GDF5 reduces MMP13 expression in human chondrocytes via DKK1 mediated canonical Wnt signaling inhibition

Objective: Growth differentiation factor 5 (GDF5) plays a key role in joint development and is genetically linked to osteoarthritis (OA), but its role in maintaining the cartilage extracellular matrix (ECM) remains unclear. Given that activation of the canonical Wnt signaling pathway contributes to cartilage degradation in OA, this study aimed to explore how GDF5 influences Wnt signaling and the expression of ECM-regulating factors in human chondrocytes.

Design: Human chondrocytes were cultured using a pellet mass system and treated with increasing concentrations of GDF5. Expression levels of ECM-modifying enzymes and Wnt pathway inhibitors—dickkopf 1 (DKK1) and frizzled-related protein (FRZB)—were assessed using quantitative PCR. Protein levels of matrix metalloproteinase 13 (MMP13), DKK1, and β-catenin were measured by ELISA. Canonical Wnt signaling was activated using Wnt3a and CHIR-99021, while DKK1 activity was inhibited with the small molecule WAY-262611.

Results: GDF5 treatment suppressed the expression of ECM-degrading enzymes MMP13 and ADAMTS4 and upregulated anabolic genes ACAN and SOX9. GDF5 also inhibited canonical Wnt signaling by inducing the expression of DKK1 and FRZB. Notably, the reduction in MMP13 expression was mediated by DKK1, indicating a functional link between GDF5 and Wnt inhibition.

Conclusion: This study identifies a novel regulatory interaction between GDF5 signaling and the canonical Wnt pathway in human chondrocytes. These findings suggest a potential mechanism by which GDF5 may contribute to cartilage homeostasis and offer insight into the molecular pathways involved in OA progression.

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