Cargando…
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 healin...
Autores principales: | , , , , , , , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Elsevier
2020
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7452713/ https://www.ncbi.nlm.nih.gov/pubmed/32853990 http://dx.doi.org/10.1016/j.ebiom.2020.102970 |
_version_ | 1783575212597444608 |
---|---|
author | Appelt, Jessika Baranowsky, Anke Jahn, Denise Yorgan, Timur Köhli, Paul Otto, Ellen Farahani, Saeed Khomeijani Graef, Frank Fuchs, Melanie Herrera, Aarón Amling, Michael Schinke, Thorsten Frosch, Karl-Heinz Duda, Georg N. Tsitsilonis, Serafeim Keller, Johannes |
author_facet | Appelt, Jessika Baranowsky, Anke Jahn, Denise Yorgan, Timur Köhli, Paul Otto, Ellen Farahani, Saeed Khomeijani Graef, Frank Fuchs, Melanie Herrera, Aarón Amling, Michael Schinke, Thorsten Frosch, Karl-Heinz Duda, Georg N. Tsitsilonis, Serafeim Keller, Johannes |
author_sort | Appelt, Jessika |
collection | PubMed |
description | 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-Kröner-Fresenius-Stiftung (EKFS), the Deutsche Forschungsgemeinschaft (DFG), and the Berlin Institute of Health (BIH). |
format | Online Article Text |
id | pubmed-7452713 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Elsevier |
record_format | MEDLINE/PubMed |
spelling | pubmed-74527132020-09-02 The neuropeptide calcitonin gene-related peptide alpha is essential for bone healing Appelt, Jessika Baranowsky, Anke Jahn, Denise Yorgan, Timur Köhli, Paul Otto, Ellen Farahani, Saeed Khomeijani Graef, Frank Fuchs, Melanie Herrera, Aarón Amling, Michael Schinke, Thorsten Frosch, Karl-Heinz Duda, Georg N. Tsitsilonis, Serafeim Keller, Johannes EBioMedicine Research paper 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-Kröner-Fresenius-Stiftung (EKFS), the Deutsche Forschungsgemeinschaft (DFG), and the Berlin Institute of Health (BIH). Elsevier 2020-08-24 /pmc/articles/PMC7452713/ /pubmed/32853990 http://dx.doi.org/10.1016/j.ebiom.2020.102970 Text en © 2020 The Author(s) http://creativecommons.org/licenses/by/4.0/ This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Research paper Appelt, Jessika Baranowsky, Anke Jahn, Denise Yorgan, Timur Köhli, Paul Otto, Ellen Farahani, Saeed Khomeijani Graef, Frank Fuchs, Melanie Herrera, Aarón Amling, Michael Schinke, Thorsten Frosch, Karl-Heinz Duda, Georg N. Tsitsilonis, Serafeim Keller, Johannes The neuropeptide calcitonin gene-related peptide alpha is essential for bone healing |
title | The neuropeptide calcitonin gene-related peptide alpha is essential for bone healing |
title_full | The neuropeptide calcitonin gene-related peptide alpha is essential for bone healing |
title_fullStr | The neuropeptide calcitonin gene-related peptide alpha is essential for bone healing |
title_full_unstemmed | The neuropeptide calcitonin gene-related peptide alpha is essential for bone healing |
title_short | The neuropeptide calcitonin gene-related peptide alpha is essential for bone healing |
title_sort | neuropeptide calcitonin gene-related peptide alpha is essential for bone healing |
topic | Research paper |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7452713/ https://www.ncbi.nlm.nih.gov/pubmed/32853990 http://dx.doi.org/10.1016/j.ebiom.2020.102970 |
work_keys_str_mv | AT appeltjessika theneuropeptidecalcitoningenerelatedpeptidealphaisessentialforbonehealing AT baranowskyanke theneuropeptidecalcitoningenerelatedpeptidealphaisessentialforbonehealing AT jahndenise theneuropeptidecalcitoningenerelatedpeptidealphaisessentialforbonehealing AT yorgantimur theneuropeptidecalcitoningenerelatedpeptidealphaisessentialforbonehealing AT kohlipaul theneuropeptidecalcitoningenerelatedpeptidealphaisessentialforbonehealing AT ottoellen theneuropeptidecalcitoningenerelatedpeptidealphaisessentialforbonehealing AT farahanisaeedkhomeijani theneuropeptidecalcitoningenerelatedpeptidealphaisessentialforbonehealing AT graeffrank theneuropeptidecalcitoningenerelatedpeptidealphaisessentialforbonehealing AT fuchsmelanie theneuropeptidecalcitoningenerelatedpeptidealphaisessentialforbonehealing AT herreraaaron theneuropeptidecalcitoningenerelatedpeptidealphaisessentialforbonehealing AT amlingmichael theneuropeptidecalcitoningenerelatedpeptidealphaisessentialforbonehealing AT schinkethorsten theneuropeptidecalcitoningenerelatedpeptidealphaisessentialforbonehealing AT froschkarlheinz theneuropeptidecalcitoningenerelatedpeptidealphaisessentialforbonehealing AT dudageorgn theneuropeptidecalcitoningenerelatedpeptidealphaisessentialforbonehealing AT tsitsilonisserafeim theneuropeptidecalcitoningenerelatedpeptidealphaisessentialforbonehealing AT kellerjohannes theneuropeptidecalcitoningenerelatedpeptidealphaisessentialforbonehealing AT appeltjessika neuropeptidecalcitoningenerelatedpeptidealphaisessentialforbonehealing AT baranowskyanke neuropeptidecalcitoningenerelatedpeptidealphaisessentialforbonehealing AT jahndenise neuropeptidecalcitoningenerelatedpeptidealphaisessentialforbonehealing AT yorgantimur neuropeptidecalcitoningenerelatedpeptidealphaisessentialforbonehealing AT kohlipaul neuropeptidecalcitoningenerelatedpeptidealphaisessentialforbonehealing AT ottoellen neuropeptidecalcitoningenerelatedpeptidealphaisessentialforbonehealing AT farahanisaeedkhomeijani neuropeptidecalcitoningenerelatedpeptidealphaisessentialforbonehealing AT graeffrank neuropeptidecalcitoningenerelatedpeptidealphaisessentialforbonehealing AT fuchsmelanie neuropeptidecalcitoningenerelatedpeptidealphaisessentialforbonehealing AT herreraaaron neuropeptidecalcitoningenerelatedpeptidealphaisessentialforbonehealing AT amlingmichael neuropeptidecalcitoningenerelatedpeptidealphaisessentialforbonehealing AT schinkethorsten neuropeptidecalcitoningenerelatedpeptidealphaisessentialforbonehealing AT froschkarlheinz neuropeptidecalcitoningenerelatedpeptidealphaisessentialforbonehealing AT dudageorgn neuropeptidecalcitoningenerelatedpeptidealphaisessentialforbonehealing AT tsitsilonisserafeim neuropeptidecalcitoningenerelatedpeptidealphaisessentialforbonehealing AT kellerjohannes neuropeptidecalcitoningenerelatedpeptidealphaisessentialforbonehealing |