GDF10 attenuates chondral fibrosis and cartilage degeneration in osteonecrosis of the femoral head: Insight into underlying regulatory mechanisms

Osteonecrosis of the femoral head-associated cartilage degeneration (ONFH-ACD) is characterized by fibrocartilaginous remodeling, loss of hyaline matrix, and mechanical impairment, but its regulatory mechanisms remain unclear. We investigated the role of Growth Differentiation Factor 10 (GDF10) in ONFH-ACD. Human ONFH-ACD and control cartilage were analysed using integrated transcriptomic and proteomic profiling. Histology, nanoindentation, and TEM were used to assess structural and biomechanical changes. In ATDC5 chondrocytes, lentiviral GDF10 knockdown or overexpression-combined with SMAD2/3 inhibition (SB-431542) or SMAD1/5/8 inhibition (LDN-193189)-was used to evaluate effects on chondrocyte phenotype, extracellular matrix (ECM) composition, and SMAD signalling balance. Multi-omics and histological analyses revealed a fibrotic ECM phenotype in ONFH-ACD, including increased COL1, decreased COL2 and glycosaminoglycans, collagen disorganization, and mechanical deterioration. GDF10 expression was significantly reduced in ONFH-ACD cartilage and inversely correlated with degeneration severity. GDF10 deficiency in vitro induced chondrocyte dedifferentiation, ECM fibrosis, and upregulation of catabolic enzymes. Conversely, GDF10 overexpression restored hyaline-like matrix synthesis and suppressed fibrotic remodelling. Mechanistically, GDF10 promoted SMAD1/5/8 phosphorylation while restraining SMAD2/3 activation; pharmacologic inhibition confirmed that excessive SMAD2/3 signalling drives the fibrotic phenotype observed with GDF10 loss, whereas SMAD1/5/8 activity is required for GDF10-mediated chondroprotection. GDF10 is an endogenous regulator of chondrocyte homeostasis that suppresses fibrosis and supports hyaline cartilage matrix synthesis by rebalancing SMAD1/5/8 and SMAD2/3 signaling. The GDF10-SMAD axis may represent a therapeutic target in ONFH-ACD.