SAT0561 In Vivo Cartilage-Specific Deletion of Ephrin-B2 in Mice Results in Bone Development Leading to Osteoarthritis Features
Authors: G. Valverde-Franco, B. Lussier, D. Hum, J. Wu, J.-P. Pelletier, M. Kapoor, J. Martel-Pelletier
Journal: Annals of the Rheumatic Diseases (2014)

<h3>Background</h3> Ephrins and their related receptors have been implicated in mediating developmental events. Our group demonstrated that a member of the ephrin family, ephrin-B2, plays a role in osteoarthritis (OA) knee joint pathology [1–3]. However, we do not yet know the role played by this ephrin in musculoskeletal growth and development. <h3>Objectives</h3> This study thus aimed to comprehensively delineate the in vivo role of ephrin-B2 in musculoskeletal growth and development using cartilage-specific ephrin-B2 knockout (ephrin-B2KO<sup>col</sup>) mice. <h3>Methods</h3> Ephrin-B2KO<sup>col</sup> mice were generated by mating collagen II promoter-driven Cre transgenic mice with floxed ephrin-B2 mice (ephrin-B2<sup>f/f</sup>). The skeletal development of the ephrin-B2KO<sup>col</sup> was evaluated using a combination of techniques including macroscopic, histologic, immunohistochemistry, morphometric, radiological, densitometer, and micro-computed tomography (μCT). Analyses were performed on postnatal days (P)0, P15, P21, 8-week and 1-year-old cartilage-specific ephrin-B2KO<sup>col</sup> mice, and ephrin-B2<sup>f/f</sup> littermates were used as controls. <h3>Results</h3> Ephrin-B2KO<sup>col</sup> mice exhibited reduced size postnatally and at P15 and P21 reduced weight (p&lt;0.01) and length (p&lt;0.01). At 8 weeks, ephrin-B2KO<sup>col</sup> mice had significantly shorter femur (p&lt;0.03) and tibia length (p&lt;0.01) and reduced bone mineral density in the total skeleton (p&lt;0.04), femur (p&lt;0.03) and spine (p&lt;0.009). μCT analyses revealed that the distal femur and proximal tibia in ephrin-B2KO<sup>col</sup> mice had decreased bone volume (p&lt;0.03) and trabecular thickness (p&lt;0.02), increased trabecular separation (p&lt;0.05), and reduction in mineralized cartilage matrix at the chondro-osseous junction of the growth plate. At 1 year the ephrin-B2KO<sup>col</sup> mice demonstrated OA features in both knee and hip. The ephrin-B2KO<sup>col</sup> mice exhibited locomotory defects associated with the hip as soon as they walked. Although at 8 weeks the hip of ephrin-B2KO<sup>col</sup> mice displayed abnormalities related to a smaller pelvic bone (p&lt;0.01) and canal width (p&lt;0.03), this was not found at 1 year. Moreover, the proximal femoral head with respect to the acetabular parameters did not show major differences, suggesting that the locomotory defect is not due to a developmental hip abnormality. <h3>Conclusions</h3> 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 long bone alterations, dysregulation of mineralization, and OA features. <h3>References</h3> Kwan Tat, S et al. Arthritis Rheum 2008:58:3820-30. Kwan Tat, S et al. Arthritis Res Ther 2009:11:R119. Valverde-Franco, G et al. Arthritis Rheum 2012:64:3614-25. <h3>Disclosure of Interest</h3> None declared <h3>DOI</h3> 10.1136/annrheumdis-2014-eular.2513