphometric parameters and biomechanical properties were examined.ResultsSmoke exposure decreased BMC and BMD, increased bone turnover (inhibited bone formation and stimulated its resorption), affected bone histomorphometry (increased trabecular separation and osteoclast surface per bone surface; decreased trabecular bone volume, trabecular thickness, trabecular number, cortical thickness, bone formation rate and osteoblast surface per bone surface), and reduced mechanical properties. EPF supplementation during cigarette smoke exposure prevented smoke-induced changes in bone mineral status and bone turnover.ConclusionThe results suggest that EPF can prevent the adverse effects of smoke exposure on bone by stimulating bone formation and inhibiting bone turnover and bone resorption.

Cellular aging towards osteoarthritis

Osteoarthritis (OA) is a common form of degenerative joint disease. Aging process is supposed to be a leading predictor for developing OA. In this review, we have discussed the potential roles of aging in OA, a better understanding of which might delay or stop the development and progression of OA. Different cellular signaling mechanisms are involved process of aging that induces age-related changes in chondrocytes. These changes influence the expression of catabolic factors resulting in increased production of matrix metalloproteinases and cytokines, reduced levels of collagen type II and aggrecan synthesis, and increased production of reactive oxygen species (ROS). ROS leads to mitochondrial dysfunction and chondrocyte death, which contributes to the development of OA. Antioxidant supplementation is probably the best way to prevent or delay the age-related OA. Some therapeutic agents like histone deacetylase inhibitors and anti-miR34a agents have been reported to be effective against age-related OA. However, further research is needed to demonstrate the efficacy of these alternative treatment strategies in clinical trials using controlled and prospective studies.

The expression of SIRT1 in articular cartilage of patients with knee osteoarthritis and its correlation with disease severity

BackgroundThe study aims to investigate the expression of SIRT1 in articular cartilage of patients with primary knee osteoarthritis (OA) and its relationship with disease severity.MethodsCartilage tissue samples were collected from 38 knee OA patients and 9 normal healthy controls and then ascribed to normal, mild, moderate, and severe groups on the basis of the improved Mankin grading system. The expression of SIRT1 in articular cartilage was detected by immunohistochemistry and western blots. The expression of p53 and acetylated p53 (Ac-p53) was also measured by western blots.ResultsThe mutual comparisons of the SIRT1 expression levels in all groups have statistical significance except the one between the mild and moderate groups. Moreover, western blot results showed that the SIRT1 was decreased and p53/Ac-p53 were increased in the OA group. The average gray level of SIRT1 increases with the improving grade of the improved Mankin grading system scorers.ConclusionsThe expression of SIRT1 in articular cartilage is negatively associated with severity of knee OA, indicating that SIRT1 may act as a monitoring indicator for determining development and progression of knee OA.

Network Meta-Analysis of Pharmacological Agents for Osteoporosis Treatment and Fracture Prevention

Background and Objective: Osteoporosis afflicts a large number of populations in the world and is featured by systemic impairment of bone mass and strength which may further trigger an increase in the risk of fragile fractures. This network meta-analysis (NMA) is designed to distinguish therapies more preferable than others with respect to efficacy and safety. Methods: We searched the medical literature for relevant studies systematically. Both direct and indirect evidence were synthesized to compare the efficacy, described by odds ratios (OR) and 95% credible intervals (CrI). Moreover, the surface under cumulative ranking curve was calculated to rank probabilities with respect to clinical outcomes. The new non-vertebral fractures, hip and wrist fractures, and adverse events were evaluated in this NMA. Results: Patients treated by alendronate, denosumab, teriparatide were associated with a reduced risk of new non-vertebral fractures compared to those treated by placebo. Alendronate, denosumab and zoledronic acid had better efficacy in preventing hip fractures. With respect to wrist fractures prevention, no significant difference was observed. Zoledronic acid exhibited significantly increased risk of adverse events than placebo, alendronate, denosumab, and raloxifene. According to SUCRA, teriparatide ranked highest in new non-vertebral fractures prevention, etidronate and denosumab balanced safety and efficacy well. Conclusion: In summary, teriparatide appeared to be the most efficacious drug for preventing new non-vertebral fractures, while etidronate and denosumab were preferable for balancing safety and efficacy well.

Alterations of amino acid metabolism in osteoarthritis: its implications for nutrition and health

Osteoarthritis (OA) is a common form of arthritis in humans. It has long been regarded as a non-inflammatory disease, but a degree of inflammation is now recognized as being a vital inducer of subpopulation of OA. Besides inflammation, the establishment and development of OA are associated with alterations in metabolism and profiles of amino acids (AA), including glutamate- and arginine-family AA as well as their related metabolites (e.g., creatinine, hydroxyproline, γ-aminobutyrate, dimethylarginines and homoarginine). Functional AA (e.g., glutamine, arginine, glutamate, glycine, proline, and tryptophan) have various benefits (i.e., anti-inflammation and anti-oxidation) in treatment of inflammation-associated diseases, including OA. Thus, these AA have potential as immunomodulatory nutrients for patients with inflammation-induced OA.