School of Biomedical Engineering, Shenzhen Campus of Sun Yat-Sen University, Shenzhen 518107, Guangdong, P. R. China.
State Key Laboratory of Materials-Oriented Chemical Engineering, College of Chemical Engineering, Nanjing Tech University, Nanjing, 211816, P. R. China.
Sci Adv. 2024 Mar 8;10(10):eadg7380. doi: 10.1126/sciadv.adg7380.
Calcitonin gene-related peptide (CGRP), an osteopromotive neurotransmitter with a short half-life, shows increase while calcitonin receptor-like (CALCRL) level is decreased at the early stage in bone fractures. Therefore, the activation of CALCRL-mediated signaling may be more critical to promote the tendon-bone healing. We found CGRP enhanced osteogenic differentiation of BMSCs through PKA/CREB/JUNB pathway, contributing to improved sonic hedgehog (SHH) expression, which was verified at the tendon-bone interface (TBI) in the mice with overexpression. The osteoblast-derived SHH and slit guidance ligand 3 were reported to favor nerve regeneration and type H (CD31EMCN) vessel formation, respectively. Encouragingly, the activation or inactivation of CALCRL-mediated signaling significantly increased or decreased intensity of type H vessel and nerve fiber at the TBI, respectively. Simultaneously, improved gait characteristics and biomechanical performance were observed in the overexpression group. Together, the gene therapy targeting CGRP receptor may be a therapeutic strategy in sports medicine.
降钙素基因相关肽（CGRP）是一种具有短半衰期的促骨神经递质，在骨折的早期阶段其水平增加，而降钙素受体样（CALCRL）水平降低。因此，激活 CALCRL 介导的信号转导可能对促进肌腱-骨愈合更为关键。我们发现 CGRP 通过 PKA/CREB/JUNB 通路增强 BMSCs 的成骨分化，从而促进了 sonic hedgehog（SHH）的表达，这在过表达 的小鼠的肌腱-骨界面（TBI）得到了验证。骨细胞衍生的 SHH 和 slit 导向配体 3 分别有利于神经再生和 H 型（CD31EMCN）血管形成。令人鼓舞的是，CALCRL 介导的信号的激活或失活分别显著增加或减少了 TBI 处 H 型血管和神经纤维的强度。同时，在 过表达组中观察到步态特征和生物力学性能的改善。总之，针对 CGRP 受体的基因治疗可能是运动医学的一种治疗策略。
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