Calcitonin Gene-Related Peptide and Bone Repair: History
View Latest Version
Please note this is an old version of this entry, which may differ significantly from the current revision.
Contributor:
Qichang Wang
,
Haotian Qin
,
Jiapeng Deng
,
Huihui Xu
,
Su Liu
,
Jian Weng
,
Hui Zeng

Calcitonin gene-related peptide (CGRP) has 37 amino acids. Initially, CGRP had vasodilatory and nociceptive effects. As research progressed, evidence revealed that the peripheral nervous system is closely associated with bone metabolism, osteogenesis, and bone remodeling. Thus, CGRP is the bridge between the nervous system and the skeletal muscle system. CGRP can promote osteogenesis, inhibit bone resorption, promote vascular growth, and regulate the immune microenvironment. The G protein-coupled pathway is vital for its effects, while MAPK, Hippo, NF-κB, and other pathways have signal crosstalk, affecting cell proliferation and differentiation. 

  • calcitonin gene-related peptide
  • osteogenic effect
  • immunomodulation
  • bone repair

1. Effects of Calcitonin Gene-Related Peptide on Bone Repair

Calcitonin gene-related peptide (CGRP) is widely distributed in bone tissue and promotes osteogenesis, inhibits osteolysis, induces angiogenesis, and regulates the immune microenvironment (Figure 1).
Biomolecules 13 00838 g001 550
Figure 1. CGRP regulates various cells to promote bone repair. CGRP is secreted by sensory nerve cells, and its effects on bone tissue are: 1. CGRP can bind to the CLR receptor on the cell surface to directly enhance the osteoblast and osteogenic gene expression; 2. CGRP can inhibit the RANKL/RANK/NF-κB pathway by increasing OPG level, inhibiting osteoclast proliferation, and reducing the osteoclast effect; 3. CGRP can enhance the angiogenesis of vascular endothelial cells by promoting the expression of VEGF and HIF factors, induce angiogenesis, and provide nutritional support for bone repair; 4. CGRP can enhance the transformation of M0 into M2 macrophages and regulate the immune microenvironment of bone repair. CGRP is a calcitonin gene-related peptide, CLR is a calcein gene-related peptide receptor, RANK is the receptor activator of nuclear factor kappa B, RANKL is the receptor activator of nuclear factor kappa B ligand, OPG is osteoprotegerin, HIF is a hypoxia-inducible factor, and VEGF is a vascular endothelial growth factor.

1.1. Distribution of Calcitonin Gene-Related Peptide and Receptors in Bone Tissue

Bone tissue is rich in CGRP, with two types of nerve fibers—substance P (SP)-positive and CGRP-positive nerve fibers. They are mainly present in bone, bone marrow, periosteum, synovium, and adjacent soft tissues. The proportion of CGRP-positive nerve fibers is dominant [1], and CGRP is a critical node that cannot be bypassed and is a bridge between nerve and bone repair. The receptors of CGRP, CLR, and RAMP1 are widely distributed in vivo, and the co-localized expression of CLR and RAMP1 is also crucial for CGRP to exert its effects. In bone tissue, macrophages, osteoblasts, and vascular tissue, CLR and RAMP1 expression is abundant in macrophages, osteoblasts, and endothelial cells [2][3][4][5][6]. This regulates osteogenesis by affecting the immune microenvironment, vasculature, and accompanying nerves. Immune cells promote bone production by secreting certain osteogenic factors [7]. In contrast, blood vessels and nerve fibers are distributed throughout the bone tissue, providing oxygen, nutrients, and supporting cells to the bone tissue. Therefore, they are essential in bone growth, development, and fracture healing [8]. In short, sensory neurons are stimulated to continuously release CGRP into bone tissue to achieve neurological bone regulation.

