The neuropeptide calcitonin gene-related peptide alpha is essential for bone healing

Background: Impaired fracture healing represents an ongoing clinical challenge, as treatment options remain limited. Calcitonin gene-related peptide (CGRP), a neuropeptide targeted by emerging anti-migraine drugs, is also expressed in sensory nerve fibres innervating bone tissue. Method: Bone healing following a femoral osteotomy stabilized with an external fixator was analysed over 21 days in alpha CGRP-deficient and WT mice. Bone regeneration was evaluated by serum analysis, mu CT analysis, histomorphometry and genome-wide expression analysis. Bone-marrow-derived osteoblasts and osteoclasts, as well as the CGRP antagonist olcegepant were employed for mechanistic studies. Findings: WT mice with a femoral fracture display increased CGRP serum levels. alpha CGRP mRNA expression after skeletal injury is exclusively induced in callus tissue, but not in other organs. On protein level, CGRP and its receptor, calcitonin receptor-like receptor (CRLR) complexing with RAMP1, are differentially expressed in the callus during bone regeneration. On the other hand, alpha CGRP-deficient mice display pro-foundly impaired bone regeneration characterised by a striking reduction in the number of bone-forming osteoblasts and a high rate of incomplete callus bridging and non-union. As assessed by genome-wide expression analysis, CGRP induces the expression of specific genes linked to ossification, bone remodeling and adipogenesis. This suggests that CGRP receptor-dependent PPAR gamma signaling plays a central role in fracture healing. Interpretation: This study demonstrates an essential role of alpha CGRP in orchestrating callus formation and identifies CGRP receptor agonism as a potential approach to stimulate bone regeneration. Moreover, as novel agents blocking CGRP or its receptor CRLR are currently introduced clinically for the treatment of migraine disorders, their potential negative impact on bone regeneration warrants clinical investigation. (C) 2020 The Author(s). Published by Elsevier B.V.