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Activation of transforming growth factor‐β (TGF‐β) signaling has been used to enhance healing of meniscal degeneration in several models. However, the exact role and molecular mechanism of TGF‐β signaling in meniscus maintenance and degeneration are still not understood due to the absence of in vivo evidence. In this study, we found that the expression of activin receptor‐like kinases 5 (ALK5) in the meniscus was decreased with the progression of age and/or osteoarthritis induced meniscal degeneration. Col2α1 positive cells were found to be specifically distributed in the superficial and inner zones of the anterior horn, as well as the inner zone of the posterior horn in mice, indicating that Col2α1‐CreERT2 mice can be a used for studying gene function in menisci. Furthermore, we deleted Alk5 in Col2α1 positive cells in meniscus by administering tamoxifen. Alterations in the menisci structure were evaluated histologically. The expression levels of genes and proteins associated with meniscus homeostasis and TGF‐β signaling were analyzed by quantitative real‐time PCR analysis (qRT‐PCR) and immunohistochemistry (IHC). Our results revealed severe and progressive meniscal degeneration phenotype in 3‐ and 6‐month‐old Alk5 cKO mice compared with Cre‐negative control, including aberrantly increased hypertrophic meniscal cells, severe fibrillation, and structure disruption of meniscus. qRT‐PCR and IHC results showed that disruption of anabolic and catabolic homeostasis of chondrocytes may contribute to the meniscal degeneration phenotype observed in Alk5 cKO mice. Thus, TGF‐β/ALK5 signaling plays a chondro‐protective role in menisci homeostasis, in part, by inhibiting matrix degradation and maintaining extracellular matrix proteins levels in meniscal tissues. The expression of activing receptor‐like kinases 5 (Alk5) in the meniscus was decreased with the progression of age and/or osteoarthritis induced meniscal degeneration. Cartilage‐specific deletion of Alk5 gene in meniscus leads to meniscus degeneration by dysregulating the extracellular matrix metabolism and enhancing the hypertrophic differentiation and apoptosis of meniscal chondrocytes. Modulating transforming growth factor‐β signaling could be a potential therapy for delaying meniscal degeneration. [ABSTRACT FROM AUTHOR]

The osteoarthritis ( OA) progression is now considered to be related to inflammation. Anemonin ( ANE) is a small natural molecule extracted from various kinds of Chinese traditional herbs and has been shown to inhibiting inflammation response. In this study, we examined whether ANE could attenuate the progression of OA via suppression of IL-1β/ NF-κB pathway activation. Destabilization of the medial meniscus ( DMM) was performed in 10-week-old male C57 BL/6J mice. ANE was then intra-articularly injected into joint capsule for 8 and 12 weeks. Human articular chondrocytes and cartilage explants challenged with interleukin-1β ( IL-1β) were treated with ANE. We found that ANE delayed articular cartilage degeneration in vitro and in vivo. In particular, proteoglycan loss and chondrocyte hypertrophy were significantly decreased in ANE -treated mice compared with vehicle-treated mice. ANE decreased the expressions of matrix metalloproteinase-13 ( MMP13), A disintegrin and metalloproteinase with thrombospondin motifs 5 ( ADAMTS5), collagen X (Col X) while increasing Aggrecan level in murine with DMM surgery. ANE treatment also attenuated proteoglycan loss in human cartilage explants treated with IL-1β ex vivo. ANE is a potent protective molecule for OA; it delays OA progression by suppressing ECM loss and chondrocyte hypertrophy partially by suppressing IL-1β/ NF-κB pathway activation. [ABSTRACT FROM AUTHOR]

Systemic application of glucocorticoids is an essential anti-inflammatory and immune-modulating therapy for severe inflammatory or autoimmunity conditions. However, its long-term effects on articular cartilage of patients' health need to be further investigated. In this study, we studied the effects of dexamethasone (Dex) on the homeostasis of articular cartilage and the progress of destabilization of medial meniscus (DMM)-induced osteoarthritis (OA) in adult mice. Long-term administration of Dex aggravates the proteoglycan loss of articular cartilage and drastically accelerates cartilage degeneration under surgically induced OA conditions. In addition, Dex increases calcium content in calcified cartilage layer of mice and the samples from OA patients with a history of long-term Dex treatment. Moreover, long term usage of Dex results in decrease subchondral bone mass and bone density. Further studies showed that Dex leads to calcification of extracellular matrix of chondrocytes partially through activation of AKT, as well as promotes apoptosis of chondrocytes in calcified cartilage layer. Besides, Dex weakens the stress-response autophagy with the passage of time. Taken together, our data indicate that long-term application of Dex may predispose patients to OA and or even accelerate the OA disease progression development of OA patients., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Objectives: This study aims to investigate the role and mechanism of FGFR3 in macrophages and their biological effects on the pathology of arthritis., Methods: Mice with conditional knockout of FGFR3 in myeloid cells (R3cKO) were generated. Gait behaviours of the mice were monitored at different ages. Spontaneous synovial joint destruction was evaluated by digital radiographic imaging and μCT analysis; changes of articular cartilage and synovitis were determined by histological analysis. The recruitment of macrophages in the synovium was examined by immunostaining and monocyte trafficking assay. RNA-seq analysis, Western blotting and chemotaxis experiment were performed on control and FGFR3-deficient macrophages. The peripheral blood from non-osteoarthritis (OA) donors and patients with OA were analysed. Mice were treated with neutralising antibody against CXCR7 to investigate the role of CXCR7 in arthritis., Results: R3cKO mice but not control mice developed spontaneous cartilage destruction in multiple synovial joints at the age of 13 months. Moreover, the synovitis and macrophage accumulation were observed in the joints of 9-month-old R3cKO mice when the articular cartilage was not grossly destructed. FGFR3 deficiency in myeloid cells also aggravated joint destruction in DMM mouse model. Mechanically, FGFR3 deficiency promoted macrophage chemotaxis partly through activation of NF-κB/CXCR7 pathway. Inhibition of CXCR7 could significantly reverse FGFR3-deficiency-enhanced macrophage chemotaxis and the arthritic phenotype in R3cKO mice., Conclusions: Our study identifies the role of FGFR3 in synovial macrophage recruitment and synovitis, which provides a new insight into the pathological mechanisms of inflammation-related arthritis., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.)