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

Autor: Melanie Fuchs, Georg N. Duda, Jessika Appelt, Timur A. Yorgan, Serafeim Tsitsilonis, Anke Baranowsky, Johannes Keller, Aarón Herrera, Frank Graef, Michael Amling, Thorsten Schinke, Denise Jahn, Saeed Khomeijani Farahani, Paul Köhli, Ellen Otto, Karl-Heinz Frosch
Rok vydání: 2020
Předmět:
0301 basic medicine
medicine.medical_specialty
Bone Regeneration
Research paper
Callus formation
Calcitonin Gene-Related Peptide
lcsh:Medicine
Gene Expression
Osteoclasts
Olcegepant
Bone healing
Calcitonin gene-related peptide
Bone tissue
Bone and Bones
General Biochemistry
Genetics and Molecular Biology
CRLR
Bone remodeling
Mice
03 medical and health sciences
0302 clinical medicine
Internal medicine
medicine
Animals
Bone regeneration
Fracture Healing
Mice
Knockout
lcsh:R5-920
Osteoblasts
business.industry
lcsh:R
Neuropeptides
X-Ray Microtomography
General Medicine
Immunohistochemistry
PPAR gamma
Disease Models
Animal
Fracture
030104 developmental biology
Endocrinology
medicine.anatomical_structure
030220 oncology & carcinogenesis
RAMP1
αCGRP
Female
lcsh:Medicine (General)
business
Signal Transduction
Zdroj: EBioMedicine
EBioMedicine, Vol 59, Iss, Pp 102970-(2020)
ISSN: 2352-3964
Popis: 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 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. Findings WT 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. Interpretation This 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. Funding This work was funded by grants from the Else-Kroner-Fresenius-Stiftung (EKFS), the Deutsche Forschungsgemeinschaft (DFG), and the Berlin Institute of Health (BIH).
Databáze: OpenAIRE
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