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Tiki2 maintains articular cartilage homeostasis and protects against osteoarthritis by inhibiting Wnt/β-catenin signaling

ABSTRACT: Osteoarthritis (OA) is a serious degenerative joint disease with high morbidity and is currently incurable because of its poorly defined underlying molecular basis. Here, we demonstrated that Tiki2, a membrane-tethered proteolytic Wnt inhibitor, is highly expressed in the articular chondrocytes of hyaline cartilage and that its expression negatively correlates with osteoarthritis. Tiki2 haploinsufficiency in mice causes spontaneous articular cartilage degeneration. Tiki2 deletion in chondrocytes accelerates instability-induced knee joint osteoarthritis progression in mice. Mechanistically, Tiki2 antagonizes Wnt signaling in chondrocytes and maintains chondrocyte anabolic gene expression. Moreover, intra-articular administration of a TIKI2-expressing adeno-associated virus significantly alleviated OA progression in mice, and expressing TIKI2 promoted chondrogenesis and chondrocyte redifferentiation and inhibited hypertrophic differentiation in vitro. Our results reveal the function of Tiki2 in articular cartilage homeostasis and osteoarthritis and suggest that Tiki2 is a potential target for osteoarthritis therapy.

ORGANISM(S): Mus musculus

PROVIDER: GSE302635 | GEO | 2025/07/20

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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Tiki2 maintains articular cartilage homeostasis and protects against osteoarthritis by inhibiting Wnt/β-catenin signaling

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