Therapeutic potential of CHI3L1 in osteoarthritis: Inhibition of cartilage matrix degradation and inflammation through TLR4-MAPK-STAT1 pathway

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AIMS: CHI3L1 has been identified as a protein expressed in various tissues and tumor tissues, playing critical roles in diverse physiological and pathological processes such as inflammation, oxidative stress, cell death, and immune regulation. Previous studies have indicated that the elevated CHI3L1 levels in synovial fluid and serum of osteoarthritis patients may serve as a biomarker for osteoarthritis. However, the mechanisms by which CHI3L1 affects chondrocytes and the significance of its upregulated expression remain to be fully elucidated. This study aims to investigate the effects of CHI3L1 on chondrocytes and elucidate its molecular mechanisms. METHODS: Interleukin-1 beta (IL-1β) was utilized in vitro to induce an inflammatory injury model in chondrocytes. The destabilization of the medial meniscus (DMM) surgery was employed to establish a mouse model of osteoarthritis in vivo. Experimental techniques, including Western blot, RT-qPCR, immunofluorescence, transcriptome sequencing, and co-immunoprecipitation, were applied to investigate the effects and mechanisms of CHI3L1 on chondrocytes. Microcomputed tomography (micro-CT), X-ray imaging, and IHC were used to evaluate the impact of CHI3L1 on knee joint osteoarthritis in mice. RESULTS: In vitro experiments demonstrated that CHI3L1 enhanced matrix synthesis markers, suppressed matrix degradation indicators, and reduced inflammatory factors levels in chondrocytes. In vivo studies showed that intra-articular overexpression of CHI3L1 via rAAV-Chi3l1 alleviated cartilage degeneration and synovial inflammation in a murine osteoarthritis model. Mechanistically, integrated transcriptomic profiling and functional assays revealed that CHI3L1 interacts with TLR4 to attenuate MAPK phosphorylation, thereby inhibiting STAT1 phosphorylation and nuclear translocation. CONCLUSION: The expression of CHI3L1 is upregulated in osteoarthritis. CHI3L1 alleviates osteoarthritis inflammation and cartilage matrix degradation through the TLR4-MAPK-STAT1 pathway, thereby inhibiting the progression of osteoarthritis. These findings indicate that CHI3L1 is a cytokine with protective effects in osteoarthritis and may represent a promising therapeutic target for alleviating osteoarthritis. ARTICLE FOCUS: The objective of this study is to investigate the effects of CHI3L1 on chondrocytes and to further elucidate the underlying mechanisms by which CHI3L1 exerts its influence on chondrocytes. KEY MESSAGES: In this study, it is proposed that CHI3L1 maintains the homeostasis of the cartilage matrix and alleviates inflammation by inhibiting the activation of the TLR4-MAPK-STAT1 signaling pathway. STRENGTHS AND LIMITATIONS: We have established the protective role of CHI3L1 in maintaining cartilage matrix homeostasis, identified potential receptors and pathways associated with CHI3L1, and elucidated its mechanisms of action. The role of CHI3L1 in osteoarthritic synovial tissue has not yet been investigated. Further research is needed to elucidate the effects of CHI3L1 secreted by synovial tissue on chondrocytes.

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