Calcitonin gene related peptide (CGRP) is a neuropeptide produced by sensory nerves and functions as a pain sensor. It acts by binding to calcitonin like receptor (CLR, protein; Calcrl, gene). CGRP inhibition has been recently introduced as therapeutic treatment of migraine-associated pain. Previous studies have shown that CGRP stimulates bone formation. The aim of our study was to determine whether the inhibition of CGRP signaling negatively impacted fracture healing. Using 伪-smooth muscle actin (伪SMA) Cre animals crossed with Ai9 reporter mice, we showed that CGRP expressing nerves are near 伪SMA+ cells in the periosteum. In vitro experiments revealed that periosteal cells express Calcrl and Receptor activity modifying protein 1 (Ramp1); and CGRP stimulation increased periosteal cell proliferation. Using a tamoxifen-inducible model 伪SMACre/CLR we targeted deletion of CLR to periosteal progenitor cells and examined fracture healing. Micro-computed tomography of fractured femurs showed a reduction in bone mass in 伪SMACre+/CLR female mice relative to controls and callus volume in males. Pharmacological CGRP-CLR inhibition was achieved by subcutaneous delivery of customized pellets with small molecule inhibitor Olcegepant (BIBN-4096) at a dose of 10 渭g/day. BIBN-4096-treated C57BL/6J mice had a higher latency toward thermal nociception than placebo treated mice, indicating impaired sensory function through CGRP inhibition. CGRP inhibition also resulted in reduced callus volume, bone mass and bone strength compared to placebo controls. These results indicate that inhibiting CGRP by deleting CLR or by using BIBN-4096, contributes to delayed bone-healing. This article is protected by copyright. All rights reserved.
Browse by Audience