1.2. Calcitonin Gene-Related Peptide Promotes Osteogenesis

Among the neuropeptides identified in bone tissue (CGRP, SP, NE, NPY), CGRP is most strongly associated with bone repair [9]. Mice with a systemic knockout of the CGRP gene have significantly reduced bone mass. In contrast, overexpression of the CGRP gene significantly enhances bone density [10][11]. Therefore, CGRP promotes bone repair accompanied by nerve fiber ingrowth. There were fewer CGRP-positive nerve fibers at inflammatory progression sites (larger defect sites) and more CGRP-positive nerve fibers at repair sites (smaller defects) during knee and ankle osteoarthritis. Thus, inflammation destroying bone may induce the ingrowth of CGRP-positive fibers, producing CGRP for local bone repair [12]. Sequencing results indicate that CGRP promotes extracellular matrix production, which may be an essential pathway for its bone repair effects [6]. Sensory nerves maintain extracellular matrix (ECM) homeostasis through the CGRP/CHSY1 axis, and the knockdown of sensory nerve CGRP induces similar disturbances in ECM metabolism [13].
CGRP can upregulate various osteogenic factors and promote osteoblast anabolism [14][15]. Haitao et al. observed that CGRP promotes elevated levels of cAMP, ATF4, and OCN expression in osteoblasts [16]. ATF4 is an ATF/CREB family member, a cell-specific CREB-related transcriptional essential for osteoblast differentiation and function factor [17]. ATF4 is identified as an osteoblast-specific transcription factor necessary for OCN transcription, an osteoblast-specific marker commonly used to indicate late osteoblast differentiation [18][19]. BMP2 is essential in osteogenesis induction and promotes ECM expression, mainly collagen production and calcium salt formation, using the Smad pathway [20][21][22]. In MG-63 cells, BMP2 can be involved in CGRP-induced osteogenic differentiation, and cAMP/p-CREB upregulation further promotes BMP2 expression [23]. Dental pulp stem cells (DPSCs) possess the qualities of bone marrow mesenchymal stem cells and are the primary source of dentin mineralization. CGRP directly stimulates a 1.8-fold increase in BMP2 mRNA expression in DPSCs, and a 2.8-fold increase in basal levels of cAMP, which promotes dentin formation. Liping et al. observed that CGRP stimulated bone marrow MSC proliferation, upregulated osteoblast gene expression, enhanced alkaline phosphatase activity, and increased calcium nodules in bone marrow mesenchymal stem cells (BMSCs) [24]. Direct action of CGRP on BMSCs elevated the migratory capacity and osteogenic differentiation and inhibited the bone marrow differentiation of MSCs to adipocytes [6][25]. This process involves molecular crosstalk between Wnt/β-catenin and CGRP signaling [26] other than enhanced cAMP response element binding protein 1 in periosteal-derived stem cells (CREB1) and SP7 (osterix, OSX) expression in periosteal-derived stem cells. Thus, osteogenic differentiation of periosteal-derived stem cells is promoted [27]. In vivo studies identified elevated CGRP levels in mice with femoral fractures [28]. Similar upregulatory effects could be seen when serum CGRP expression was examined in femoral neck fracture patients [29]. CGRP was used to transiently act on bone healing tissue and bone formation regulators (IL1b, Ccl7, MMP13, Mrc1), which increased the PPARγ pathway (Adipoq, Fabp4, Scd1, Cfd) members [28]. Thus, local bone defect repairing was induced by releasing CGRP from nerve endings within the periosteum [27]. Electrical stimulation (ES) of the spinal dorsal root ganglion directly enhances the biosynthesis and release of CGRP by activating Ca2+ and accelerating femur fracture healing in osteoporotic rats [30]. Therefore, CGRP is essential in the early generation of bone healing tissue by activating osteogenic effect-related pathways. CGRP also promotes the production of osteogenic factors, collagen, and extracellular matrix, facilitating bone repair.

1.3. Calcitonin Gene-Related Peptide Inhibits Bone Resorption

CGRP inhibits osteoclasts, increases bone volume, and reduces bone resorption [10][31]. Previous studies have indicated that sympathetic and sensory nerves are cross-linked to the osteoclastic effect. In contrast, CGRP reverses the isoproterenol (Isp)-mediated osteoclastic effect [32] and inhibits the proliferation of granulocyte-macrophage lineage progenitor cells (precursor osteoclast cells) [33]. CGRP increases OCN and OPG in osteoblasts and inhibits RANKL expression [16]. RANKL is a RANK ligand, an activatable NF-κB pathway that promotes the proliferation and effects of osteoclasts. CGRP inhibits osteogenesis by suppressing RANKL expression, inhibiting the NF-κB pathway, and downregulating the expression of osteoclast TRAP and histone K [24]. However, NF-κB also has a vital role in senescence and apoptosis, and attention must be paid to whether CGRP plays a crucial role in their senescence and apoptosis.

1.4. Calcitonin Gene-Related Peptide-Induced Angiogenesis

CGRP is vital in blood vessel formation and growth [34] and can indirectly affect bone development and formation [35][36]. Bone development cannot be separated from the expression of CGRP, vascular endothelial growth factor (VEGF), a cluster of differentiation 31 (CD31), and lymphatic vessel endothelial hyaluronan receptor 1 (LYVE1) [37]. CGRP-positive nerve fibers during early embryonic development are present in blood vessels, developing muscles, or developing cartilage bones [38]. Angiogenesis and bone regeneration were observed by local CGRP injection into the defect site in rats [39]. CGRP promotes VEGF expression to enhance endothelial cell proliferation and migration [40][41], a mechanism validated in tumor-associated angiogenesis [42]. Moreover, CGRP promotes endothelial progenitor cell proliferation and restricts apoptosis by inhibiting MAPK signaling [43]. OCN upregulation, ALP gene expression, and increase in mineralized nodules in osteoblast (OB) monoculture and human umbilical vein endothelial cell (HUVEC) OB co-culture systems could be associated with particular cytokine expression regulation in HUVEC by CGRP [44]. Biodegradable biomagnesium implants can accelerate bone repair by upregulating CGRP and promoting angiogenesis [45]. BMSCs overexpressing CGRP can improve bone repair by promoting peripheral angiogenesis in diabetic rats having tibial defects [46]. CGRP release at the bone defect site can contribute to angiogenesis, enhancing repair [47].

