Abstract
BackgroundCalcitonin 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 FindingsWe 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, CGRP8–37, 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 CGRP8–37 was associated with increased targeted remodeling in the fatigue-loaded ulna. Administration of CGRP or CGRP8–37 both increased reparative bone formation over the study period. Plasma concentration of TRAP5b was not significantly influenced by either CGRP or CGRP8–37 administration.ConclusionsCGRP 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.
Highlights
The failure of repair responses to protect the skeleton from fracture is an important problem, but the physiological pathways that regulate skeletal responses to loading are not fully understood
A minimally displaced intracortical stress fracture was noted in 31 of the 32 fatigue-loaded ulnae evaluated for microdamage; as expected, no intracortical fatigue damage was seen in the contralateral ulnae
Plasma Calcitonin gene related peptide (CGRP) was elevated in the CGRP group compared with the CGRP8–37 group (p = 0.05), but not the Saline group (p,0.07) (Fig. 2A)
Summary
The failure of repair responses to protect the skeleton from fracture is an important problem, but the physiological pathways that regulate skeletal responses to loading are not fully understood. In situations where fatigue damage is present within bone, repair responses include targeted remodeling of microdamage [6] and woven bone formation on adjacent bone surfaces. Load-induced skeletal responses are thought to be locally regulated by bone cells [7,8]. Recent work suggests that the sensory innervation of bone may have regulatory effects on skeletal responses to bone loading [9,10]. Relatively little is known about the physiological role of CGRP in-vivo in the skeletal responses to bone loading, fatigue loading
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