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. 2022 Dec 10;8(12):e12288. doi: 10.1016/j.heliyon.2022.e12288

Calcitonin gene-related peptide is potential therapeutic target of osteoporosis

Hua Wu a, Xue-qin Lin b, Yu Long b, Jing Wang c,∗
PMCID: PMC9758432  PMID: 36536904

Abstract

Osteoporosis is a skeletal disorder characterised by the decrease of bone mineral density and is becoming prevalent with the entry of an ageing era. There are two catalogues of osteoporosis, including primary osteoporosis and secondary osteoporosis, according to the pathological causes. Since the demonstrations of osteoporosis are usually covered by other diseases, its therapeutic strategies are not satisfactory for both patients and clinicians. Calcitonin gene-related peptide (CGRP) is a peptide expressed in both bone tissues and peripheral nerves innervating bone tissue, and its expression in osteoporosis patients is increased. Recent studies have indicated that CGRP could promote the osteogenesis by osteblasts and bone absorption by osteoclasts, thus maintaining the bone homeostasis. The effects of CGRP on bone homeostasis are related with its promotion of angiogenesis through vascular endothelial growth factor and its modulation of multiple signal pathways including receptor activator of nuclear factor kappa-Β ligand. In addition, CGRP could interact with neuronal system through neural growth factor to modulate osteoporosis. Application of implants or nanoparticles also verified the beneficial effect of CGRP on osteoporosis. There studies imply a great therapeutic potential of CGRP in treating osteoporosis. Although massive studies about CGRP in osteoporosis have been performed with positive results, there is little development in clinical application. The review summarises recent advancement in the roles of CGRP in modulating osteoporosis, which will be helpful in providing some directions for further study of CGRP in treating osteoporosis.

Keywords: Calcitonin gene-related peptide, Osteoporosis, Osteoblast, Osteoclast, Osteogenesis, Bone marrow stromal cells

Graphical abstract

Image 1

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Calcitonin gene-related peptide, Osteoporosis, Osteoblast, Osteoclast, Osteogenesis, Bone marrow stromal cells.

1. Introduction

As a metabolic skeletal disorder characterized by decrease of bone mineral density (BMD) and bone quality, osteoporosis is becoming prevalent. There are two types of osteoporosis, primary osteoporosis and secondary osteoporosis. Primary osteoporosis mainly includes postmenopausal osteoporosis (PMO) and senile osteoporosis, while secondary osteoporosis is mainly caused by some diseases or medications (Porter et al., 2022). Osteoporosis can induce multiple complications including pain, fracture, and disability. The mechanism of osteoporosis is complicated, including impaired osteogenesis and enhancement of osteoclastogenesis (Wang et al., 2021b), which makes it difficult for the therapy of osteoporosis in clinic. For example, although recent studies found that receptor activator of nuclear factor kappa-Β ligand (RANKL) is involved in osteoporosis and receptor activator of NF-kappa-B (RANK) antagonists, denosumab and romosozumab, increases bone mass, the continuous effect of RANKL antagonists is still susceptible (Appelman-Dijkstra et al., 2022). The other therapeutic strategies like raloxifene, bisphosphonates, estrogen, denosumab, tibolone, abaloparatide, or teriparatide may have other side effects. Therefore, other therapeutic targets and strategies are further required.

Hormone replacement or peptide therapy is usually considered to be an effective therapeutic strategy for osteoporosis. However, there are still some problems with this method. For example, the potential peptide human calcitonin is easy to form fibrillation in aqueous solution, which leads to reduced efficacy. Recent studies indicate that calcitonin gene-related peptide (CGRP) is involved in many phaysiological and pathological processes, including bone homeostasis, vasodilator activities, pain, cardiovascular diseases, vessel remodeling, and ageing (Russell et al., 2014e), and there is a correlation between PMO and the expression of CGRP (Xiao et al., 2016a) while CGRP is proposed to be one biological marker for PMO women with depression (Hartman et al., 2006). These studies imply that CGRP is involved in the development and modulation of osteoporosis.