1.5. Calcitonin Gene-Related Peptide Regulates the Immune Microenvironment

Inflammation occurrence is essential for bone repair [48][49]. Mice with CGRP knockdown exhibit a higher degree of oxidative stress accompanied by reduced nitric oxide synthase (NOS) expression, increased phosphorylated p47 expression, elevated 4 hydroxynonenal (4HNE) levels, and macrophage infiltration [50]. CGRP inhibits LPS-induced TNFα production by macrophages [51] and osteoblasts [52]. Sensory nerve fibers secrete CGRP to inhibit inflammation by suppressing type 1 T helper cytokine production and leukocyte proliferation. CGRP affects the polarization of M0-type to M2-type macrophages, affecting bone tissue remodeling in the later stages of fracture repair [53]. Moreover, CGRP induces bone regeneration and differentiation by elevating M2-type macrophage proportion [54]. Lack of CGRP promotes M1 and inhibits M2 polarization in macrophages. Thus, CGRP knockdown mice hinder osseointegration in bone grafts, and its overexpression improves osseointegration by regulating the macrophage phenotype [55].
However, osteogenic factors (BMP2, BMP6, WNT10b, and OSM) secreted by M2 macrophages were reduced in the early stages and elevated at later stages of CGRP action [56]. Pajarinen et al. indicated that proper inflammation is beneficial in the early stages of bone repair. M1 macrophages may exert their effects in the early and middle stages of osteogenesis. In contrast, M2 macrophages later affect bone matrix mineralization [7], which aligns with the prevailing view of immune regulation of bone repair. Thus, CGRP plays a vital role in regulating the immune microenvironment for bone repair [49][57].

2. Calcitonin Gene-Related Peptide in Orthopedic Treatment

2.1. Prospects for the Application of Calcitonin Gene-Related Peptide as a Drug

Scientists accelerate the clinical conversion of CGRP by performing animal experiments. Table 1 shows a study on CGRP at the animal level. Scientists consider that CGRP has good application prospects as a drug.
Table 1. Study on CGRP at the animal level.
Model Author Year Modeling Method Phenotype
Gene editing Ballica [10] 1999 Construction of mouse model of CGRP overexpression Inhibit osteoclasts, stimulate insulin-like growth factor, and inhibit the tumor necrosis factor-α production
Hoff [58] 2002 Construction of CGRP knockout mouse model The bone mass of gene-knockout mice was maintained after ovariectomy, and that of gene-knockout wild-type mice decreased within two months.
Schinke [11] 2004 Construction of CALCA and CGRP knockout mouse model CALCA knockout mice revealed a high bone mass, while CGRP knockout mice showed a low bone mass.
Toda [34] 2008 Construction of CGRP knockout mouse model The expression of vascular endothelial growth factor within wound granulation tissue of CGRP knockout mice decreased. Angiogenesis and wound closure was significantly inhibited.
Lei Yang [50] 2013 Construction of CGRP knockout mouse model CGRP can inhibit oxidative stress and the proliferation of vascular smooth muscle cells induced by vascular injury.
Kauther [59] 2013 Construction of CGRP knockout mouse model In mice, OPG and OCN increased significantly, osteoclasts elevated, and RANKL decreased significantly.
Takahashi [31] 2016 Construction of TRPV1 knockout mouse model TRPV1 affects osteoclast formation by CGRP regulation
Niedermair [53] 2020 Construction of CGRP knockout mouse model CGRP relieved pain and promoted the polarization of M2 macrophages but did not affect bone maturation.
Appelt [28] 2020 Construction of CGRP knockout mouse model The number of bone-forming osteoblasts in CGRP-deficient mice decreased significantly, and bone healing was poor.
Bone graft Zhong Fang [60] 2013 Implantation of CGRP overexpressed ADSCs/β-TCP Bracket ADSCs overexpressing the CGRP/β-TCP stent promotes bone repair
Wei Liang [61] 2016 Implantation of CPC containing CGRP and Sr CPC containing CGRP and Sr promotes bone repair among osteoporotic rats
Xijiao Yu [62] 2019 Implantation of CGRP overexpressed collagen scaffolds in BMSCs BMScs collagen scaffold overexpressing CGRP leads to skull repair in rats
Sen Jia [25] 2019 Construction of a rat model of distraction osteogenesis CGRP enhances new bone formation by elevating the migration and differentiation of bone marrow stromal cells.
Ye Li [47] 2021 Construction of a rat model of distraction osteogenesis Magnesium-containing intramedullary nail promotes bone defect repair in rats by the upregulating CGRP/FAK/VEGF pathway.
Wangyong Zhu [45] 2021 Construction of a rat model of drug-related osteonecrosis Magnesium grafts promote angiogenesis and bone repair by regulating VEGF and CGRP, thereby alleviating drug-related osteonecrosis.
Injection of drugs Mapp [41] 2012 Normal knee joint Promote angiogenesis
Yanjun Guo [46] 2020 Construction of diabetic rat model CGRP injection overexpressed BMSCs can elevate ALP activity and promote mRNA and protein expression of VEGF, ALP, and OPN
Hang Li 2021 Construction of senile mouse model and osteoporotic mouse model Promote bone formation in aged mice, decrease fat accumulation, and delay osteoporosis occurrence in mice.
Other Aoki [35] 1994 Tibial bone defect model Local blood flow and callus formation increased.
Irie [63] 2002 Normal bone tissue There are abundant CGRP-positive nerve fibers around the bone tissue.
Maeda [37] 2017 Normal fetal rat bone tissue CGRP is essential in osteogenesis and angiogenesis in bone development.
Feng Gao [64] 2018 Construction of obese mouse model In obese mice, CGRP, FGF, and TGF-β levels decreased, while TNF-α levels increased, and bone repair was delayed.
CGRP drug has not been used in clinical practice despite having anti-osteoporotic and osteoinductive effects [15]. Regular intravenous supplementation of CGRP in aged osteoporotic mice significantly increased osteogenesis and decreased bone marrow fat accumulation [6][65]. CGRP carriage as a drug into calcium phosphate bone cement (Sr-CPC) significantly enhanced cell proliferation and elevated ALP secretion in BMSCs [61]. Adipose mesenchymal stem cells (ADSCs) overexpressing CGRP promote the expression of collagen type I (COL1) and bone bridging protein (OPN) with a stronger potential to differentiate into osteoblasts in vitro. Moreover, transplantation of ADSCs overexpressing CGRP into bone defect sites can cause osteopathic effects [60]. BMSCs overexpressing CGRP also possessed better osteogenic effects. Thus, BMSCs carried into collagen scaffolds were more capable of repairing cranial defects in rats [62]. However, direct CGRP trigger supplementation enhances local pain, suggesting a debatable medicinal value of CGRP.

