Review The role of calcitonin and a-calcitonin gene-related peptide in bone formation Antje K. Huebner a,b,c , Johannes Keller a,b , Philip Catala-Lehnen a,b , Sandra Perkovic a,b , Thomas Streichert d , Ronald B. Emeson e , Michael Amling a,b , Thorsten Schinke a,b, * a Center of Biomechanics and Skeletal Biology, University Medical Center Hamburg—Eppendorf, Martinistrasse 52, Hamburg 20246, Germany b Department of Trauma, Hand, and Reconstructive Surgery, University Medical Center Hamburg—Eppendorf, Hamburg 20246, Germany c Institute of Clinical Chemistry and Laboratory Diagnostics, Friedrich-Schiller-University, Jena 07740, Germany d Department of Clinical Chemistry, University Medical Center Hamburg—Eppendorf, Hamburg 20246, Germany e Departments of Pharmacology, Molecular Physiology, and Biophysics, Vanderbilt University School of Medicine, Nashville, TN 37232, USA Received 13 December 2007, and in revised form 8 February 2008 Available online 16 February 2008 Abstract The Calca gene encodes two polypeptides, calcitonin (CT) and a-calcitonin gene-related peptide (a-CGRP), generated through alter- native splicing. While CT, a hormone mainly produced by thyroidal C cells, has been described as a major regulator of bone resorption, a-CGRP, a neuropeptide expressed in the cells of the central and peripheral nervous system, is mostly known as a regulator of vascular tone. Surprisingly, the generation and skeletal analyses of two mouse deficiency models has recently uncovered a physiological function for both peptides in the regulation of bone formation. In the first model, where the replacement of exons 2–5 of the Calca gene resulted in the combined deficiency of CT and a-CGRP, an increased bone formation rate (BFR) was observed, whereas decreased BFR was found in the second model, where the introduction of a translational termination codon into exon 5 of the Calca gene resulted in the specific absence of a-CGRP. Ó 2008 Elsevier Inc. All rights reserved. Keywords: Calcitonin; CGRP; Bone formation; Osteoblast; Bone resorption; Osteoclast Bone is a highly dynamic tissue that is constantly remodeled through the activities of bone-resorbing osteo- clasts and bone-forming osteoblasts [1]. Thus, a relative increase of bone resorption over bone formation can lead to progressive loss of bone mass, thereby resulting in a major health problem, namely osteoporosis [2]. Many gene products have been demonstrated to regulate bone remodeling in mice and humans, but in terms of a ther- apeutical approach to treat bone loss disorders, extracel- lular ligands and their receptors are particularly interesting [3]. In this regard, the calcitonin family of secreted polypeptides has gained a lot of attention in the last years, since they were all shown to affect bone cells, and since they bind to G-protein-coupled serpentine receptors that are generally considered to be excellent drug targets [4–7]. Three members of the calcitonin family are discussed in this paper, namely calcitonin (CT 1 ) itself and the cal- citonin gene-related peptides, termed a-CGRP and b- CGRP. CT and a-CGRP are both derived from the Calca gene, but do not share significant sequence homol- ogy after being processed from an inactive precursor 0003-9861/$ - see front matter Ó 2008 Elsevier Inc. All rights reserved. doi:10.1016/j.abb.2008.02.013 * Corresponding author. Address: Center of Biomechanics and Skeletal Biology, University Medical Center Hamburg—Eppendorf, Martinist- rasse 52, Hamburg 20246, Germany. Fax: +49 40 42803 8010. E-mail address: schinke@uke.uni-hamburg.de (T. Schinke). 1 Abbreviations used: CT, calcitonin; a-CGRP, a-calcitonin gene-related peptide; b-CGRP, b-calcitonin gene-related peptide; BFR, bone formation rate; CTRLR, CTR-like receptor; RAMP, receptor activity-modifying protein; Iapp, islet amyloid polypeptide. www.elsevier.com/locate/yabbi Available online at www.sciencedirect.com Archives of Biochemistry and Biophysics 473 (2008) 210–217 ABB