In addition, recent studies indicate that CGRP is also highly expressed in sensory neurons innervating the skeleton, promotes bone healing by regulating bone homeostasis and regeneration (Xu et al., 2020a), and has been used in treating migraine (Al-Hassany et al., 2022b). These studies suggest that CGRP is involved in the modulation of osteoporosis and is a potential therapeutic target for osteoporosis through neural-bone interaction (Abeynayake et al., 2021b; Suzuki et al., 2013b).

2. Expression in bone tissues and clinical application of CGRP system

CGRP, including two isoforms CGRP-α and CGRP-β in human (Amara et al., 1985; Russell et al., 2014c) (Figure 1A), is a 37-amino acid neuropeptide which is widely expressed in multiple tissues including stem cells, and is involved in many clinical diseases (Graeme S.Cottrell, 2018; Lv et al., 2022; Russell et al., 2014b). CGRP plays its roles by binding to its receptor, calcitonin receptor-like receptor (CRLR) composited with receptor activity-modifiying protein 1 (RAMP1), calcitonin-like receptor (CLR) and receptor component protein (RCP) (Graeme S.Cottrell, 2018; MaassenVanDenBrink et al., 2016; Russell et al., 2014d) (Figure 1B). CGRP was first thought to be primarily expressed in Aδ- and C-fibers of sensory neurons (Russell et al., 2014a), but recent study shows that the CGRP mRNA is widely expressed in rat bone, and increased in rib proximal but decreased in rib distal with the development during E12.5 to P5 (Sawada et al., 2021), implying that CGRP may promote cartilage formation in the distal regions of the rib after birth through increasing the expression of VEGF-A. CGRP is detected in the tibial microstructure and increased in rats subjected to ovariectomy (OVX) (Kato et al., 2020b; Xie et al., 2020a). The CGRP receptors are also expressed in osteoblasts differentiated from bone marrow stromal cells (BMSCs) and can be increased by LiCl (Zhou et al., 2016a). Furthermore, the expression of CGRP and CGRP receptor is increased in callus of bone during regeneration (Appelt et al., 2020e) and in fracture of femur (Tang et al., 2017). In OVX-induced osteoporosis, the CGRP level is decreased in the femur but increased in the spinal cord of animals subjected to OVX (Wakabayashi et al., 2019a; Zhang et al., 2021d). In a distraction osteoporosis model, magnesium nail increases the expression of CGRP in the new bone (Ye et al., 2021b). Consistently, antagonist of CGRP receptor reduces bone formation and bone mass in diet-induced obesity (Köhli et al., 2021a). These studies indicate that CGRP plays an important role in the pathology of osteoporosis and may be a potential strategy in treating osteoporosis.

Figure 1.

Figure 1

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CGRP and CGRP receptor: A) the amino acid sequence of human α-CGRP and β-CGRP; B) the schematic of CGRP receptor.

In order to verify the potential of CGRP in osteoporosis, recent studies have tried to apply CGRP with multiple strategies. For example, in a study of implant of magnisum-treated pin in the femur of rats, the new born bone was accompanied by enhanced expression of CGRP in the peripheral femoral cortx and dorsal root ganglion. Furthermore, knockdown of CGRP reversed the osteogenesis induced by the magnisum-treated implant while overexpression of CGRP could potentiate the osteogenesis (Zhang et al., 2016). The results from the same laboratory further indicated that indicated that CGRP could promote the osteogeneic differentiation of periosteum-derived stem cells in ligament reconstruction using periosteum pretreated with magnisum (Wang et al., 2021a). The effect of the CGRP released from the magnesium implant on distraction osteogenesis is proposed to be related with its capabilities to promote angiogenesis through vascular endothelial growth factor (VEGF) (Ye et al., 2021a). In the A recent study also demonstrated that scaffolds of borosilicate bioactive glass coated with CGRP could improve the biocompathibility and osteogenesis of human bone marrow mesenchymal stem cells (HBMSCs) (Li et al., 2022a). Moreover, the synthesized nanoparticles of bone mineral coated with magnesium could improve the secretion of CGRP and the differentiation of osteoblasts and neurons (Yang et al., 2020), which is different from local implantation and may have greater systemic effects on osteoporosis. These results strongly imply the potential of CGRP in treating osteoporosis.