2.2. Biomaterials Can Promote Bone Repair by Modulating Calcitonin Gene-Related Peptide

Although the CGRP drug has not been intensively studied, promoting CGRP expression in vivo for osteogenesis is a potent research topic. Previous studies demonstrated that CGRP has a vital role in bone repair. CGRP-positive nerve fibers are widely distributed in the periosteum and bone marrow [63]. Promoting CGRP release and elevating its local concentration is a more reliable fracture treatment to accelerate bone healing. CGRP is mainly found in vesicles in vivo. Researchers have extracted extracellular vesicles (EV) from adipose mesenchymal stem cells and carried CGRP-rich EV in polylactic acid-hydroxyacetic acid copolymer (PLGA) to enhance the growth of alveolar bone and improve bone repair [66]. Magnesium (Mg) could promote CGRP release and accelerate the bone repair process [27][47]. Mg and its alloys have good biodegradability and biocompatibility and can become bone-replacement materials [67]. Larger healing bone tissues with significantly increased mechanical strength were observed when Mg rods were implanted at the fracture site in osteoporotic rats. Mg promotes osteogenic effects by releasing CGRP from the dorsal root ganglion (DRG) and periosteal nerve fibers and activating cAMP/CREB signaling, wherein periosteal-derived stem cells were identified as CGRP targets [27]. A follow-up study observed that implanting Mg nails into the bone defect site and distraction osteogenesis elevated CGRP concentration in the new bone tissue. Furthermore, this accelerated vascular growth into the bone defect site and bone repair through the CGRP/FAK/VEGF signaling axis [47].

2.3. Modulation of Calcitonin Gene-Related Peptide for Bone Repair by Electrical Stimulation

Electrical stimulation promotes the long entry of CGRP-positive nerve fibers inside the damaged area [68]. Researchers have promoted the biosynthesis and release of CGRP directly during discharge by placing electrodes in the dorsal root ganglion area of the lumbar spine. This enhances osteoporotic fracture healing within the rat femur [30]. 

