Targeting EFEMP1 enhances chondrogenesis and inhibits hypertrophic differentiation in a spontaneous osteoarthritis mouse model.

Osteoarthritis (OA) is a degenerative joint disease characterized by progressive cartilage degradation. EGF-containing fibulin-like extracellular matrix protein 1 (EFEMP1) has been implicated in cartilage development and OA pathogenesis, as its expression inhibits chondrogenesis and declines during mesenchymal stem cell differentiation. This study was aimed at investigating the role of EFEMP1 in cartilage regulation and evaluating the therapeutic potential of EFEMP1 inhibition in OA. EFEMP1 knockdown mediated by small interfering RNA (siRNA) was performed in human chondrocyte and mouse preosteoblast cultures. In chondrocytes, EFEMP1 knockdown downregulated hypertrophic markers (MMP-13, COL10A1) and upregulated SOX9 and aggrecan. Furthermore, phosphokinase analysis revealed increased activities of p70S6K, β-catenin, and HSP60. In osteoblasts, EFEMP1 knockdown reduced RUNX2 expression, calcification, and ALP activity. In vivo, STR/ort spontaneous OA mice were treated with EFEMP1-neutralizing antibody to assess cartilage preservation and cytokine modulation. As a result, EFEMP1 antibody treatment increased matrix-producing chondrocytes, improved cartilage integrity, and lowered OARSI scores. It also enhanced SOX9 and COL2A1 expression while suppressing COL10A1. Although no significant changes were observed in subchondral bone parameters, cytokine analysis revealed a chondroprotective effect in the EFEMP1 antibody-treated group. In conclusion, EFEMP1 inhibition promotes chondrogenesis, suppresses chondrocyte hypertrophy, and modulates inflammatory signaling, contributing to cartilage preservation and attenuation of OA progression. These findings identify EFEMP1 as a potential therapeutic target for OA. KEY MESSAGES: EFEMP1 inhibition promotes chondrogenesis and reduces hypertrophic markers, supporting cartilage maintenance and delaying OA progression. EFEMP1 antibody treatment enhances chondroprotective cytokines while suppressing inflammatory cytokines, contributing to joint preservation in OA mice. Despite its beneficial effects on cartilage, EFEMP1 inhibition does not significantly alter subchondral bone parameters, highlighting its selective role in OA pathology.