In the clinic, it is found that the expression of CGRP, SP, and VIP in postmenopausal women with osteoarthritis and osteoporosis is significantly increased (Xiao et al., 2016b). In patients with degenerated intervertebral disc (IVD) and low back pain, the expression of CGRP is upregulated (Miyagi et al., 2022; Sun et al., 2021) while degenerated intervertebral disc (IVD) is usually associated with primary osteoporosis (Li et al., 2022b; Wáng et al., 2022); and both IVD degeneration and osteoporosis can induce chronic pain (Foizer et al., 2022; Wang et al., 2019). Furthermore, inhibition of CGRP has been approved to treat chronic pain (Al-Hassany et al., 2022a; Seidel et al., 2022a) which is a common symptom of osteoporosis. These studies further imply the feasibility of CGRP in treating osteoporosis.

3. Potential mechanism of CGRP in modulating osteoporosis

3.1. CGRP and bone homeostasis

Previous study indicates that CGRP plays an important role in maintaining bone homeostasis and bone regeneration (Xu et al., 2020b). The bone volume fraction and trabeculae number (Tb. N) are decreased while the trabecular spacing is increased in animals subjected to OVX. Moreover, the expression of SP, CGRP and VIP is decreased while the expression of NPY, NPY1R and NPY2R is increased in OVX-treated animals. In addition, animals subjected to OVX demonstrate hyperalgesia to mechanical stimulation (Xie et al., 2020b). In SD rat, OVX decreases the expression of TACR1, CGRP, CALCRL, NPY, and NPY Y2 in the brain, and SP, CALCRL, VIP, and VPAC2 in the bone, but increases the expression of TACR1 in bone (Liu et al., 2018). In aged mice, the level of CGRP is significantly decreased while CGRP promotes bone formation and reduces fat accumulation in bone marrow. In mice subjected to OVX, CGRP promotes bone formation (Li et al., 2021). In mice with deletion of α-CGRP, the bone mass and angiogenesis are significantly decreased while overexpression of α-CGRP partially blocks this defect, suggesting α-CGRP plays important role in modulating bone homeostasis (Appelt et al., 2020d; Wang et al., 2018a).

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). Furthermore, mechanical loading induces the adaptation of mice tibias and upexpression of CGRP in tibias, suggesting CGRP may be involved in bone formation (Heffner et al., 2017). All these studies suggest that CGRP could improve the balance of bone homeostasis.

3.2. Regulation of osteogenesis through BMSC differentiation

The balance between osteogenesis and osteoclastogenes through BMSCs plays an important role in healthy bone tissues (Wang 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). The expression of CGRP in bone marrow from aged mice is decreased at transcriptional and translational levels, while the addition of CGRP inhibits the differentiation of BMSCs into adiptocytes (Li et al., 2021) via the RANKL signalling system (Ishizuka et al., 2005). CGRP improves the proliferation and migration of BMSCs, and enhances the expression of ALP and runt-related transcription factor 2, thus increasing the BMD of rats in vivo (Jia et al., 2019a). In a strategy of strontium-enriched calcium phosphate cement, CGRP promotes the proliferation of BMSCs into osteoblasts and the activity of alkaline phosphatase (ALP) during differentiation of BMSCs, CGRP also enhances the calcification in cultured cells. These effects are mediated through ALP, Collagen type I, Bmp2, Osteonectin, and Runx2 during osteogenic differentiation (Liang et al., 2016c). CGRP enhances the osteoblastic differentiation of adipose-derived stem cells, and promotes the formation of mineralization and the expression of osteopontin, osteocalcin, and collagen I in differentiated osteoblasts (Fang et al., 2013). It is found that CGRP can increase differentiation of osteoblasts from BMSCs and inhibit the apoptosis of BMSCs by enhancing the activity of alkaline phosphatase in through CGRP receptors in BMSCs. CGRP also increases the expression of genes associated with differentiation of BMSCs, including alkaline phosphatase, collagen type I, Bmp2, Osteonectin, Runx2, c-myc, cyclin D1, Lef1, Tcf7 and β-catenin and the activity of ALP during differentiation of BMSCs (Zhou et al., 2016b) (Liang et al., 2015b, 2016b).

