MicroRNA-21-5p as a novel therapeutic target for osteoarthritis.

OBJECTIVE: Growing evidence indicates that microRNAs (miRNA) play a critical role in the pathogenesis of OA, and overexpressing or silencing miRNA expression in OA models can contribute to the development of miRNA-based therapeutics. The objective of this study was to determine whether intra-articular injection of miRNA can inhibit OA progression. METHODS: The miRNA expression profile was determined in OA cartilage tissues and controls. Functional analysis of the miRNAs on extracellular matrix degradation was performed after miRNA mimic or inhibitor transfection. Luciferase reporter assays and western blotting were employed to determine miRNA targets. To investigate the functional mechanism of miR-21-5p in OA development, miR-21-5pfl/flCol2a1-CreER and wild-type mice were subject to surgical destabilization of the medial meniscus. Therapeutically, wild-type mice undergoing surgical destabilization of the medial meniscus were treated with intra-articular injection of agomir- and antagomir-21-5p. RESULTS: We found that expression of miR-21-5p was significantly up-regulated in OA cartilage tissues. The articular cartilage degradation of miR-21-5p conditional knockout mice was significantly alleviated compared with that of wild-type mice in spontaneous and destabilization of the medial meniscus models. Through gain-of-function and loss-of-function studies, miR-21-5p was shown to significantly affect matrix synthesis genes expression, and chondrocyte proliferation and apoptosis. Further, fibroblast growth factor 18 (FGF18) was identified as a target of miR-21-5p. Intra-articular injection of antagomir-21-5p significantly attenuated the severity of experimental OA. Clinically, FGF18 expression level was correlated with miR-21-5p expression and a modified Mankin scale. CONCLUSION: Our findings reveal a miRNA functional pathway important for OA development, highlighting miRNA-21-5p silencing as an attractive therapeutic regimen in future clinical trials involving patients with OA.

Long non-coding RNA SNHG15 is a competing endogenous RNA of miR-141-3p that prevents osteoarthritis progression by upregulating BCL2L13 expression.

Increasing evidence has demonstrated that the dysregulated expression of long noncoding RNAs (lncRNAs) has important roles in the progression of osteoarthritis (OA), but the function of the lncRNA SNHG15 remains unclear. In the present study, we observed that SNHG15 was downregulated in OA cartilage tissues and IL-1ß-induced chondrocytes. The lower expression of SNHG15 was negatively associated with the observed modified Mankin scale scores, extracellular matrix (ECM) degradation and chondrocyte apoptosis. Downregulated expression of SNHG15 increased chondrocyte viability and decreased chondrocyte apoptosis and ECM degradation in vitro and reduced damage to articular cartilage in vivo. Mechanistically, we demonstrated that SNHG15 overexpression promotes the expression of BCL2L13 by sponging miR-141-3p. The higher expression of miR-141-3p was negatively correlated with SNHG15 and BCL2L13 levels in OA cartilage tissues, and a positive correlation was also shown between SNHG15 and BCL2L13 levels. Furthermore, ectopic expression of miR-141-3p or knockdown of BCL2L13 expression could both reduce the effects of SNHG15 on chondrocyte proliferation, apoptosis and ECM degradation. Collectively, these findings reveal that SNHG15 inhibits OA progression by acting as an miR-141-3p sponge to promote BCL2L13 expression, suggesting that knockdown of SNHG15 expression in chondrocytes can be a potential therapeutic strategy to ameliorate OA progression.

The effect of vitamin D supplementation on knee osteoarthritis: A meta-analysis of randomized controlled trials.

OBJECTIVE: We conducted a meta-analysis of RCTs to evaluate the effects of vitamin D supplementation in the prevention of symptom and structural progression of knee OA. METHODS: PubMed, Embase, and Web of Science databases were searched to identify relevant studies. Outcomes included Western Ontario and McMaster Universities Arthritis Index (WOMAC) pain, function, stiffness, tibial cartilage volume, and serum vitamin D3 levels, and adverse events. Results were expressed as weight mean difference (WMD) with 95% confidence interval (CI), and risk ratio (RR) with 95%CI. RESULTS: Four RCTs involving 1136 patients were included in this study. Pooled estimates suggested that vitamin D supplementation was associated with a significant reduction in WOMAC pain, and WOMAC function, but not in WOMAC stiffness. Vitamin D supplementation increased the serum vitamin D3 level, but had no effect on tibial cartilage volume. Subgroup analysis showed that, a daily supplement of more than 2000 IU vitamin D significantly decreased the WOMAC pain and WOMAC function. There was no significant difference in incidence of adverse events between the vitamin D and placebo groups. CONCLUSION: Vitamin D supplementation was effective in improving the WOMAC pain and function in patients with knee OA. However, it had no beneficial effect on the prevention of tibial cartilage loss. Therefore, there is currently a lack of evidence to support the use of vitamin D supplementation in preventing the progression of knee OA.