Effects of ephrin B1 Gene Ablation in Osteoblasts or Osteocytes on Cortical and Trabecular Bone Morphology

Presentation Number: SAT 347
Date of Presentation: April 1st, 2017

Manish Raisingani*1, Zhongbo Liu2, Tianzhen Han2, Emi Shimizu2 and Shoshana Yakar2
1New York University School of Medicine, New York, NY, 2New York University College of Dentistry, New York, NY

Abstract

Eph receptors belong to a subfamily of receptor tyrosine kinases activated by membrane bound ligands called ephrins. Recent studies have shown that osteoblasts express the EphB4 receptor and it’s ligand ephrinB2 and B1, while osteoclasts express a few members of the ephrinBs, suggesting that these proteins are involved in bone modeling during growth.

Past studies have shown that parathyroid hormone (PTH) stimulates bone modeling via enhanced expression of the insulin-like growth factor-1 (IGF‐I) and the ephrinB2 and EphB4 in osteoblasts.

To define the interactions between PTH/IGF-1/Eph signaling pathways in bone, male mice at 4 weeks of age were injected 80 mcg/kg/day for 5 days. To our surprise we found 3 fold increase in the expression of Ephrin B1 in the femoral cortical shells from male mice, while the expression of ephrinB2 or EphB4 did not differ significantly between PTH treated and untreated groups. Thus, we used the osteoblast- and osteocyte-specific ephrinB1 knockout (KO) mice (using the osteocalcin-cre and the dentin matrix protein (DMP)-1-cre, respectively) to investigate their bone response to intermittent PTH treatment.

We used micro Computer Tomography (CT) to characterize the basal morphology of femurs dissected from male mice. We found decreases in tissue mineral density in cortical bone of the mid-shaft femur in both Osteocalcin-ephrinB1 (1.45 ± 0.05 g/cm3, p=0.01) and DMP-1-ephrinB1 KO mice (1.465 ± 0.05 mg/cm3, p=0.02) as compared to controls (1.64 ± 0.02 mg/cm3). Similarly, we found decreased bone mineral density in the trabecular bone assessed at the distal femur (Osteocalcin-eprinB1 0.147±0.005 p=0.004, DMP-1-ephrinB1 0.175 ± 0.02 p=0.06, and controls 0.248 ± 0.02 mg/cm3). However, cortical and trabecular bone morphology of males did not differ between the groups. Female DMP-ephrinB1 KO mice showed decreased total cross-sectional area (1.14 ± 0.09 vs 1.27±0.06 mm2, p = 0.02), polar moment of inertia (0.12 ± 0.03 vs 0.14± 0.01 mm4, p= 0.03), and marrow area (0.76 ± 0.03 vs 0.86 ± 0.06 mm2, p = 0.03) as compared to control mice with no significant difference in tissue mineral density. Female DMP-ephrinB1 KO mice did not show any trabecular bone phenotype.

Bone anabolic response to intermittent PTH treatment in Osteocalcin-eprinB1 and DMP-1-ephrinB1 KO mice is under investigation.

 

Nothing to Disclose: MR, ZL, TH, ES, SY