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Role of calcitonin gene-related peptide in bone repair after cyclic fatigue loading.

Sample SJ, Hao Z, Wilson AP, Muir P - PLoS ONE (2011)

Bottom Line: Administration of CGRP(8-37) was associated with increased targeted remodeling in the fatigue-loaded ulna.Plasma concentration of TRAP5b was not significantly influenced by either CGRP or CGRP(8-37) administration.CGRP signaling modulates targeted remodeling of microdamage and reparative new bone formation after bone fatigue, and may be part of a neuronal signaling pathway which has regulatory effects on load-induced repair responses within the skeleton.

View Article: PubMed Central - PubMed

Affiliation: Comparative Orthopaedic Research Laboratory, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, Wisconsin, United States of America.

ABSTRACT

Background: Calcitonin gene related peptide (CGRP) is a neuropeptide that is abundant in the sensory neurons which innervate bone. The effects of CGRP on isolated bone cells have been widely studied, and CGRP is currently considered to be an osteoanabolic peptide that has effects on both osteoclasts and osteoblasts. However, relatively little is known about the physiological role of CGRP in-vivo in the skeletal responses to bone loading, particularly fatigue loading.

Methodology/principal findings: We used the rat ulna end-loading model to induce fatigue damage in the ulna unilaterally during cyclic loading. We postulated that CGRP would influence skeletal responses to cyclic fatigue loading. Rats were fatigue loaded and groups of rats were infused systemically with 0.9% saline, CGRP, or the receptor antagonist, CGRP(8-37), for a 10 day study period. Ten days after fatigue loading, bone and serum CGRP concentrations, serum tartrate-resistant acid phosphatase 5b (TRAP5b) concentrations, and fatigue-induced skeletal responses were quantified. We found that cyclic fatigue loading led to increased CGRP concentrations in both loaded and contralateral ulnae. Administration of CGRP(8-37) was associated with increased targeted remodeling in the fatigue-loaded ulna. Administration of CGRP or CGRP(8-37) both increased reparative bone formation over the study period. Plasma concentration of TRAP5b was not significantly influenced by either CGRP or CGRP(8-37) administration.

Conclusions: CGRP signaling modulates targeted remodeling of microdamage and reparative new bone formation after bone fatigue, and may be part of a neuronal signaling pathway which has regulatory effects on load-induced repair responses within the skeleton.

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Reparative bone formation induced by fatigue loading was increased after treatment with CGRP or CGRP8–37.Confocal photomicrographs of calcified transverse sections of ulna at 60% of bone length, from proximal to distal [37]. Administration of either CGRP or CGRP8–37 for 10 days after cyclic fatigue loading of the right ulna increased reparative bone formation in the loaded ulna compared with saline-treated rats. Endosteal bone formation was particularly evident after CGRP8–37 treatment. Rats treated with CGRP8–37 also had greater bone formation in the contralateral (left) ulna, which was not loaded, when compared to the left ulna of the saline-treated rats. New bone formation was double labeled with calcein. White arrows indicate periosteal new woven bone formation; pink arrows indicate endosteal new bone. Bar = 250 µm. Cr, cranial; Cd, caudal; Med, medial; Lat, lateral. Saline group, n = 8; CGRP group n = 12; CGRP8–37 group, n = 12.
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pone-0020386-g006: Reparative bone formation induced by fatigue loading was increased after treatment with CGRP or CGRP8–37.Confocal photomicrographs of calcified transverse sections of ulna at 60% of bone length, from proximal to distal [37]. Administration of either CGRP or CGRP8–37 for 10 days after cyclic fatigue loading of the right ulna increased reparative bone formation in the loaded ulna compared with saline-treated rats. Endosteal bone formation was particularly evident after CGRP8–37 treatment. Rats treated with CGRP8–37 also had greater bone formation in the contralateral (left) ulna, which was not loaded, when compared to the left ulna of the saline-treated rats. New bone formation was double labeled with calcein. White arrows indicate periosteal new woven bone formation; pink arrows indicate endosteal new bone. Bar = 250 µm. Cr, cranial; Cd, caudal; Med, medial; Lat, lateral. Saline group, n = 8; CGRP group n = 12; CGRP8–37 group, n = 12.

Mentions: The effect of CGRP and CGRP8–37 on load-induced bone formation after cyclic fatigue was evaluated in both the fatigue-loaded right ulnae and contralateral left ulnae. Rats treated with either CGRP or CGRP8–37 for 10 days after cyclic fatigue loading had increased reparative bone formation, when compared to the rats that were treated with saline (Fig. 6). Ps.L.B.Ar was increased in the right ulnae of the CGRP (p<0.001) and the CGRP8–37 (p<0.001) groups, and in the left ulna of the CGRP8–37 group (p<0.0001), when compared to the Saline group; Ps.L.B.Ar was also increased in the left ulna of the CGRP8–37 group when compared to the CGRP group (Fig. 7A, p<0.05). Similarly, Tt.L.B.Ar was increased in the right ulnae of the CGRP (p<0.001) and the CGRP8–37 (p<0.0001) groups, and in the left ulna of the CGRP8–37 group (p<0.05), when compared to the Saline group (Fig. 7B). Es.L.B.Ar was also increased in the right ulna of the CGRP (p<0.05) and the CGRP8–37 (p<0.001) groups, when compared to the Saline group (Fig. 7C). No differences in humeral bone formation were seen between any of the groups.


Role of calcitonin gene-related peptide in bone repair after cyclic fatigue loading.

