YKL-40 alleviates the TNF-α-Induced chondrocyte injury in osteoarthritis in vitro

Osteoarthritis (OA) is a degenerative joint disease with high global prevalence, and YKL-40 is an important factor related to the pathological process of OA. Increased levels of YKL-40 exert a protective influence against TNF-α-induced apoptosis in chondrocytes, thereby enhancing chondrocyte survival and activation, while counteracting TNF-α-driven expression of specific inflammatory mediators such as S100A8/A9.This study aims to evaluate the role and molecular mechanism of YKL-40 on chondrocytes in OA and provide a potential therapeutic avenue requiring further validation. A meta-analysis compared serum YKL-40 and TNF-α levels between OA patients and healthy controls. In vitro experiments examined the effects of YKL-40 on TNF-α-induced OA chondrocytes, assessing proliferation, differentiation, apoptosis, and inflammatory pathways. Meta-analysis revealed significantly elevated serum levels of YKL-40 and TNF-α in osteoarthritis (OA) patients compared to healthy controls. In vitro, TNF-α (10 ng/mL) induced extracellular matrix (ECM) degradation in chondrocytes, significantly reducing glycosaminoglycan (GAG) and type II collagen content. This degradation was effectively rescued by YKL-40 (100 ng/mL). RNA sequencing identified differentially expressed genes in TNF-α-treated chondrocytes, enriched in pathways like IL-17 and NF-κB signaling. YKL-40 treatment reversed the expression of key genes altered by TNF-α. Crucially, these differentially expressed genes (including S100A8/A9, ISG15, CDSN, BAAT, PTPN4, NPTX1, SMARCA1) were validated in independent OA cartilage and synovium GEO datasets. Protein–protein interaction (PPI) networks highlighted central genes within treatment groups. Western blotting confirmed YKL-40 counteracted TNF-α-induced NF-κB pathway activation (reduced p65 and IκBα phosphorylation) and modulated key targets (S100A8/A9, ASB7, ZFPM2), consistent with qRT-PCR data. YKL-40 is a promising biomarker and therapeutic target for OA. Its interplay with TNF-α provides a molecular basis for novel therapies targeting chondrocyte dysfunction, guiding future translational research.