Background 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.
Objectives 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-B2KOcol) mice.
Methods Ephrin-B2KOcol mice were generated by mating collagen II promoter-driven Cre transgenic mice with floxed ephrin-B2 mice (ephrin-B2f/f). The skeletal development of the ephrin-B2KOcol 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-B2KOcol mice, and ephrin-B2f/f littermates were used as controls.
Results Ephrin-B2KOcol mice exhibited reduced size postnatally and at P15 and P21 reduced weight (p<0.01) and length (p<0.01). At 8 weeks, ephrin-B2KOcol mice had significantly shorter femur (p<0.03) and tibia length (p<0.01) and reduced bone mineral density in the total skeleton (p<0.04), femur (p<0.03) and spine (p<0.009). μCT analyses revealed that the distal femur and proximal tibia in ephrin-B2KOcol mice had decreased bone volume (p<0.03) and trabecular thickness (p<0.02), increased trabecular separation (p<0.05), and reduction in mineralized cartilage matrix at the chondro-osseous junction of the growth plate. At 1 year the ephrin-B2KOcol mice demonstrated OA features in both knee and hip. The ephrin-B2KOcol mice exhibited locomotory defects associated with the hip as soon as they walked. Although at 8 weeks the hip of ephrin-B2KOcol mice displayed abnormalities related to a smaller pelvic bone (p<0.01) and canal width (p<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.
Conclusions 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.
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Disclosure of Interest None declared
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