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Bone adaptation to mechanical loading in a mouse model of reduced peripheral sensory nerve function.

ABSTRACT: Underlying mechanisms contributing to the imbalance in bone turnover during osteoporosis remain only partially explained. Reduced sensory nerve function may contribute to this imbalance, as sensory neuropeptides affect the activity of osteoblasts and osteoclasts in vivo, especially during bone adaptation. In this study, we investigated bone adaptation in mice following two weeks of tibial compression (peak magnitude 3 N or 7 N). To induce decreased sensory nerve function, mice were treated with capsaicin as neonates. We hypothesized that decreased sensory nerve function would diminish the adaptation of bone to mechanical loading, assessed with ?CT and dynamic histomorphometry. We found that tibial compression induced significant changes in cortical microarchitecture that depended on compression magnitude and location along the length of the tibia; in contrast, there was no effect of loading on trabecular bone of the tibial metaphysis. Tibial compression significantly increased periosteal, and decreased endosteal, bone formation. Contrary to our initial hypothesis, capsaicin-treated mice generally displayed a similar, if not larger, adaptive response to mechanical loading, including greater increases in bone mineral content and mineral apposition rate. To integrate mechanical loading of bone with sensory nerve activation, we examined whether concentration of the neuropeptides calcitonin gene-related peptide (CGRP) and substance P (SP) in bone were affected following 1 or 5 days of 5 N tibial compression or hindlimb unloading. We found that 1 day of tibial compression significantly increased CGRP concentrations in bone, and hindlimb unloading also exhibited a trend toward increased CGRP in bone. These results may suggest a role of sensory nerves in the bone adaptation response to the mechanical environment, though this remains unclear.

SUBMITTER: Heffner MA

PROVIDER: S-EPMC5663494 | biostudies-other | 2017

REPOSITORIES: biostudies-other

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Bone adaptation to mechanical loading in a mouse model of reduced peripheral sensory nerve function.

Heffner Mollie A MA Genetos Damian C DC Christiansen Blaine A BA

PloS one 20171031 10

Underlying mechanisms contributing to the imbalance in bone turnover during osteoporosis remain only partially explained. Reduced sensory nerve function may contribute to this imbalance, as sensory neuropeptides affect the activity of osteoblasts and osteoclasts in vivo, especially during bone adaptation. In this study, we investigated bone adaptation in mice following two weeks of tibial compression (peak magnitude 3 N or 7 N). To induce decreased sensory nerve function, mice were treated with ...[more]

PMID: 29088267

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Project description:Loss-of-function mutations in the Sost gene lead to high bone mass phenotypes. Pharmacological inhibition of Sost/sclerostin provides a new drug strategy for treating osteoporosis. Questions remain as to how physical activity may affect bone mass under sclerostin inhibition and if that effect differs between males and females. We previously observed in female Sost knockout (KO) mice an enhanced cortical bone formation response to a moderate level of applied loading (900 ?? at the tibial midshaft). The purpose of the present study was to examine cortical bone adaptation to the same strain level applied to male Sost KO mice. Strain-matched in vivo compressive loading was applied to the tibiae of 10-, 26- and 52-week-old male Sost KO and littermate control (LC) mice. The effect of tibial loading on bone (re)modeling was measured by microCT, 3D time-lapse in vivo morphometry, 2D histomorphometry and gene expression analyses. As expected, Sost deficiency led to high cortical bone mass in 10- and 26-week-old male mice as a result of increased bone formation. However, the enhanced bone formation associated with Sost deficiency did not appear to diminish with skeletal maturation. An increase in bone resorption was observed with skeletal maturation in male LC and Sost KO mice. Two weeks of in vivo loading (900 ?? at the tibial midshaft) induced only a mild anabolic response in 10- and 26-week-old male mice, independent of Sost deficiency. A decrease in the Wnt inhibitor Dkk1 expression was observed 3 h after loading in 52-week-old Sost KO and LC mice, and an increase in Lef1 expression was observed 8 h after loading in 10-week-old Sost KO mice. The current results suggest that long-term inhibition of sclerostin in male mice does not influence the adaptive response of cortical bone to moderate levels of loading. In contrast with our previous strain-matched study in females showing enhanced bone responses with Sost ablation, these results in males indicate that the influence of Sost deficiency on the cortical bone formation response to a moderate level of loading differs between males and females. Clinical studies examining antibodies to inhibit sclerostin may need to consider that the efficacy of additional physical activity regimens may be sex dependent.

Project description:It is estimated that more than 90% of human genes express multiple mRNA transcripts due to alternative splicing. Consequently, the proteins produced by different splice variants will likely have different functions and expression levels. Several genes with splice variants are known in bone, with functions that affect osteoblast function and bone formation. The primary goal of this study was to evaluate the extent of alternative splicing in a bone subjected to mechanical loading and subsequent bone formation. We used the rat forelimb loading model, in which the right forelimb was loaded axially for 3 min, while the left forearm served as a non-loaded control. Animals were subjected to loading sessions every day, with 24 h between sessions. Ulnae were sampled at 11 time points, from 4 h to 32days after beginning loading. RNA was isolated and mRNA abundance was measured at each time point using Affymetrix exon arrays (GeneChip® Rat Exon 1.0 ST Arrays). An ANOVA model was used to identify potential alternatively spliced genes across the time course, and five alternatively spliced genes were validated with qPCR: Akap12, Fn1, Pcolce, Sfrp4, and Tpm1. The number of alternatively spliced genes varied with time, ranging from a low of 68 at 12h to a high of 992 at 16d. We identified genes across the time course that encoded proteins with known functions in bone formation, including collagens, matrix proteins, and components of the Wnt/?-catenin and TGF-? signaling pathways. We also identified alternatively spliced genes encoding cytokines, ion channels, muscle-related genes, and solute carriers that do not have a known function in bone formation and represent potentially novel findings. In addition, a functional characterization was performed to categorize the global functions of the alternatively spliced genes in our data set. In conclusion, mechanical loading induces alternative splicing in bone, which may play an important role in the response of bone to mechanical loading.

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Dataset Information

Bone adaptation to mechanical loading in a mouse model of reduced peripheral sensory nerve function.

Publications

Bone adaptation to mechanical loading in a mouse model of reduced peripheral sensory nerve function.

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