Increased Calcitonin Gene-Related Peptide Expression in DRG and Nerve Fibers Proliferation Caused by Nonunion Fracture in Rats

Do Not Lose Your Nerve, Be Callus: Insights Into Neural Regulation of Fracture Healing

“…Nonunion is another significant driving force of pain development [ 97 , 98 ]. Nonunions in mice have been shown to present a significantly increased pain response, accompanied by CGRP and GAP-43-positive increased nerve density in the bone marrow [ 97 , 99 ].…”

“…Nonunion is another significant driving force of pain development [ 97 , 98 ]. Nonunions in mice have been shown to present a significantly increased pain response, accompanied by CGRP and GAP-43-positive increased nerve density in the bone marrow [ 97 , 99 ]. Indeed, it is suggested that ongoing pain in nonunion may be a result of improper pruning and the development of neuroma-like nerve endings within the bone [ 99 ].…”

Calcitonin gene-related peptide is potential therapeutic target of osteoporosis

“…In addition, previous studies indicate that the CGRP receptor is also expressed in the regenerating bone tissue and CGRP is increased in bone fracture tissues at both transcriptional and translational levels ( Appelt et al., 2020c ; Kasai et al., 2021 ; Mi et al., 2022b ; Tang et al., 2017 ), and that CGRP could promote trabecular bone expansion after patellectomy in rabbits ( Chen et al., 2021 ). In contrast, it is found that CGRP deficient mice demonstrate impaired bone formation and reduction in osteoblast number ( Appelt et al., 2020b ), and antagonism of CGRP receptor reduces bone formation in diet-induced obesity and induces inflammatory cytokines ( Köhli et al., 2021b ).…”

“…The development of osteoporosis is proposed to be the disturbed balance between the activities of osteoblasts-induced bone formation and osteoclasts-induced bone resorption. More and more studies found that CGRP also modulates the activities of osteoblasts, osteoclasts and BMMSCs ( Jia et al., 2019b ; Kasai et al., 2021 ; Liang et al., 2015a , 2016a ; Xu et al., 2020c ) ( Figure 2 ). For example, CGRP stimulates proliferation of BMSC, increases expression of osteoblastic genes, ALP activity and mineralization in BMSCs ( Wang et al., 2010b ).…”

“…It was found that these DRG neurons innervating bone including lumbar vertebral body, periosteum, mineralized bone and bone marrow, also expressed CGRP ( Aso et al., 2014 ; Castañeda-Corral et al., 2011 ; Ohtori et al., 2007 ). Furthermore, in these fibers innervating knee joint of rats, CGRP was also detected ( Hoshino et al., 2018b ) and the expression of CGRP in DRG was enhanced by fracture ( Kasai et al., 2021 ), injury ( Orita et al., 2010b ), and in mice with osteoporosis induced by OVX ( Suzuki et al., 2013a ). In addition to the upregulation of CGRP and TRPV1 in DRG neurons and decrease of BMD, OVX also resulted in mechanical hyperalgesia in the hind limbs of mice subjected to OVX; all these changes in OVX-treated mice were prevented by teriparatide (TPTD), an anabolic agent treating osteoporosis in the clinic ( Kato et al., 2020a ).…”