Sensory denervation increases potential of bisphosphonates to induce osteonecrosis via disproportionate expression of calcitonin gene–related peptide and substance P. Issue 1 (10th December 2020)

• Record Type: Journal Article
• Authors: Xie, Dongni; Xu, Yamei; Yang, Yao; Hua, Ziyi; Li, Jiao; Fu, Gang; Wu, Qingqing
• Other Names: Zaidi Mone guestEditor.
• Is Part Of: Annals of the New York Academy of Sciences. Volume 1487:Issue 1(2021)
• Page Start: 56
• Page End: 73
• Publication Date: 2020-12-10
• Subjects: bisphosphonates -- bisphosphonate‐related osteonecrosis of the jaw -- inferior alveolar nerve -- calcitonin gene–related peptide -- substance P; Medical sciences -- Periodicals; Medicine -- Periodicals; Science -- Periodicals; 610
• DOI: 10.1111/nyas.14540
• Languages: English
• ISSNs: 0077-8923

Abstract

Abstract: Bisphosphonate‐related osteonecrosis of the jaw (BRONJ) is a serious side effect of systematic administration of bisphosphonates (BPs). Sensory innervation is crucial for bone healing. We established inferior alveolar nerve injury (IANI) and inferior alveolar nerve transection (IANT) models characterized by disorganized periosteum, increased osteoclasts, and unbalanced neuropeptide expression. Zoledronate injection disrupted neuropeptide expression in the IANI and IANT models by decreasing calcitonin gene–related peptide (CGRP) and increasing substance P (SP); associated with this, BRONJ prevalence was significantly higher in the IANT model, followed by the IANI model and the sham control. CGRP treatment significantly reduced BRONJ occurrence, whereas SP administration had the opposite effect. In vitro, RAW 264.7 cells were treated with BPs and then CGRP and/or SP to study changes in zoledronate toxicity; combined application of CGRP and SP decreased zoledronate toxicity, whereas CGRP or SP applied alone showed no effects. These results demonstrate that sensory denervation facilitates the occurrence of BRONJ and that CGRP used therapeutically may prevent BRONJ progression, provided that SP is also present. Further studies are necessary to determine the optimal ratio of CGRP to SP for promoting bone healing and to uncover the mechanism by which CGRP and SP cooperate. Abstract : We established a bisphosphonate‐related osteonecrosis of the jaw (BRONJ) animal model in which the inferior alveolar nerve was injured or transected, and used it to observe whether sensory denervation facilitates the occurrence of BRONJ. We then performed rescue therapy using sensory neuropeptides to determine whether intensive neuropeptide treatment can reverse the pathological process of BRONJ. Finally, we studied the effect of neuropeptides on preosteoclasts treated with BPs in vitro to preliminarily reveal the molecular mechanism underlying their effects.