Hypoxia-Inducible Factor-1α Stabilization Alleviates Hypoxia-Induced Temporomandibular Joint Osteoarthritis by Activating MDM2 to Suppression of p53 Signalling.

INTRODUCTION AND AIMS: Temporomandibular joint osteoarthritis (TMJOA) is characterized by cartilage degradation and chronic inflammation. Although hypoxia is recognized to drive the pathological process in osteoarthritis, its underlying mechanisms in TMJOA remain elusive. This study aimed to elucidate the roles of hypoxia and hypoxia-inducible factor-1α (HIF-1α) in TMJOA. METHODS: A rat TMJOA model was established, and a hypoxia probe confirmed a hypoxic niche in condylar cartilage. Primary chondrocytes were exposed to hypoxia, with HIF-1α stabilized by dimethyloxaloylglycine (DMOG) and validated using the p53 agonist NSC-207895. Transcriptomic profiling identified downstream pathways. Coimmunoprecipitation, chromatin immunoprecipitation-qPCR, and proteasome inhibitor MG132 intervention further dissected the ubiquitin-dependent regulatory mechanism between HIF-1α, MDM2, and p53. RESULTS: A hypoxic niche was detected in early TMJOA prior to overt degeneration. Hypoxia strongly induced inflammatory responses and matrix degradation in chondrocytes. Stabilization of HIF-1α by DMOG rescued these catabolic effects in vitro and significantly alleviated TMJOA pathology in vivo. Transcriptomic, pharmacological, and biochemical assays demonstrated that HIF-1α confers chondroprotection via MDM2-mediated suppression of the p53 signalling pathway: stabilized HIF-1α transcriptionally activates Mdm2, promoting p53 ubiquitination and proteasomal degradation to dampen downstream catabolic outputs. CONCLUSIONS: Early TMJOA is accompanied by a pathological hypoxic microenvironment in condylar cartilage. Stabilization of HIF-1α exerts a chondroprotective effect by transcriptionally activating Mdm2 to suppress p53 signalling, thereby reducing hypoxia-induced inflammation and matrix degradation. The HIF-1α/MDM2/p53 axis may serve as a promising therapeutic target for early-stage TMJOA. CLINICAL RELEVANCE: TMJOA lacks effective disease-modifying treatments. Our findings highlight the HIF-1α/MDM2/p53 axis as a novel target, with prolyl hydroxylase inhibitors such as DMOG offering potential for noninvasive early intervention to slow disease progression.