Figure 2.

Figure 2

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The schematic mechanism of CGRP in modulating osteoporosis. ┴, Inhibition; ↓, Facilitation.

In addition, CGRP also regulates osteogenesis by participating in the osteoimmune response of M2 macrophages via yes-associated protein 1 (Yap1) (Zhang et al., 2021b) and inhibits osteoprotegerin in human osteoblast-like cells through the cAMP/PKA signal pathway and thus modulates osteoclastogenesis (Villa et al., 2006). These studies suggest CGRP plays a double role in modulating the activities of osteoblast and osteoclast to balance the normal bone structure.

3.3. Regulation of angiogenesis by CGRP

Previous studies indicate that CGRP can enhance the migration of endothelial cells, expression of VEGF receptor, and bone formation in a distraction osteogenesis model (Ye et al., 2021d), and promotes the formation of vascular tube in human umbilical vein endothelial cells (Tuo et al., 2013). CGRP also upregulates the expression of VEGF, angiopoietin 1, type 4 collagen, matrix metalloproteinase in endothelial cells (Leroux et al., 2020). It is found that α-CGRP is essential for bone healing (Appelt et al., 2020a) by synergizing angiogenesis and osteogenesis (Wang et al., 2018b). While angiogenesis could prevent osteoporosis and improve osteoporotic fracture healing (Abdurahman et al., 2022; Yang et al., 2022). These results imply that CRGP may modulate osteoporosis through regulating angiogenesis (Figure 2). The angiogenetic effect of CGRP is also related to its effect on affecting endothelial progenitor cells (EPCs). In a bone defect model, CGRP enhanced bone regeneration, vessel formation, fraction of CD31(+)CD144(+)EPCs, capillary density, EPC population in the endothelial differentiation of BMSCs, activation of PI3K/AKT, and tube-like structures (Mi et al., 2021).

3.4. Interaction with neural tissues in the regulation of osteoporosis

Interaction between bone tissues and neural fibers innervating bone tissues has been implicated in bone health [for detail, see review (Abeynayake et al., 2021a)]. In SD rats subjected to OVX, the expression of CGRP and TRPV4 were increased in L3 DRG innervating vertebrate showing lower BMD (Orita et al., 2018). Dorsal root ganglion (DRG) is a cluster of cell body afferent neurons innervating peripheral tissues, including bone. 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). Electrical stimulation of DRG increased the expression of CGRP in DRG and healing bone tissue by promoting angiogenesis and osteogenesis via Ca(2+)/CaMKII/CREB signaling pathway (Mi et al., 2022a). In cadmium-treated mice, the deterioration of femoral trabecular microstructure, reduction of CGRP+ nerve fibers, and mechanical hyperactivities were accompanied (Torres-Rodríguez et al., 2022). In addition, the expression of CGRP in the femur was reduced while the expression of CGRP and serotonin in the spinal cord was increased by OVX (Zhang et al., 2021c). These studies indicate that the crosstalk between the neural system and bone (Wan et al., 2021) may play an important role in osteoporosis.