This entry is adapted from the peer-reviewed paper 10.3390/biom13050838

References

  1. Bjurholm, A.; Kreicbergs, A.; Brodin, E.; Schultzberg, M. Substance P- and CGRP-immunoreactive nerves in bone. Peptides 1988, 9, 165–171.
  2. Haegerstrand, A.; Dalsgaard, C.J.; Jonzon, B.; Larsson, O.; Nilsson, J. Calcitonin gene-related peptide stimulates proliferation of human endothelial cells. Proc. Natl. Acad. Sci. USA 1990, 87, 3299–3303.
  3. Hosoi, J.; Murphy, G.F.; Egan, C.L.; Lerner, E.A.; Grabbe, S.; Asahina, A.; Granstein, R.D. Regulation of Langerhans cell function by nerves containing calcitonin gene-related peptide. Nature 1993, 363, 159–163.
  4. Naot, D.; Cornish, J. The role of peptides and receptors of the calcitonin family in the regulation of bone metabolism. Bone 2008, 43, 813–818.
  5. Chrissobolis, S.; Zhang, Z.; Kinzenbaw, D.A.; Lynch, C.M.; Russo, A.F.; Faraci, F.M. Receptor activity-modifying protein-1 augments cerebrovascular responses to calcitonin gene-related peptide and inhibits angiotensin II-induced vascular dysfunction. Stroke 2010, 41, 2329–2334.
  6. Li, H.; Qu, J.; Zhu, H.; Wang, J.; He, H.; Xie, X.; Wu, R.; Lu, Q. Corrigendum: CGRP Regulates the Age-Related Switch Between Osteoblast and Adipocyte Differentiation. Front Cell Dev. Biol. 2021, 9, 715740.
  7. Pajarinen, J.; Lin, T.; Gibon, E.; Kohno, Y.; Maruyama, M.; Nathan, K.; Lu, L.; Yao, Z.; Goodman, S.B. Mesenchymal stem cell-macrophage crosstalk and bone healing. Biomaterials 2019, 196, 80–89.
  8. Marrella, A.; Lee, T.Y.; Lee, D.H.; Karuthedom, S.; Syla, D.; Chawla, A.; Khademhosseini, A.; Jang, H.L. Engineering vascularized and innervated bone biomaterials for improved skeletal tissue regeneration. Mater. Today 2018, 21, 362–376.
  9. Brazill, J.M.; Beeve, A.T.; Craft, C.S.; Ivanusic, J.J.; Scheller, E.L. Nerves in Bone: Evolving Concepts in Pain and Anabolism. J. Bone Miner. Res. 2019, 34, 1393–1406.
  10. Ballica, R.; Valentijn, K.; Khachatryan, A.; Guerder, S.; Kapadia, S.; Gundberg, C.; Gilligan, J.; Flavell, R.A.; Vignery, A. Targeted expression of calcitonin gene-related peptide to osteoblasts increases bone density in mice. J. Bone Miner. Res. 1999, 14, 1067–1074.
  11. Schinke, T.; Liese, S.; Priemel, M.; Haberland, M.; Schilling, A.F.; Catala-Lehnen, P.; Blicharski, D.; Rueger, J.M.; Gagel, R.F.; Emeson, R.B.; et al. Decreased bone formation and osteopenia in mice lacking alpha-calcitonin gene-related peptide. J. Bone Miner. Res. 2004, 19, 2049–2056.
  12. Hukkanen, M.; Konttinen, Y.T.; Rees, R.G.; Gibson, S.J.; Santavirta, S.; Polak, J.M. Innervation of bone from healthy and arthritic rats by substance P and calcitonin gene related peptide containing sensory fibers. J. Rheumatol. 1992, 19, 1252–1259.
  13. Hu, B.; Lv, X.; Wei, L.; Wang, Y.; Zheng, G.; Yang, C.; Zang, F.; Wang, J.; Li, J.; Wu, X.; et al. Sensory Nerve Maintains Intervertebral Disc Extracellular Matrix Homeostasis Via CGRP/CHSY1 Axis. Adv. Sci. (Weinh) 2022, 9, e2202620.
  14. Vignery, A.; McCarthy, T.L. The neuropeptide calcitonin gene-related peptide stimulates insulin-like growth factor I production by primary fetal rat osteoblasts. Bone 1996, 18, 331–335.
  15. Liang, W.; Zhuo, X.; Tang, Z.; Wei, X.; Li, B. Calcitonin gene-related peptide stimulates proliferation and osteogenic differentiation of osteoporotic rat-derived bone mesenchymal stem cells. Mol. Cell. Biochem. 2015, 402, 101–110.
  16. He, H.; Chai, J.; Zhang, S.; Ding, L.; Yan, P.; Du, W.; Yang, Z. CGRP may regulate bone metabolism through stimulating osteoblast differentiation and inhibiting osteoclast formation. Mol. Med. Rep. 2016, 13, 3977–3984.
  17. Elefteriou, F.; Ahn, J.D.; Takeda, S.; Starbuck, M.; Yang, X.; Liu, X.; Kondo, H.; Richards, W.G.; Bannon, T.W.; Noda, M.; et al. Leptin regulation of bone resorption by the sympathetic nervous system and CART. Nature 2005, 434, 514–520.
