Abstract
BackgroundImpaired 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.MethodBone healing following a femoral osteotomy stabilized with an external fixator was analysed over 21 days in αCGRP-deficient and WT mice. Bone regeneration was evaluated by serum analysis, µCT 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.FindingsWT mice with a femoral fracture display increased CGRP serum levels. αCGRP 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, αCGRP-deficient mice display profoundly 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 PPARγ signaling plays a central role in fracture healing.InterpretationThis study demonstrates an essential role of αCGRP 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.FundingThis work was funded by grants from the Else-Kröner-Fresenius-Stiftung (EKFS), the Deutsche Forschungsgemeinschaft (DFG), and the Berlin Institute of Health (BIH).
Highlights
Surgical techniques to treat bone fractures have tremendously improved in the past decades, impaired bone healingThe authors declare no conflicts of interest
In order to assess the role of aCGRP in bone regeneration, we first employed ELISA to measure Calcitonin gene-related peptide (CGRP) levels in the serum of wild type (WT) mice with a femoral fracture stabilized with an external fixator (Fx mice)
Our study shows that CGRP and its receptor are differentially expressed in callus tissue during bone regeneration, and that aCGRP
Summary
Surgical techniques to treat bone fractures have tremendously improved in the past decades, impaired bone healingThe authors declare no conflicts of interest. Including delayed unions and non-unions following injury still represents an ongoing clinical challenge [1]. Nonunions can be observed in up to 15% of patients with fractures, even after state-of-the-art surgical and non-surgical fracture fixation, causing high socioeconomic costs and significantly lowering the quality of life of affected patients [2,3]. As treatment options remain limited, the identification of factors regulating bone repair is of high scientific and clinical interest to provide the best possible care for affected patients [4,5]. 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 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 aCGRP-deficient and WT mice. Bone-marrow-derived osteoblasts and osteoclasts, as well as the CGRP antagonist olcegepant were employed for mechanistic studies
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