Authors
Mengyuan Ji, Xinyu Wang, Wentao Zhang, Zihui Xie, Xu Zhu, Hao Xue, Zhao Ding, Yanxun Han, Dapeng Li, Liang Ge, Zhongdong Hu, Xiaojun Zha, Wei Lin
Published in
Biochemical pharmacology. Pages 118553. Oct 17, 2026. Epub Oct 17, 2026.
Abstract
Temporomandibular joint osteoarthritis (TMJ-OA) is a progressive degenerative joint disease characterized by cartilage destruction, extracellular matrix (ECM) degradation, and chronic inflammation, yet effective disease-modifying therapeutic targets and pharmacological interventions remain limited. Using a monosodium iodoacetate (MIA)-induced rat TMJ-OA model and interleukin-1β (IL-1β)-stimulated chondrocytes, we integrated transcriptomic analysis, chromatin accessibility profiling, and molecular screening to elucidate disease mechanisms and identify candidate compounds. Integrated RNA sequencing (RNA-seq) analysis revealed Wnt family member 5a (Wnt5a) as a critical upstream regulator significantly associated with TMJ-OA progression, while assay for transposase-accessible chromatin using sequencing (ATAC-seq) uncovered an inflammatory chromatin landscape characterized by enhanced activator protein-1 (AP-1) activity and JUN-dependent transcriptional regulation ofmatrix metalloproteinase 9 (Mmp9). Mechanistically, Wnt5a activated c-Jun N-terminal kinase (JNK) signaling to promote JUN nuclear accumulation and enhance AP-1-mediatedMmp9transcription, leading to ECM degradation and chondrocyte dysfunction. Structure-based virtual screening and biophysical assays, including surface plasmon resonance (SPR), cellular thermal shift assay (CETSA), and drug affinity responsive target stability (DARTS), identified genistein (GEN) as a small-molecule compound capable of directly binding Wnt5a, supported by cellular target-engagement evidence. Functionally, genistein suppressed the Wnt5a/JNK/JUN/MMP9 signaling axis, partially restored type II collagen (COL2A1) expression, alleviated oxidative stress, and preserved cartilage integrity in TMJ-OA rats. Collectively, these findings establish Wnt5a as a therapeutically actionable driver of TMJ-OA progression and identify genistein as a Wnt5a-targeting compound with cartilage-protective activity, providing a mechanism-based rationale for developing disease-modifying interventions for degenerative joint diseases.
PMID:
42892544
Bibliographic data and abstract were imported from PubMed on 18 Oct 2026.
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