  18. Komori, T. Functions of Osteocalcin in Bone, Pancreas, Testis, and Muscle. Int. J. Mol. Sci. 2020, 21, 7513.
  19. Wang, Y.; Xia, C.; Chen, Y.; Jiang, T.; Hu, Y.; Gao, Y. Resveratrol Synergistically Promotes BMP9-Induced Osteogenic Differentiation of Mesenchymal Stem Cells. Stem Cells Int. 2022, 2022, 8124085.
  20. Tsuji, K.; Bandyopadhyay, A.; Harfe, B.D.; Cox, K.; Kakar, S.; Gerstenfeld, L.; Einhorn, T.; Tabin, C.J.; Rosen, V. BMP2 activity, although dispensable for bone formation, is required for the initiation of fracture healing. Nat. Genet. 2006, 38, 1424–1429.
  21. Rosen, V. BMP2 signaling in bone development and repair. Cytokine Growth Factor Rev. 2009, 20, 475–480.
  22. Jiang, F.; Qi, X.; Wu, X.; Lin, S.; Shi, J.; Zhang, W.; Jiang, X. Regulating macrophage-MSC interaction to optimize BMP-2-induced osteogenesis in the local microenvironment. Bioact. Mater 2023, 25, 307–318.
  23. Tian, G.; Zhang, G.; Tan, Y.H. Calcitonin gene-related peptide stimulates BMP-2 expression and the differentiation of human osteoblast-like cells in vitro. Acta Pharmacol. Sin. 2013, 34, 1467–1474.
  24. Wang, L.; Shi, X.; Zhao, R.; Halloran, B.P.; Clark, D.J.; Jacobs, C.R.; Kingery, W.S. Calcitonin-gene-related peptide stimulates stromal cell osteogenic differentiation and inhibits RANKL induced NF-kappaB activation, osteoclastogenesis and bone resorption. Bone 2010, 46, 1369–1379.
  25. Jia, S.; Zhang, S.J.; Wang, X.D.; Yang, Z.H.; Sun, Y.N.; Gupta, A.; Hou, R.; Lei, D.L.; Hu, K.J.; Ye, W.M.; et al. Calcitonin gene-related peptide enhances osteogenic differentiation and recruitment of bone marrow mesenchymal stem cells in rats. Exp. Ther. Med. 2019, 18, 1039–1046.
  26. Zhou, R.; Yuan, Z.; Liu, J.; Liu, J. Calcitonin gene-related peptide promotes the expression of osteoblastic genes and activates the WNT signal transduction pathway in bone marrow stromal stem cells. Mol. Med. Rep. 2016, 13, 4689–4696.
  27. Zhang, Y.; Xu, J.; Ruan, Y.C.; Yu, M.K.; O’Laughlin, M.; Wise, H.; Chen, D.; Tian, L.; Shi, D.; Wang, J.; et al. Implant-derived magnesium induces local neuronal production of CGRP to improve bone-fracture healing in rats. Nat. Med. 2016, 22, 1160–1169.
  28. Appelt, J.; Baranowsky, A.; Jahn, D.; Yorgan, T.; Köhli, P.; Otto, E.; Farahani, S.K.; Graef, F.; Fuchs, M.; Herrera, A.; et al. The neuropeptide calcitonin gene-related peptide alpha is essential for bone healing. EBioMedicine 2020, 59, 102970.
  29. Onuoha, G.N.; Alpar, E.K. Elevation of plasma CGRP and SP levels in orthopedic patients with fracture neck of femur. Neuropeptides 2000, 34, 116–120.
  30. Mi, J.; Xu, J.K.; Yao, Z.; Yao, H.; Li, Y.; He, X.; Dai, B.Y.; Zou, L.; Tong, W.X.; Zhang, X.T.; et al. Implantable Electrical Stimulation at Dorsal Root Ganglions Accelerates Osteoporotic Fracture Healing via Calcitonin Gene-Related Peptide. Adv. Sci. (Weinh) 2022, 9, e2103005.
  31. Takahashi, N.; Matsuda, Y.; Sato, K.; de Jong, P.R.; Bertin, S.; Tabeta, K.; Yamazaki, K. Neuronal TRPV1 activation regulates alveolar bone resorption by suppressing osteoclastogenesis via CGRP. Sci. Rep. 2016, 6, 29294.
  32. Ishizuka, K.; Hirukawa, K.; Nakamura, H.; Togari, A. Inhibitory effect of CGRP on osteoclast formation by mouse bone marrow cells treated with isoproterenol. Neurosci. Lett. 2005, 379, 47–51.
  33. Akopian, A.; Demulder, A.; Ouriaghli, F.; Corazza, F.; Fondu, P.; Bergmann, P. Effects of CGRP on human osteoclast-like cell formation: A possible connection with the bone loss in neurological disorders. Peptides 2000, 21, 559–564.
  34. Toda, M.; Suzuki, T.; Hosono, K.; Kurihara, Y.; Kurihara, H.; Hayashi, I.; Kitasato, H.; Hoka, S.; Majima, M. Roles of calcitonin gene-related peptide in facilitation of wound healing and angiogenesis. Biomed. Pharmacother. 2008, 62, 352–359.
  35. Aoki, M.; Tamai, K.; Saotome, K. Substance P- and calcitonin gene-related peptide-immunofluorescent nerves in the repair of experimental bone defects. Int. Orthop. 1994, 18, 317–324.