Nerve growth factor (NGF) is an insulin-like neurotrophic peptide that binds to two receptors-tyrosine receptor kinase A (TrkA) with high-affinity and p75 neurotrophin receptor with low-affinity-and is one therapeutic target for several physiological and pathological conditions, including bone formation and regeneration (Alastra et al., 2021). NGF is found to be expressed in femurs and articular cartilage (Chartier et al., 2017) and regulates osteogenesis/osteoclastogenesis (for review, see (Sun et al., 2020)) while inhibiting NGF can decrease the expression of CGRP in DRG innervating the inter-vertebral disc (Orita et al., 2010a). In a secondary osteonecrosis model induced by steroids, NGF and CGRP change in opposite (Wang et al., 2010c). These studies suggest NGF may also be involved in osteoporosis modulation through modulating CGRP. However, it remains to be further studied to clarify the role of NGF in osteoporosis.

3.5. RANKL and other signalling pathways of CGRP in the regulation of osteoporosis

The RANKL system, including RNAKL-RNAK-OPG, is well known to be involved in the modulation of bone homeostasis through the PI3K/AKT and TNFα/IL signaling pathway (for review, see (Takegahara et al., 2022)). Previous studies indicated that CGRP inhibited the activation of RANKL and osteoclastic genes like TRAP and cathepsin K, and bone resorption activity of BMMS induced by RANKL (Wang et al., 2010a). CGRP also decreased the expression of RANKL in osteoblasts but increased the expression of cAMP, osteocalcin, activating transcription factor-4, and osteoprotegerin (He et al., 2016). These studies suggest that the RANKL signaling pathway is one important player in CGRP modulated bone homeostasis and may be one important target for osteoporosis (Figure 2).

Since inflammation plays an important role in CGRP-related bone disorders (Hoshino et al., 2018a; Seidel et al., 2022b; Sun et al., 2021), anti-IL-6R antibody and alendronate (ALN) treatment significantly blocked mechanical hyperalgesia and CGRP upregulation in the spinal cord induced by OVX (Wakabayashi et al., 2019b). ALN also prevented bone loss, upregulation of CGRP and TRPV1 in DRG induced by OVX (Naito et al., 2017). In addition, deletion of the sensory nerve with capsaicin blocked the effect of CGRP (Ye et al., 2021c). These studies indicated that CGRP can modulate osteoporosis through involvement in inflammatory response.

In addition, CGRP could first decrease and then increase the expression of osteogenic factors such as bone morphogenetic proteins and oncostatin M in M2 macrophages (Zhang et al., 2021a), suggesting CGRP may modulate osteoimmune response by macrophages to regulate osteoporosis.

4. Prospective in treating osteoporosis with CGRP

Although the potential therapeutic effect of CGRP in treating osteoporosis has been extensively studied with experimental models, there is still no clear clinical verification and a long pathway from lab bench to bedside is waiting ahead. Following the elucidation of the mechanisms of CGRP in modulating osteoporosis, we will be one step toward to the application of CGRP and related materials in treating osteoporosis. Recent studies of the biomedical implants and nanoparticles with CGRP have further verified the feasibility of CGRP in treating osteoporosis and imply its clinical potential. In addition, other short peptides showed effect in preventing periodontal ligament and gingival mesenchymal stem cells from senescence (Sinjari et al., 2020) or promoting differentiation of neural stem cells (Caputi et al., 2019), which might be helpful for the study of interaction between CGRP and neural system and/or BMMSCs.

Declaration

Author contribution statement

All authors listed have significantly contributed to the development and the writing of this article.

Funding statement

Dr Jing Wang was supported by the Basic Research Foundation of Medical and Health Care of Bao'an Health and Family Planning Commission [No. 2019JD044], Science, Technology and Innovation Commission of Shenzhen Municipality [No. JCYJ20210324111010028].

Data availability statement

No data was used for the research described in the article.

Declaration of interests statement

The authors declare no conflict of interest.

Additional information

No additional information is available for this paper.

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