Osteoblast-derived CTGF contributes to detrimental bone-cartilage crosstalk via EGFR/ NF-κB signaling pathway in estrogen-deficiency-induced osteoarthritis

INTRODUCTION: Osteoarthritis (OA) is a prevalent degenerative joint disease, with postmenopausal women being disproportionately affected. Early pathological alterations in subchondral bone remodeling are increasingly recognized as pivotal precursors to articular cartilage degeneration. However, the precise mechanisms by which estrogen deficiency drives this deleterious bone-to-cartilage crosstalk remain poorly understood. OBJECTIVE: This study aimed to elucidate the role of osteoblast-derived Connective Tissue Growth Factor (CTGF) in mediating bone-to-cartilage crosstalk under estrogen-deficient conditions and to delineate the underlying molecular signaling pathways. METHODS: To simulate postmenopausal conditions, we established an estrogen-deficient OA model via bilateral ovariectomy (OVX-OA). Integrated bioinformatic strategies were utilized to screen for potential protein contributors of the osteoblast-chondrocyte interaction and identify candidate upstream transcription factors. Cartilage degeneration was assessed via Safranin O staining and qRT-PCR. The expression of CTGF, EGFR, NF-κB, and cartilage matrix markers was quantified by immunohistochemistry (IHC), qRT-PCR, and western blotting. Immunoprecipitation-mass spectrometry (IP-MS) was employed to characterize the molecular interactome of the identified mediators. RESULTS: We identified CTGF as the key contributor of OVX-osteoblast-induced chondrocyte dysfunction. CTGF knockdown in OVX-osteoblasts reversed the detrimental effects of osteoblasts on chondrocytes. CTGF was found to form a complex with EGFR, activating the EGFR/NF-κB pathway and promoting OA development. Treatment with the CTGF-neutralizing antibody neutralized excessive CTGF activity, significantly attenuating subchondral bone remodeling and alleviating cartilage degeneration. CONCLUSION: Abnormally increased CTGF contributes to detrimental bone-to-cartilage crosstalk following estrogen loss by activating the EGFR/NF-κB axis in chondrocytes. These results delineate CTGF as a critical pathological nexus, the pharmacological sequestration of which may yield potent therapeutic avenues for attenuating estrogen deficiency-induced OA.