Sample SJ, Hao Z, Wilson AP, Muir P - PLoS ONE (2011)

Reparative bone formation induced by fatigue loading was increased after treatment with CGRP or CGRP8–37.Confocal photomicrographs of calcified transverse sections of ulna at 60% of bone length, from proximal to distal [37]. Administration of either CGRP or CGRP8–37 for 10 days after cyclic fatigue loading of the right ulna increased reparative bone formation in the loaded ulna compared with saline-treated rats. Endosteal bone formation was particularly evident after CGRP8–37 treatment. Rats treated with CGRP8–37 also had greater bone formation in the contralateral (left) ulna, which was not loaded, when compared to the left ulna of the saline-treated rats. New bone formation was double labeled with calcein. White arrows indicate periosteal new woven bone formation; pink arrows indicate endosteal new bone. Bar = 250 µm. Cr, cranial; Cd, caudal; Med, medial; Lat, lateral. Saline group, n = 8; CGRP group n = 12; CGRP8–37 group, n = 12.
© Copyright Policy
Related In: Results  -  Collection

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pone-0020386-g006: Reparative bone formation induced by fatigue loading was increased after treatment with CGRP or CGRP8–37.Confocal photomicrographs of calcified transverse sections of ulna at 60% of bone length, from proximal to distal [37]. Administration of either CGRP or CGRP8–37 for 10 days after cyclic fatigue loading of the right ulna increased reparative bone formation in the loaded ulna compared with saline-treated rats. Endosteal bone formation was particularly evident after CGRP8–37 treatment. Rats treated with CGRP8–37 also had greater bone formation in the contralateral (left) ulna, which was not loaded, when compared to the left ulna of the saline-treated rats. New bone formation was double labeled with calcein. White arrows indicate periosteal new woven bone formation; pink arrows indicate endosteal new bone. Bar = 250 µm. Cr, cranial; Cd, caudal; Med, medial; Lat, lateral. Saline group, n = 8; CGRP group n = 12; CGRP8–37 group, n = 12.
Mentions: The effect of CGRP and CGRP8–37 on load-induced bone formation after cyclic fatigue was evaluated in both the fatigue-loaded right ulnae and contralateral left ulnae. Rats treated with either CGRP or CGRP8–37 for 10 days after cyclic fatigue loading had increased reparative bone formation, when compared to the rats that were treated with saline (Fig. 6). Ps.L.B.Ar was increased in the right ulnae of the CGRP (p<0.001) and the CGRP8–37 (p<0.001) groups, and in the left ulna of the CGRP8–37 group (p<0.0001), when compared to the Saline group; Ps.L.B.Ar was also increased in the left ulna of the CGRP8–37 group when compared to the CGRP group (Fig. 7A, p<0.05). Similarly, Tt.L.B.Ar was increased in the right ulnae of the CGRP (p<0.001) and the CGRP8–37 (p<0.0001) groups, and in the left ulna of the CGRP8–37 group (p<0.05), when compared to the Saline group (Fig. 7B). Es.L.B.Ar was also increased in the right ulna of the CGRP (p<0.05) and the CGRP8–37 (p<0.001) groups, when compared to the Saline group (Fig. 7C). No differences in humeral bone formation were seen between any of the groups.

Bottom Line: Administration of CGRP(8-37) was associated with increased targeted remodeling in the fatigue-loaded ulna.Plasma concentration of TRAP5b was not significantly influenced by either CGRP or CGRP(8-37) administration.CGRP signaling modulates targeted remodeling of microdamage and reparative new bone formation after bone fatigue, and may be part of a neuronal signaling pathway which has regulatory effects on load-induced repair responses within the skeleton.

View Article: PubMed Central - PubMed

Affiliation: Comparative Orthopaedic Research Laboratory, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, Wisconsin, United States of America.

ABSTRACT

Background: Calcitonin gene related peptide (CGRP) is a neuropeptide that is abundant in the sensory neurons which innervate bone. The effects of CGRP on isolated bone cells have been widely studied, and CGRP is currently considered to be an osteoanabolic peptide that has effects on both osteoclasts and osteoblasts. However, relatively little is known about the physiological role of CGRP in-vivo in the skeletal responses to bone loading, particularly fatigue loading.

Methodology/principal findings: We used the rat ulna end-loading model to induce fatigue damage in the ulna unilaterally during cyclic loading. We postulated that CGRP would influence skeletal responses to cyclic fatigue loading. Rats were fatigue loaded and groups of rats were infused systemically with 0.9% saline, CGRP, or the receptor antagonist, CGRP(8-37), for a 10 day study period. Ten days after fatigue loading, bone and serum CGRP concentrations, serum tartrate-resistant acid phosphatase 5b (TRAP5b) concentrations, and fatigue-induced skeletal responses were quantified. We found that cyclic fatigue loading led to increased CGRP concentrations in both loaded and contralateral ulnae. Administration of CGRP(8-37) was associated with increased targeted remodeling in the fatigue-loaded ulna. Administration of CGRP or CGRP(8-37) both increased reparative bone formation over the study period. Plasma concentration of TRAP5b was not significantly influenced by either CGRP or CGRP(8-37) administration.

Conclusions: CGRP signaling modulates targeted remodeling of microdamage and reparative new bone formation after bone fatigue, and may be part of a neuronal signaling pathway which has regulatory effects on load-induced repair responses within the skeleton.

Show MeSH
Related in: MedlinePlus