Increasing evidence has shown that macrophage pyroptosis in different tissues participates in chronic aseptic inflammation and is related to tissue fibrosis. Our last studies also revealed the vital role of synovial fibroblast pyroptosis in the onset and development of knee osteoarthritis (KOA). In this study, we aimed to investigate whether synovial macrophage pyroptosis did occur and whether this form of cell death should be related to synovitis and fibrosis of KOA. In the synovial tissue of KOA model rats, we observed a decrease of caspase1, NLRP3, ASC, and GSDMD caused by macrophage depletion in both the mRNA and protein expressions. Besides, rats treated with the specific caspase1 inhibitor Ac-YVAD-CMK showed less inflammatory reaction and fibrosis, not only in the expression of proinflammatory factors IL-1β, IL-18, and HMGB1 and fibrosis markers TGF-β, PLOD2, COL1A1, and TIMP1 but also in the observation of HE staining, Sirius Red staining, and the transverse diameters of the right knees. Subsequently, we established an LPS+ATP-induced model in macrophages mimicking the inflammatory environment of KOA and inducing macrophage pyroptosis. Macrophages transfected with caspase1 siRNA showed reduced cell death; meanwhile, the relative expression of pyroptosis-related proteins were also downregulated. In addition, the level of fibrotic markers in synovial fibroblasts were significantly decreased after coculture with siRNA GSDMD-transfected macrophages. To conclude, synovial macrophage pyroptosis may occur in the pathological processes of KOA and inhibition of synovial macrophage pyroptosis alleviates synovitis and fibrosis in KOA model rats.

Fibroblast-like synoviocytes (FLSs) are the main effector cells of knee osteoarthritis (KOA) synovial fibrosis. Our last report showed that NLRP1 and NLRP3 inflammasomes may mediate LPS/ATP-induced FLSs pyroptosis in KOA. In the present study, we found an elevated hypoxia-inducible factor-1α (HIF-1α) level in the synovial tissue of KOA model rats, and inhibiting the increase of HIF-1α could improve synovial fibrosis in rats. Subsequently, we established LPS/ATP-induced model in FLSs mimicking the inflammatory environment of KOA. FLSs transfected with siRNA HIF-1α showed a reduced cell death; meanwhile, the relative expression of pyroptosis-related proteins was also downregulated. Additionally, FLSs transfected with or without siRNA GSDMD were exposed to hypoxia. GSDMD silencing can significantly reduce both gene and protein levels of fibrogenic markers transforming growth factor-β (TGF-β), procollagen-lysine, 2-oxoglutarate 5-dioxygenase2 (PLOD2), collagen type I α1 chain (COL1A1), and tissue inhibitor of metalloproteinases 1 (TIMP1). Taken together, our findings indicate that increased HIF-1α is highly involved in the KOA synovial fibrosis. Moreover, elevated HIF-1α may aggravate synovial fibrosis via FLS pyroptosis.

Bone changes have always been the focus of research on osteoarthritis, but the number of studies on synovitis has increased only over the last 10 years. Our current understanding is that the mechanism of osteoarthritis involves all the tissues that make up the joints, including nerve sprouting, pannus formation, and extracellular matrix environmental changes in the synovium. These factors together determine synovial fibrosis and may be closely associated with the clinical symptoms of pain, hyperalgesia, and stiffness in osteoarthritis. In this review, we summarize the consensus of clinical work, the potential pathological mechanisms, the possible therapeutic targets, and the available therapeutic strategies for synovial fibrosis in osteoarthritis to gain insight and provide a foundation for further study.

To evaluate the effect of intramedullary nail and locking plate in the treatment of proximal humerus fracture (PHF). China National Knowledge Infrastructure (CNKI), Chinese Scientific Journals Database (VIP), Wan-fang database, Chinese Biomedicine Database (CBM), PubMed, EMBASE, Web of Science, and Cochrane Library were searched until July 2018. The eligible references all show that the control group uses locking plates to treat PHF, while the experimental group uses intramedullary nails to do that. Two reviewers independently retrieved and extracted the data. Reviewer Manager 5.3 was used for statistical analysis. Thirty-eight retrospective studies were referred in this study which involves 2699 patients. Meta-analysis results show that the intramedullary nails in the treatment of proximal humeral fractures are superior to locking plates in terms of intraoperative blood loss, operative time, fracture healing time, postoperative complications, and postoperative infection. But there is no significance in constant, neck angle, VAS, external rotation, antexion, intorsion pronation, abduction, NEER, osteonecrosis, additional surgery, impingement syndrome, delayed union, screw penetration, and screw back-out. The intramedullary nail is superior to locking plate in reducing the total complication, intraoperative blood loss, operative time, postoperative fracture healing time and postoperative humeral head necrosis rate of PHF. Due to the limitations in this meta-analysis, more large-scale, multicenter, and rigorous designed RCTs should be conducted to confirm our findings. PROSPERO CRD42019120508

Background: This study used a network pharmacology approach to elucidate the molecular mechanism governing the effect of Radix Achyranthis Bidentatae (RAB) on osteoarthritis (OA). Methods: Based on oral bioavailability and drug-likeness, the main active components of RAB were screened via the Traditional Chinese Medicine Systems Pharmacology platform. The GeneCard, OMIM, PharmGkb, Therapeutic Targets database, and DrugBank database were used to establish a database of osteoarthritis targets. The interactive active network map of “ingredient-target” was constructed with Cytoscape software (Version 3.7.1). The protein-protein interaction network was constructed with the STRING database, and the related protein interaction relationship was analysed. GO biological function analysis and KEGG enrichment analysis for core targets were performed. Finally, docking of the active components with the core target was carried out. Results: Sixteen active components of RAB were obtained, and 63 potential targets for OA were identified. Network analysis results indicate that these targets are primarily involved in regulating biological processes, such as cell metabolism, apoptosis, and cell proliferation. Pathways involved in the treatment of osteoarthritis include virus-related signalling pathways, apoptosis signalling pathways, IL-17 signalling pathways, and PI3K/AKT signalling pathways. Conclusion: RAB has the characteristics of being multi-system, multi-component and multi-target. Possible mechanisms of action for RAB include regulating the immune and inflammatory responses, reducing chondrocyte apoptosis, and protecting the joint synovial membrane and cartilage to control disease development. The active ingredients in RAB, such as sterols and flavonoids, exhibit strong potential as candidate drugs for the treatment of osteoarthritis.