The neuropeptide calcitonin gene-related peptide alpha is essential for bone healing
The neuropeptide calcitonin gene-related peptide alpha is essential for bone healing
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DOI：
10.1016/j.ebiom.2020.102970
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发表时间：
2020-09-01
期刊：
影响因子：
11.1
通讯作者：
Keller, Johannes
中科院分区：
文献类型：
--
作者：
Appelt, Jessika;Baranowsky, Anke;Keller, Johannes
背景：骨折愈合不良是一个持续的临床挑战，因为治疗选择仍然有限。降钙素基因相关肽（CGRP），一种神经肽为目标的新兴抗偏头痛药物，也表达在感觉神经纤维支配骨tissue.Method：骨愈合后股骨截骨术稳定与外固定器进行了分析超过21天的α CGRP缺陷和野生型小鼠。通过血清分析、mu CT分析、组织形态计量学和全基因组表达分析评价骨再生。骨髓来源的成骨细胞和破骨细胞，以及CGRP拮抗剂olcegepant用于mechanistic studies.Findings：WT小鼠股骨骨折显示CGRP血清水平增加。骨骼损伤后α CGRP mRNA的表达仅在骨痂组织中诱导，而在其他器官中不诱导。在蛋白水平上，CGRP及其受体，降钙素受体样受体（CRLR）与RAMP 1复合，在骨痂中的差异表达在骨再生过程中。另一方面，α CGRP缺陷小鼠表现出严重受损的骨再生，其特征在于成骨细胞数量显著减少，骨痂桥接不完全和骨不连的发生率高。通过全基因组表达分析评估，CGRP诱导与骨化、骨重塑和脂肪生成相关的特定基因的表达。这表明，CGRP受体依赖性的过氧化物酶体增殖物激活受体γ信号在骨折愈合中起着重要的作用。解释：这项研究表明了一个重要的作用，α降钙素基因相关肽在编排愈伤组织的形成，并确定CGRP受体激动剂作为一种潜在的方法，以刺激骨再生。此外，由于阻断CGRP或其受体CRLR的新型药物目前在临床上被引入用于治疗偏头痛疾病，因此它们对骨再生的潜在负面影响值得临床研究。(C)2020作者（S）由爱思唯尔公司出版
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.