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

ABSTRACT: Background: 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. Materials and methods: 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. Results: 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. Conclusion: 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.

ORGANISM(S): Oryctolagus cuniculus

PROVIDER: GSE328136 | GEO | 2026/07/01

REPOSITORIES: GEO

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Project description:Osteoarthritis (OA) of the hand is a common disease resulting in pain and impaired function. The pathogenesis of hand OA (HOA) is elusive and models to study it have not been described so far. Culture of chondrocytes is a model to study the development of cartilage degeneration, which is a hallmark of OA and well established in OA of the knee and hip. In the current study we investigated the feasibility human chondrocyte culture derived from proximal interphalangeal (PIP) finger joints of dissecting room cadavers. Index and middle fingers without signs of osteoarthritis were obtained from 30 cadavers using two different protocols. Hyaline cartilage from both articulating surfaces of the proximal interphalangeal (PIP) joint was harvested and digested in collagenase. Cultured chondrocytes were monitored for contamination, viability, and expression of chondrocyte specific genes. Chondrocytes derived from knee joints of the cadavers were cultured under identical conditions. Gene expression comparing chondrocytes from PIP and knee joints was carried out using Affymetrix GeneChip Human 2.0 ST arrays. The resulting differentially expressed genes were validated by real-time PCR and immunohistochemistry.Chondrocytes harvested up to 101 hours after death of the donors were viable. mRNA expression of collagen 2A1, aggrecan and Sox9 was significantly higher in chondrocytes as compared to cultured fibroblasts. Comparison of gene expression by chondrocytes from PIP and knee joints yielded 528 differentially expressed genes. Chondrocytes from the same joint region had a higher grade of similarity than chondrocytes of the same individual. These results were validated using real-time PCR and immunohistochemistry.We demonstrate for the first time a reliable method for culture of chondrocytes derived from PIP joints. PIP chondrocytes show a specific gene expression pattern and could be used as tool to study cartilage degeneration in HOA. Three samples of cultured chondrocytes from knee and proximal interphalangeal finger joints were compared. Gene expression of the four most differentially regulated genes was confirmed by real-time PCR in 10 independent samples.

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

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