MiR-337-3p confers protective effect on facet joint osteoarthritis by targeting SKP2 to inhibit DUSP1 ubiquitination and inactivate MAPK pathway.

OBJECTIVE: To probe the performance of miR-337-3p on the facet joint osteoarthritis (FJOA) and its underlying mechanism. METHODS: qRT-PCR and Western blot were utilized to analyze the levels of miR-337-3p and DUSP1 in the synovial tissues from 36 FJOA patients and 10 healthy controls. The human synovial fibroblasts of FJOA were isolated and cultured followed by cell transfection. Then, cells were exposed to 10 ng/mL of IL-1ß to induce inflammatory response of synovial fibroblasts. The alternation on cell biological function in cell models was determined. The binding of miR-337-3p and SKP2 was predicted by StarBase, TargetScan, DIANA-microT and miRmap, and further verified by RIP assay and dual-luciferase reporter assay. Co-IP experiment and ubiquitination assay were used to display the binding of SKP2 and DUSP1 as well as the ubiquitination and degradation of DUSP1. After that, the FJOA rat model was established and miR-337-3p mimic or negative control was given to rats by tail vein injection. The pathological changes of synovial tissues, synovitis score, and inflammation level in rats were assessed. RESULTS: The low expressions of miR-337-3p and DUSP1 were noticed in the synovial tissues of FJOA patients and in IL-1ß-induced synovial fibroblasts, and highly expressed p-p38 MAPK was noticed. Upregulation of miR-337-3p/DUSP1 or downregulation of SKP2 inhibited IL-1ß-induced proliferation and inflammatory response of synovial fibroblasts. SKP2 was the target gene of miR-337-3p, and SKP2 induced the ubiquitination and degradation of DUSP1. MiR-337-3p exerted a protective effect on FJOA rats by alleviating damage of rat synovial tissues, promoting cell apoptosis and repressing inflammatory response. CONCLUSION: MiR-337-3p plays a protective role in FJOA by negatively targeting SKP2 to suppress DUSP1 ubiquitination and inactivate the p38 MAPK pathway.

Cartilage tissue engineering: From proinflammatory and anti­inflammatory cytokines to osteoarthritis treatments (Review).

Osteoarthritis (OA), one of the most common joint diseases, is characterized by fibrosis, rhagadia, ulcers and attrition of articular cartilage due to a number of factors. The etiology of OA remains unclear, but its occurrence has been associated with age, obesity, inflammation, trauma and genetic factors. Inflammatory cytokines are crucial for the occurrence and progression of OA. The intra­articular proinflammatory and anti­inflammatory cytokines jointly maintain a dynamic balance, in accordance with the physiological metabolism of articular cartilage. However, dynamic imbalance between proinflammatory and anti­inflammatory cytokines can cause abnormal metabolism in knee articular cartilage, which leads to deformation, loss and abnormal regeneration, and ultimately destroys the normal structure of the knee joint. The ability of articular cartilage to self­repair once damaged is limited, due to its inability to obtain nutrients from blood vessels, nerves and lymphatic vessels, as well as limitations in the extracellular matrix. There are several disadvantages inherent to conventional repair methods, while cartilage tissue engineering (CTE), which combines proinflammatory and anti­-inflammatory cytokines, offers a new therapeutic approach for OA. The aim of the present review was to examine the proinflammatory factors implicated in OA, including IL­1ß, TNF­α, IL­6, IL­15, IL­17 and IL­18, as well as the key anti­inflammatory factors reducing OA­related articular damage, including IL­4, insulin­like growth factor and TGF­ß. The predominance of proinflammatory over anti­inflammatory cytokine effects ultimately leads to the development of OA. CTE, which employs mesenchymal stem cells and scaffolding technology, may prevent OA by maintaining the homeostasis of pro­ and anti­inflammatory factors.