Streptozocin-induced type-1 diabetes mellitus results in decreased density of CGRP sensory and TH sympathetic nerve fibers that are positively correlated with bone loss at the mouse femoral neck

Abstract

Type-1 diabetes mellitus (T1DM) results in loss of innervation in some tissues including epidermis and retina; however, the effect on bone innervation is unknown. Likewise, T1DM results in pathological bone loss and increased risk of fracture. Thus, we quantified the density of calcitonin gene-related peptide (CGRP⁺) sensory and tyrosine hydroxylase (TH⁺) sympathetic nerve fibers and determined the association between the innervation density and microarchitecture of trabecular bone at the mouse femoral neck. Ten weeks-old female mice received 5 daily administrations of streptozocin (i.p. 50mg/kg) or citrate (control group). Twenty weeks later, femurs were analyzed by microCT and processed for immunohistochemistry. Confocal microscopy analysis revealed that mice with T1DM had a significant loss of both CGRP⁺ and TH⁺ nerve fibers in the bone marrow at the femoral neck. Likewise, microCT analysis revealed a significant decrease in the trabecular bone mineral density (tBMD), bone volume/total volume ratio (BV/TB), trabecular thickness (Tb.Th), trabecular number (Tb.N) and trabecular separation (Tb.Sp) in mice with T1DM as compared to control mice. Analysis of correlation revealed a positive and significant association between density of CGRP⁺ or TH⁺ nerve fibers with tBMD, BV/TV, Tb.Th and Tb.Sp, but not with trabecular number (there was a positive association only for CGRP⁺) and degree of anisotropy (DA). This study suggests an interaction between sensory and sympathetic nervous system and T1DM-induced bone loss. Identification of the factors involved in the loss of CGRP⁺ sensory and TH⁺ sympathetic fibers and how they regulate bone loss may result in new avenues to treat T1DM-related osteoporosis.

Keywords: Bone-remodeling; Hip-fracture; Innervation; Osteoporosis; microCT.