title: Role of calcitonin gene-related peptide in functional adaptation of the skeleton.
abstract: Peptidergic sensory nerve fibers innervating bone and periosteum are rich in calcitonin gene-related peptide (CGRP), an osteoanabolic neurotransmitter. There are two CGRP isoforms, CGRPα and CGRPβ. Sensory fibers are a potential means by which the nervous system may detect and respond to loading events within the skeleton. However, the functional role of the nervous system in the response of bone to mechanical loading is unclear. We used the ulna end-loading model to induce an adaptive modeling response in CGRPα and CGRPβ knockout mouse lines and their respective wildtype controls. For each knockout mouse line, groups of mice were treated with cyclic loading or sham-loading of the right ulna. A third group of mice received brachial plexus anesthesia (BPA) of the loaded limb before mechanical loading. Fluorochrome labels were administered at the time of loading and 7 days later. Ten days after loading, bone responses were quantified morphometrically. We hypothesized that CGRP signaling is required for normal mechanosensing and associated load-induced bone formation. We found that mechanically-induced activation of periosteal mineralizing surface in mice and associated blocking with BPA were eliminated by knockout of CGRPα signaling. This effect was not evident in CGRPβ knockout mice. We also found that mineral apposition responses to mechanical loading and associated BPA blocking were retained with CGRPα deletion. We conclude that activation of periosteal mineralizing surfaces in response to mechanical loading of bone is CGRPα-dependent in vivo. This suggests that release of CGRP from sensory peptidergic fibers in periosteum and bone has a functional role in load-induced bone formation.
authors.affiliation: Comparative Orthopaedic Research Laboratory, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, Wisconsin, United States of America.
authors.forename: Susannah J
authors.initials: SJ
authors.lastname: Sample
authors.affiliation: Comparative Orthopaedic Research Laboratory, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, Wisconsin, United States of America.
authors.forename: Caitlin M
authors.initials: CM
authors.lastname: Heaton
authors.affiliation: Department of Comparative Biosciences, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, Wisconsin, United States of America.
authors.forename: Mary
authors.initials: M
authors.lastname: Behan
authors.affiliation: Comparative Orthopaedic Research Laboratory, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, Wisconsin, United States of America.
authors.forename: Jason A
authors.initials: JA
authors.lastname: Bleedorn
authors.affiliation: Comparative Orthopaedic Research Laboratory, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, Wisconsin, United States of America.
authors.forename: Molly A
authors.initials: MA
authors.lastname: Racette
authors.affiliation: Comparative Orthopaedic Research Laboratory, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, Wisconsin, United States of America.
authors.forename: Zhengling
authors.initials: Z
authors.lastname: Hao
authors.affiliation: Comparative Orthopaedic Research Laboratory, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, Wisconsin, United States of America.
authors.forename: Peter
authors.initials: P
authors.lastname: Muir
mesh_terms: D000222:Adaptation, Physiological; D000704:Analysis of Variance; D000818:Animals; D001696:Biomechanical Phenomena; D015519:Bone Density; D001842:Bone and Bones / Q000502:physiology*; D002113:Calcification, Physiologic; D015740:Calcitonin Gene-Related Peptide / Q000378:metabolism*; D005456:Fluorescent Dyes / Q000378:metabolism; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010012:Osteogenesis; D010521:Periosteum / Q000502:physiology; D015398:Signal Transduction; D014457:Ulna / Q000502:physiology; D016474:Weight-Bearing / Q000502:physiology
chemical_list: D005456:Fluorescent Dyes; D015740:Calcitonin Gene-Related Peptide