Age-dependent impact of inferior alveolar nerve transection on mandibular bone metabolism and the underlying mechanisms

Aging is associated with peripheral nerve degradation and bone destruction. The aim of the study is to elucidate the influence of sensory denervation on bone metabolism in different age groups by establishing a modified unilateral inferior alveolar nerve transection (IANT) model. The rats, divided into young, middle-aged and aged group, were sacrificed at 1, 2, 4 and 8 weeks after right IANT. The histological changes of mandibles were analyzed by fluorescent double labeling, micro-CT, HE, TRAP and anti-CGRP immunohistochemical staining. Molecular mechanisms underlying the changes were analyzed by qPCR and western blot. Differences between the test and control side were evaluated by paired-samples t test. The Friedman test and separate Wilcoxon signed-rank tests were applied to analyze age-dependent difference. The impact of IANT was the most intensive in developing bone, the most persistent in full grown bone and the faintest in the aged bone. The role of IAN in keeping homeostasis was closely related to the anabolic effect of CGRP, which suppressed the number of osteoclasts through OPG/RANKL ratio and controlled growth factors expression like BMP2. This study contributes to a better understanding of the molecular mechanisms of CGRP in vivo and the relationship among sensory nerve, bone metabolism and aging.

[1]  R. Turner,et al.  Effects of neonatal sympathectomy and capsaicin treatment on bone remodeling in rats , 1991, Neuroscience.

[2]  S. Santavirta,et al.  Rapid proliferation of calcitonin gene-related peptide-immunoreactive nerves during healing of rat tibial fracture suggests neural involvement in bone growth and remodelling , 1993, Neuroscience.

[3]  D. Luo,et al.  Involvement of endothelial cell-derived CGRP in heat stress-induced protection of endothelial function. , 2007, Vascular pharmacology.

[4]  J. Szolcsányi.  Forty years in capsaicin research for sensory pharmacology and physiology , 2004, Neuropeptides.

[5]  S. Wakisaka,et al.  Effects of neonatal injury of the inferior alveolar nerve on the development and regeneration of periodontal nerve fibers in the rat incisor , 2000, Brain Research.

[6]  T. Guo,et al.  Capsaicin‐Sensitive Sensory Neurons Contribute to the Maintenance of Trabecular Bone Integrity , 2004, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[7]  Ming Shen,et al.  CBX7 deficiency plays a positive role in dentin and alveolar bone development , 2016, Journal of Molecular Histology.

[8]  Rui L Reis,et al.  Crosstalk between osteoblasts and endothelial cells co-cultured on a polycaprolactone-starch scaffold and the in vitro development of vascularization. , 2009, Biomaterials.

[9]  D. Cochran,et al.  Risk assessment of inferior alveolar nerve injury for immediate implant placement in the posterior mandible: a virtual implant placement study. , 2014, Journal of dentistry.

[10]  Jing Zhang,et al.  Healing of periodontal defects and calcitonin gene related peptide expression following inferior alveolar nerve transection in rats , 2013, Journal of Molecular Histology.

[11]  Yan Han,et al.  The changes of Proteome in MG-63 cells after induced by calcitonin gene-related peptide. , 2014, Biochemical and biophysical research communications.

[12]  U. Lerner,et al.  Osteotropic effects by the neuropeptides calcitonin gene-related peptide, substance P and vasoactive intestinal peptide. , 2008, Journal of musculoskeletal & neuronal interactions.

[13]  R. Rabin,et al.  Statins Decrease Expression of the Proinflammatory Neuropeptides Calcitonin Gene-Related Peptide and Substance P in Sensory Neurons , 2008, Journal of Pharmacology and Experimental Therapeutics.

[14]  A. Rubinacci,et al.  Calcitonin gene‐related peptide (CGRP) inhibits apoptosis in human osteoblasts by β‐catenin stabilization , 2010, Journal of cellular physiology.

[15]  M H Rivner,et al.  Influence of age and height on nerve conduction , 2001, Muscle & nerve.

[16]  Wanghong,et al.  Expression of calcitonin gene-related peptide in rat pulp and periodontal tissues by indirect immunofluorescence method. , 2013 .

[17]  Jian Zhou,et al.  The biological effects and mechanisms of calcitonin gene-related peptide on human endothelial cell , 2013, Journal of receptor and signal transduction research.

[18]  P. Patil,et al.  Inferior alveolar and mental nerve injuries associated with open reduction and internal fixation of mandibular fractures: a Seven Year retrospective study. , 2014, Journal of cranio-maxillo-facial surgery : official publication of the European Association for Cranio-Maxillo-Facial Surgery.

[19]  T. Shimo,et al.  Expression pattern of sonic hedgehog signaling and calcitonin gene-related peptide in the socket healing process after tooth extraction. , 2015, Biochemical and biophysical research communications.

[20]  Jing Zhang,et al.  Expression of neuropeptides and bone remodeling-related factors during periodontal tissue regeneration in denervated rats , 2015, Journal of Molecular Histology.

[21]  A. Togari,et al.  Pharmacological topics of bone metabolism: the physiological function of the sympathetic nervous system in modulating bone resorption. , 2008, Journal of pharmacological sciences.

[22]  F Bonnel,et al.  Cortical and trabecular bone distribution in the femoral neck in osteoporosis and osteoarthritis. , 2008, Bone.

[23]  Calcitonin gene-related peptide and its receptors: molecular genetics, physiology, pathophysiology, and therapeutic potentials. , 1996, Endocrine reviews.

[24]  H. Kondo,et al.  Effects of capsaicin-induced sensory denervation on bone metabolism in adult rats. , 2010, Bone.

[25]  A. Silman,et al.  Influence of age and sex steroids on bone density and geometry in middle-aged and elderly European men , 2010, Osteoporosis International.

[26]  A. Tenenhouse,et al.  Change in bone mineral density as a function of age in women and men and association with the use of antiresorptive agents , 2008, Canadian Medical Association Journal.

[27]  D. Ceballos,et al.  Morphometric and ultrastructural changes with ageing in mouse peripheral nerve , 1999, Journal of anatomy.

[28]  K. Heyeraas,et al.  Effect of capsaicin treatment or inferior alveolar nerve resection on dentine formation and calcitonin gene-related peptide- and substance P-immunoreactive nerve fibres in rat molar pulp. , 1996, Archives of oral biology.

[29]  B. Baroukh,et al.  Effects of Capsaicin‐Induced Sensory Denervation on Osteoclastic Resorption in Adult Rats , 2000, Experimental physiology.

[30]  T. Yamashiro,et al.  Inferior alveolar nerve transection inhibits increase in osteoclast appearance during experimental tooth movement. , 2000, Bone.

[31]  D. Jiang,et al.  The Role and Mechanism of Exogenous Calcitonin Gene-Related Peptide on Mesenchymal Stem Cell Proliferation and Osteogenetic Formation , 2014, Cell Biochemistry and Biophysics.

[32]  P. Reeh,et al.  Noxious heat‐induced CGRP release from rat sciatic nerve axons in vitro , 2001, The European journal of neuroscience.

[33]  Li Yan,et al.  Effect of calcitonin gene-related peptide on osteoblast differentiation in an osteoblast and endothelial cell co-culture system , 2012, Cell biology international.