Background/Purpose: The ephrins and their related receptors comprise the largest subfamily of receptor protein-tyrosine kinases and have been implicated in mediating developmental events. We have previously demonstrated that a member of the ephrin family, ephrin-B2, plays a role in knee joint pathology associated with osteoarthritis (OA). Specifically, we have shown a deregulation in the production of the receptor EphB4 and its specific ligand ephrin-B2 in human subchondral bone and cartilage, and in vitro activation of this system or in vivo overexpression of EphB4 positively impacts the pathological process of OA. The aim of this study was to comprehensively delineate the in vivo role of ephrin-B2 in musculoskeletal growth and development using cartilage-specific ephrin-B2 knockout mice.

Methods: Cartilage-specific ephrin-B2 knockout (ephrin-B2KO^CRE) mice were generated using the LoxP-Cre system. The effect of ephrin-B2 genetic deletion was evaluated on bone development using a combination of techniques including macroscopic, histologic, morphometric, radiological, densitometer, and micro-computed tomography (micro-CT). Analyses were performed on postnatal days 0, 15, and 21 (P0, P15, P21), on 8-week-old cartilage-specific ephrin-B2KO^CREmice, and in littermates with no Cre as controls.

Results: Data showed that the ephrin-B2KO^CRE mice exhibited developmental defects leading to abnormal locomotory patterns. Ephrin-B2KO^CRE mice at P15 exhibited reduced weight (p<0.002) and length (p<0.01) and, most importantly, limping and dragging of limbs apparent from the time they started to walk (about 2-3 weeks of age). Interestingly, the hip of ephrin‑B2KO^CRE mice displayed abnormalities associated with smaller pelvic width (p<0.03) and hip bones (p<0.01), as well as reduced acetabular rim length (p<0.05) and angle (p<0.05). In addition, ephrin-B2KO^CRE mice had significantly smaller femur (p<0.03) and tibia length (p<0.01) and reduced bone mineral density in the total skeleton (p<0.02), femur (p<0.03) and spine (p<0.04). Micro-CT analyses revealed that the distal femur and proximal tibia in ephrin‑B2KO^CREmice had a significantly decreased bone volume/tissue volume (BV/TV; p<0.03, p<0.02), trabecular thickness (TbTh; p<0.02, p<0.02), and trabecular separation (TbS; p<0.03, p<0.05).

Conclusion: This study was the first to show that in vivo ephrin-B2 is essential for normal bone growth and development and that conditional cartilage-specific ephrin-B2 deficiency leads to significant alterations in hip bones resulting in developmental locomotory defects. The changes in the long bones are probably a secondary effect of the hip loading force abnormalities.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/in-vivo-cartilage-specific-deletion-of-ephrin-b2-in-mice-results-in-developmental-locomotory-defects-associated-with-hip-bone-abnormality/