Background Osteoarthritis (OA) is characterized by progressive joint destruction including synovial membrane inflammation and abnormalities including fibrosis. Members of the Eph/ephrin family, the EphB4 receptor and its specific ligand ephrin-B2, were found to positively impact the abnormal structure and metabolism of OA subchondral bone and cartilage(1,2). An in vivo study(3) on overexpression of EphB4 in bone demonstrated a protective effect on the subchondral bone and cartilage during OA.
Objectives We further investigated, in vivo, the effect of bone-specific EphB4 overexpression on synovial membrane during OA.
Methods Knee OA was surgically induced by destabilization of the medial meniscus (DMM) in 10-week-old male bone-specific EphB4 homozygous (TgEphB4) and wild-type (WT) mice. Synovial membrane evaluation was performed at 12 weeks post-surgery using histology and immunohistochemistry. Factors including fibrotic markers and signaling molecules were determined by real-time PCR, immunohistochemistry, and Western blot.
Results Data demonstrated a significant decrease in synovial membrane thickness (p≤0.02), pro-collagen type I (p≤0.01), and fibrin (p≤0.04) in DMM-TgEphB4 compared to DMM-WT. The expression levels of the fibrotic markers connective tissue growth factor (CTGF, p≤0.02), smooth muscle actine α (SMAα, p≤0.03) and serum cartilage oligomeric matrix protein (COMP, p≤0.03) were significantly reduced in DMM-TgEphB4 compared with DMM-WT. Although TGF-β was decreased in the DMM-TgEphB4 mice, the difference did not reach statistical significance. However, the level of TGF-β signaling profibrotic members, TGFR1/ALK1, pSmad-1 and a member of the heat shock protein family, HSP90β, known to play a crucial role in enhancing TGF-β signaling, were all significantly decreased (p≤0.04) in DMM-TgEphB4.
Conclusions This is the first in vivo evidence that protecting the subchondral bone prophylactically reduces the severity of structural and pathological changes in the synovial membrane during the OA process. Moreover, overexpression of bone-specific EphB4 in mice clearly demonstrated a downregulation of profibrotic members of TGF-β signaling in synovial membrane, thereby preventing the development and/or progression of fibrosis in this OA tissue. This study stresses the in vivo importance of subchondral bone structure/biology in OA joints.
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Disclosure of Interest None declared