It is well known that the epidermal growth factor receptor (EGFR), its ligands, and the structurally related receptor ERBB2/neu are expressed in skeletal cells. However, the functions of EGFR ligands in bone cells remain poorly defined. In this study, we employed a transgenic mouse line overexpressing the EGFR ligand amphiregulin (AREG) specifically in osteoblasts under the α1(I)-collagen promoter. AREG-tg mice did not show changes in body weight or gross phenotype. Compared to WT littermates, expression of AREG mRNA was 94-fold higher in femurs of 4-week-old AREG-tg mice. pQCT analysis of the femoral metaphysis revealed increased trabecular BMD in AREG-tg mice at 4, 8, and 10 weeks of age. However, the high bone mass phenotype was transient and disappeared in 20- and 72-week-old animals. Micro-CT analysis of the secondary spongiosa confirmed increased trabecular BMD, trabecular bone volume and trabecular number in the distal femur of 4-week-old AREG-tg mice as compared to WT controls. Furthermore, μ-CT analysis of the primary spongiosa did not show evidence of alterations in the production of new bone trabeculae in distal femora of AREG-tg mice. Histomorphometric analysis revealed a reduced number of osteoclasts in 4-week-old AREG-tg mice, but not at later time points. Cancellous bone formation rate remained unchanged in AREG-tg mice at all time points. In addition, bone mass and bone turnover in lumbar vertebral bodies were similar in AREG-tg and WT mice at all ages examined. Proliferation and differentiation of osteoblasts isolated from neonatal calvariae did not differ between AREG-tg and WT mice. Taken together, these data suggest that AREG overexpression in osteoblasts leads to a transient high bone mass phenotype in the trabecular compartment of the appendicular skeleton by a growth-related, non-cell autonomous mechanism, leading to a positive bone balance with unchanged bone formation and lowered bone resorption.
17 May 2014 - 20 May 2014