Histone demethylase KDM5C is critical for cartilage development and protects against osteoarthritis by increasing HIF-1α to maintain mitochondrial function.

Objective: With age-related incidence and prevalence, osteoarthritis (OA) is becoming a major source of disability with an increased medical burden worldwide. Lysine Demethylase 5 C (KDM5C) mutation causes abnormalities of epilepsy and short stature. Our previous study has demonstrated KDM5C is indispensable for osteogenesis and bone formation. However, the role of KDM5C in cartilage development and OA remains unknown.

Methods: We used KDM5C chondrocyte-specific knockout mice model to investigate its role in cartilage development and OA. Western blotting, quantitative RT-PCR, immunofluorescence staining, RNA-seq, and immune-precipitation assay were applied to detect the levels of genes or proteins. Destabilization of the medial meniscus (DMM) model was used to investigate the effect of KDM5C overexpression on OA progression.

Results: In this study, we found decreased expression of KDM5C in chondrocytes of murine and human OA samples. Meanwhile, KDM5C was indispensable for chondrogenic differentiation. The RNAseq analysis showed KDM5C knockout impaired mitochondrial function with inhibition of the oxidative phosphorylation, tricarboxylic acid cycle, and hypoxia-inducible factor-1α (HIF-1α) signaling pathway. We further demonstrated that KDM5C interacted with and increased HIF-1α in chondrocytes. The deletion of KDM5C significantly decreased HIF-1α, leading to increased ROS production and impaired mitochondrial function, which finally disturbed cartilage homeostasis and promoted OA progression. Most importantly, intra-articular injection of lentiviral vector expressing KDM5C could inhibit OA progression in mice.

Conclusions: KDM5C plays a critical role in cartilage development and OA progression. It maintains mitochondrial function and articular cartilage homeostasis by increasing HIF-1α.