  36. Liu, W.C.; Chen, S.; Zheng, L.; Qin, L. Angiogenesis Assays for the Evaluation of Angiogenic Properties of Orthopaedic Biomaterials - A General Review. Adv. Healthc. Mater. 2017, 6, 1600434.
  37. Maeda, Y.; Miwa, Y.; Sato, I. Expression of CGRP, vasculogenesis and osteogenesis associated mRNAs in the developing mouse mandible and tibia. Eur. J. Histochem. 2017, 61, 2750.
  38. Bidegain, M.; Roos, B.A.; Hill, E.L.; Howard, G.A.; Balkan, W. Calcitonin gene-related peptide (CGRP) in the developing mouse limb. Endocr. Res. 1995, 21, 743–755.
  39. Mi, J.; Xu, J.; Yao, H.; Li, X.; Tong, W.; Li, Y.; Dai, B.; He, X.; Chow, D.; Li, G.; et al. Calcitonin Gene-Related Peptide Enhances Distraction Osteogenesis by Increasing Angiogenesis. Tissue Eng. Part A 2021, 27, 87–102.
  40. Zheng, S.; Li, W.; Xu, M.; Bai, X.; Zhou, Z.; Han, J.; Shyy, J.Y.; Wang, X. Calcitonin gene-related peptide promotes angiogenesis via AMP-activated protein kinase. Am. J. Physiol. Cell Physiol. 2010, 299, C1485–C1492.
  41. Mapp, P.I.; McWilliams, D.F.; Turley, M.J.; Hargin, E.; Walsh, D.A. A role for the sensory neuropeptide calcitonin gene-related peptide in endothelial cell proliferation in vivo. Br. J. Pharmacol. 2012, 166, 1261–1271.
  42. Toda, M.; Suzuki, T.; Hosono, K.; Hayashi, I.; Hashiba, S.; Onuma, Y.; Amano, H.; Kurihara, Y.; Kurihara, H.; Okamoto, H.; et al. Neuronal system-dependent facilitation of tumor angiogenesis and tumor growth by calcitonin gene-related peptide. Proc. Natl. Acad. Sci. USA 2008, 105, 13550–13555.
  43. Wu, J.; Liu, S.; Wang, Z.; Ma, S.; Meng, H.; Hu, J. Calcitonin gene-related peptide promotes proliferation and inhibits apoptosis in endothelial progenitor cells via inhibiting MAPK signaling. Proteome Sci. 2018, 16, 18.
  44. Bo, Y.; Yan, L.; Gang, Z.; Tao, L.; Yinghui, T. Effect of calcitonin gene-related peptide on osteoblast differentiation in an osteoblast and endothelial cell co-culture system. Cell Biol. Int. 2012, 36, 909–915.
  45. Zhu, W.Y.; Guo, J.; Yang, W.F.; Tao, Z.Y.; Lan, X.; Wang, L.; Xu, J.; Qin, L.; Su, Y.X. Biodegradable magnesium implant enhances angiogenesis and alleviates medication-related osteonecrosis of the jaw in rats. J. Orthop. Translat. 2022, 33, 153–161.
  46. Guo, Y.; Chen, H.; Jiang, Y.; Yuan, Y.; Zhang, Q.; Guo, Q.; Gong, P. CGRP regulates the dysfunction of peri-implant angiogenesis and osseointegration in streptozotocin-induced diabetic rats. Bone 2020, 139, 115464.
  47. Li, Y.; Xu, J.; Mi, J.; He, X.; Pan, Q.; Zheng, L.; Zu, H.; Chen, Z.; Dai, B.; Li, X.; et al. Biodegradable magnesium combined with distraction osteogenesis synergistically stimulates bone tissue regeneration via CGRP-FAK-VEGF signaling axis. Biomaterials 2021, 275, 120984.
  48. Brown, B.N.; Badylak, S.F. Expanded applications, shifting paradigms and an improved understanding of host-biomaterial interactions. Acta Biomater. 2013, 9, 4948–4955.
  49. Gibon, E.; Lu, L.; Goodman, S.B. Aging, inflammation, stem cells, and bone healing. Stem Cell Res. Ther. 2016, 7, 44.
  50. Yang, L.; Sakurai, T.; Kamiyoshi, A.; Ichikawa-Shindo, Y.; Kawate, H.; Yoshizawa, T.; Koyama, T.; Iesato, Y.; Uetake, R.; Yamauchi, A.; et al. Endogenous CGRP protects against neointimal hyperplasia following wire-induced vascular injury. J. Mol. Cell. Cardiol. 2013, 59, 55–66.
  51. Feng, Y.; Tang, Y.; Guo, J.; Wang, X. Inhibition of LPS-induced TNF-alpha production by calcitonin gene-related peptide (CGRP) in cultured mouse peritoneal macrophages. Life Sci. 1997, 61, PL 281–PL 287.
  52. Millet, I.; Vignery, A. The neuropeptide calcitonin gene-related peptide inhibits TNF-alpha but poorly induces IL-6 production by fetal rat osteoblasts. Cytokine 1997, 9, 999–1007.
