Genetic variation influences the skeletal response to hindlimb unloading in the eight founder strains of the diversity outbred mouse population

Abstract

During disuse, mechanical unloading causes extensive bone loss, decreasing bone volume and strength. Variations in bone mass and risk of osteoporosis are influenced by genetics; however, it remains unclear how genetic variation affects the skeletal response to unloading. We previously found that genetic variation affects the musculoskeletal response to 3 weeks of immobilization in the 8 Jackson Laboratory J:DO founder strains: C57Bl/6J, A/J, 129S1/SvImJ, NOD/ShiLtJ, NZO/HlLtJ, CAST/EiJ, PWK/PhJ, and WSB/EiJ. Hindlimb unloading (HLU) is the best model for simulating local and systemic contributors of disuse and therefore may have a greater impact on bones than immobilization. We hypothesized that genetic variation would affect the response to HLU across the eight founder strains. Mice of each founder strain were placed in HLU for 3 weeks, and the femurs and tibias were analyzed. There were significant HLU and mouse strain interactions on body weight, femur trabecular BV/TV, and femur ultimate force. This indicates that unloading only caused significant catabolic effects in some mouse strains. C57BL/6 J mice were most affected by unloading while other strains were more protected. There were significant HLU and mouse strain interactions on gene expression of genes encoding bone metabolism genes in the tibia. This indicates that unloading only caused significant effects on bone metabolism genes in some mouse strains. Different mouse strains respond to HLU differently, and this can be explained by genetic differences. These results suggest the outbred J:DO mice will be a powerful model for examining the effects of genetics on the skeletal response to HLU.

Receptors Implicated in Microgravity-Induced Bone Loss

“…Finally, it is worth noting that the loss of bone is variable, suggesting that some people are better suited for long-term missions in low gravity than others [159]. Recent studies of muscle and bone loss in mice in simulated microgravity suggest a genetic basis for differences [188,189], consistent with the idea that bone loss in microgravity may be influenced by genes. In the future, astronaut selection may, in part, depend on genetic characteristics that limit pathological responses to low gravity and other adverse, but unavoidable, elements (radiation for example) of space flight [190].…”

“…Moreover, like on Earth, these may reflect genetic differences. Direct evidence suggests that this is the case with respect to muscle wasting and bone loss in mice [188,189], which have served as a useful model for human musculoskeletal disorders. Currently, astronaut and cosmonaut selection includes numerous characteristics that are genetically linked, including height, correctable vision, allergies, migraines, and colorblindness [244].…”

Hindlimb Unloading Induces Bone Microarchitectural and Transcriptomic Changes in Murine Long Bones in an Age-Dependent Manner

“…Disuse initiates changes in bone strength, but perhaps three weeks are not sufficient to observe large changes in mechanical strength at these age groups. In 4-month-old mice there are changes in ultimate force after HLU, but no significant changes in any other parameter[19].…”

“…We included two additional datasets in our comparison analysis. First, 4-month-old C57BL/6J male mice subject to HLU for a period of three-weeks from our recently published study, which included detailed analysis of bone geometry and mechanical properties[19]. Second, a dataset (GSE169292) from the NIH GEO which contained results from 3-month-old female C57BL/6N mice subjected to HLU for a period of seven days[24].…”

“…Animals were dual-housed. The disuse-related model of bone loss was established by hindlimb unloading (HLU) for 3 weeks, as has been performed extensively in our laboratory [17][18][19]. These experiments were performed using rat cages with a wire mesh bottom (Allentown) to allow for tail suspension.…”