EDIL3 regulates caveolin-1-dependent endothelial permeability in subchondral bone during osteoarthritis

Osteoarthritis (OA) is a major cause of disability worldwide, and pathological alterations in the subchondral bone microenvironment play a critical role in disease progression. Emerging evidence indicates that the extracellular matrix protein EDIL3 is involved in angiogenesis, inflammatory regulation, and cell adhesion, but its role in OA pathogenesis remains unclear. This study aimed to determine whether EDIL3 regulates subchondral vascular permeability and to elucidate its underlying mechanism in OA progression.

A mouse model of OA was established using the destabilization of the medial meniscus (DMM) technique. EDIL3^-/- mice were generated through targeted gene knockout to assess its role in OA development. Histological analysis was performed, alongside the first application of FITC-Dextran fluorescence quantification to assess vascular permeability. Angiogenesis and bone remodeling were also systematically evaluated.

EGF-like repeats and discoidin I-like domains 3 (EDIL3) was markedly upregulated during osteoclasts (OC) differentiation and in early OA subchondral bone. Mechanistically, EDIL3 was found to promoted endothelial permeability and pathological angiogenesis via a caveolin-1-dependent pathway. Notably, EDIL3-deficient mice exhibited protective effects against OA progression, characterized by significantly reduced subchondral vascular permeability, suppression of aberrant angiogenesis, improved bone remodeling dynamics, and marked attenuation of cartilage degeneration.

These findings suggest that EDIL3 functions as an important mediator of pathological vascular permeability and angiogenesis in the subchondral bone during OA progression. Targeting EDIL3 to restore subchondral bone microenvironment homeostasis may represent a novel therapeutic strategy for OA management.