Decreased Bone Formation and Osteopenia in Mice Lacking α‐Calcitonin Gene‐Related Peptide

We recently described an unexpected high bone mass phenotype in mice lacking the Calca gene that encodes CT and αCGRP. Here we show that mice specifically lacking αCGRP expression display an osteopenia caused by a decreased bone formation. These results show that αCGRP is a physiological activator of bone formation and that the high bone mass phenotype of the Calca-deficient mice is caused by the absence of CT. Introduction: Calcitonin (CT) and α-calcitonin gene-related peptide (αCGRP) are two polypeptides without completely defined physiologic functions that are both derived from the Calca gene by alternative splicing. We have recently described an unexpected high bone mass phenotype in mice carrying a targeted deletion of the Calca gene. To uncover whether this phenotype is caused by the absence of CT or by the absence of αCGRP, we analyzed a mouse model, where the production of αCGRP is selectively abolished. Materials and Methods: Bones from Calca−/− mice, αCGRP−/− mice, and their corresponding wildtype controls were analyzed using radiography, μCT imaging, and undecalcified histology. Cellular activities were assessed using dynamic histomorphometry and by measuring the urinary collagen degradation products. CT expression was determined using radioimmunoassay and RT-PCR. Immunohistochemistry was performed using an anti-CGRP antibody on decalcified bone sections. Results: Unlike the Calca-deficient mice, the αCGRP-deficient mice do not display a high bone mass phenotype. In contrast, they develop an osteopenia that is caused by a reduced bone formation rate. Serum levels and thyroid expression of CT are not elevated in αCGRP-deficient mice. While CGRP expression is detectable in neuronal cell close to trabecular bone structures, the components of the CGRP receptor are expressed in differentiated osteoblast cultures. Conclusion: The discrepancy between the bone phenotypes of Calca−/− mice and αCGRP−/− mice show that the high bone mass phenotype of the Calca−/− mice is caused by the absence of CT. The osteopenia observed in the αCGRP−/− mice that have normal levels of CT further show that αCGRP is a physiologic activator of bone formation.