In vivo bone-specific EphB4 overexpression in mice protects both subchondral bone and cartilage during osteoarthritis


Gladys Valverde-Franco PhD, Jean-Pierre Pelletier MD, Hassan Fahmi PhD, David Hum MSc, Koichi Matsuo MD, PhD, Bertrand Lussier DVM, MSc, Dipl. ACVS, Mohit Kapoor PhD, Johanne Martel-Pelletier PhD


In vitro activation of the receptor EphB4 positively impacts human osteoarthritis (OA) articular cell metabolism. However, the specific in vivo role of this ephrin receptor in OA remains unknown. We investigated in mice the in vivo effect of bone-specific EphB4 overexpression on OA pathophysiology. Morphometric, morphological, and radiological evaluations were performed on postnatal day 5 (P5) and on 10-week-old mice. Knee OA was surgically induced (DMM) in 10-week-old male EphB4 homozygous (TgEphB4) and wild-type (WT) mice. Medial compartment evaluations of cartilage were performed using histology and immunohistochemistry, and of subchondral bone using histomorphometry, osteoclast staining, and micro-computed tomography. There was no obvious phenotypic difference in skeletal development between TgEphB4 and WT mice at P5 and 10 weeks. At 8 and 12 weeks post-DMM surgery, TgEphB4 mice demonstrated significantly less cartilage alteration than the WT in the medial tibial plateau and the femoral condyle. This was associated with a significant reduction in the operated TgEphB4 mice of aggrecan and type II collagen degradation products, type X collagen and collagen fibril disorganization. The medial tibial subchondral bone demonstrated at both times post-DMM surgery that, compared to the WT, the TgEphB4 mice had a significant reduction in sclerosis, bone volume, trabecular thickness, and number of tartrate resistant acid phosphatase positive osteoclasts.This is the first in vivo evidence that bone-specific EphB4 overexpression exerts a protective effect on OA joint structural changes. This study stresses the in vivo importance of subchondral bone biology in cartilage integrity.

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