  53. Niedermair, T.; Straub, R.H.; Brochhausen, C.; Grässel, S. Impact of the Sensory and Sympathetic Nervous System on Fracture Healing in Ovariectomized Mice. Int. J. Mol. Sci. 2020, 21, 405.
  54. Loi, F.; Córdova, L.A.; Zhang, R.; Pajarinen, J.; Lin, T.H.; Goodman, S.B.; Yao, Z. The effects of immunomodulation by macrophage subsets on osteogenesis in vitro. Stem. Cell Res. Ther. 2016, 7, 15.
  55. Yuan, Y.; Jiang, Y.; Wang, B.; Guo, Y.; Gong, P.; Xiang, L. Deficiency of Calcitonin Gene-Related Peptide Affects Macrophage Polarization in Osseointegration. Front Physiol. 2020, 11, 733.
  56. Zhang, Q.; Wu, B.; Yuan, Y.; Zhang, X.; Guo, Y.; Gong, P.; Xiang, L. CGRP-modulated M2 macrophages regulate osteogenesis of MC3T3-E1 via Yap1. Arch. Biochem. Biophys. 2021, 697, 108697.
  57. Maruyama, M.; Rhee, C.; Utsunomiya, T.; Zhang, N.; Ueno, M.; Yao, Z.; Goodman, S.B. Modulation of the Inflammatory Response and Bone Healing. Front. Endocrinol. (Lausanne) 2020, 11, 386.
  58. Hoff, A.O.; Catala-Lehnen, P.; Thomas, P.M.; Priemel, M.; Rueger, J.M.; Nasonkin, I.; Bradley, A.; Hughes, M.R.; Ordonez, N.; Cote, G.J.; et al. Increased bone mass is an unexpected phenotype associated with deletion of the calcitonin gene. J. Clin. Invest. 2002, 110, 1849–1857.
  59. Kauther, M.D.; Neuerburg, C.; Wefelnberg, F.; Bachmann, H.S.; Schlepper, R.; Hilken, G.; Broecker-Preuss, M.; Grabellus, F.; Schilling, A.F.; Jäger, M.; et al. RANKL-associated suppression of particle-induced osteolysis in an aged model of Calcitonin and α-CGRP deficiency. Biomaterials 2013, 34, 2911–2919.
  60. Fang, Z.; Yang, Q.; Xiong, W.; Li, G.H.; Liao, H.; Xiao, J.; Li, F. Effect of CGRP-adenoviral vector transduction on the osteoblastic differentiation of rat adipose-derived stem cells. PLoS ONE 2013, 8, e72738.
  61. Liang, W.; Li, L.; Cui, X.; Tang, Z.; Wei, X.; Pan, H.; Li, B. Enhanced proliferation and differentiation effects of a CGRP- and Sr-enriched calcium phosphate cement on bone mesenchymal stem cells. J. Appl. Biomater. Funct. Mater. 2016, 14, e431–e440.
  62. Yu, X.; Liu, S.; Chen, X.; Du, Y.; Yin, X.; Du, Y.; Li, S. Calcitonin gene related peptide gene-modified rat bone mesenchymal stem cells are effective seed cells in tissue engineering to repair skull defects. Histol. Histopathol. 2019, 34, 1229–1241.
  63. Irie, K.; Hara-Irie, F.; Ozawa, H.; Yajima, T. Calcitonin gene-related peptide (CGRP)-containing nerve fibers in bone tissue and their involvement in bone remodeling. Microsc. Res. Tech. 2002, 58, 85–90.
  64. Gao, F.; Lv, T.R.; Zhou, J.C.; Qin, X.D. Effects of obesity on the healing of bone fracture in mice. J. Orthop Surg Res. 2018, 13, 145.
  65. Chen, J.; Ma, G.; Liu, W.; Liu, Y.; Ding, Y. The influence of the sensory neurotransmitter calcitonin gene-related peptide on bone marrow mesenchymal stem cells from ovariectomized rats. J. Bone Miner. Metab. 2017, 35, 473–484.
  66. Yang, Y.; Zhang, B.; Yang, Y.; Peng, B.; Ye, R. PLGA Containing Human Adipose-Derived Stem Cell-Derived Extracellular Vesicles Accelerates the Repair of Alveolar Bone Defects via Transfer of CGRP. Oxid. Med. Cell Longev. 2022, 2022, 4815284.
  67. Zhao, D.; Witte, F.; Lu, F.; Wang, J.; Li, J.; Qin, L. Current status on clinical applications of magnesium-based orthopaedic implants: A review from clinical translational perspective. Biomaterials 2017, 112, 287–302.
  68. Ding, Y.; Yan, Q.; Ruan, J.W.; Zhang, Y.Q.; Li, W.J.; Zhang, Y.J.; Li, Y.; Dong, H.; Zeng, Y.S. Electro-acupuncture promotes survival, differentiation of the bone marrow mesenchymal stem cells as well as functional recovery in the spinal cord-transected rats. BMC Neurosci. 2009, 10, 35.
More
© Text is available under the terms and conditions of the Creative Commons Attribution (CC BY) license; additional terms may apply. By using this site, you agree to the Terms and Conditions and Privacy Policy.
This entry is offline, you can click here to edit this entry!
Video Production Service
Feedback