Genetic variability affects the skeletal response to immobilization in founder strains of the diversity outbred mouse population

Friedman, Michael; Abood, Abdullah; Senwar, Bhavya; Zhang, Yue; Maroni, Camilla Reina; Ferguson, Virginia L.; Farber, Charles R.; Donahue, Henry J.

doi:10.1016/j.bonr.2021.101140

Cited by 7 publications

(20 citation statements)

References 55 publications

(70 reference statements)

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“…For example, casting for 3 weeks increased crystallinity only in C57BL/6J and NZO/ HiLtJ mice, and only the carbonate:phosphate ratios in A/J mice. (42) These preclinical findings add to the complexity of the disuse scenario and suggest a strong genetic propensity for disuse-induced bone mineralization changes.…”

Section: Bone Matrix-mechanical and Chemicalmentioning

confidence: 86%

“…Although the C57BL/6J mouse is widely used, it is important to note C57BL/6J mice show enhanced bone loss due to disuse compared to other mouse strains, (42,75) and therefore may not accurately reflect all aspects of disuse-induced bone loss in humans. Bed rest and spaceflight studies in humans show wide variation, with changes in trabecular volumetric bone mineral density (Tb.vBMD) being anywhere from +0.5% to À3% per month, driven by changes in both Tb.N and Tb.Th.…”

Section: Cortical and Cancellous Microarchitecturementioning

confidence: 99%

“…(72,79,80) For example, our laboratory demonstrated immobilization by casting among eight genetically diverse inbred mouse strains led to high variability among disuseinduced cancellous and cortical changes. (42) Among the mouse inbred strains, differences between diaphyseal Ct.Ar/T.Ar of immobilized and control limbs ranged from +0.62% to À7.42% with the greatest decrease in C57BL/6J and NOD/ShiLtJ mice. Differences between trabecular BV/TV of immobilized and control limbs ranged from À36.5% to À8.3%, with the greatest decrease in CAST/EiJ and C57BL/6J mice.…”

Section: Cortical and Cancellous Microarchitecturementioning

confidence: 99%

“…(40,41) Furthermore, SLI in C57BL/6J mice induces femoral and tibial bone loss preferentially in the epiphyseal and metaphyseal cancellous sites and loss of lower limb musculature compared to contralateral limbs. (40,42) Clinical reports of lower extremity fractures in adolescents and adults treated by casting immobilization also demonstrate preferential loss of lower limb BMD (particularly at the distal tibia and proximal femur) compared to uninjured limbs and healthy controls. (43,44) Therefore, SLI effectively mimics lower limb bone loss seen in casted/immobilized patients following unilateral and lower extremity trauma.…”

Section: Immobilization and Paralysismentioning

confidence: 99%

“…(92,93) Preclinical models of extreme disuse such as HLU, casting, and sciatic neurectomy across multiple rodent strains demonstrate variable decreases in structural (stiffness, ultimate load) and material properties (modulus, ultimate stress) accompanied by increases in mineral:matrix ratio, crystallinity, and carbonate:phosphate ratio, compared to controls. (42,73,74,94,95) Similarly, aged 19-20-month-old C57BL/6J and BALB/cByJ mice display increased mineral:matrix ratio, crystallinity, and carbonate:phosphate ratio resulting in inferior mechanical properties (stiffness, energy to fracture) compared to 5-month-old controls. (73,74,96,97) Importantly, multiple studies using the PWB model in C57BL/6J and BALB/cByJ mice suggest structural, but not material, level alterations with moderate disuse.…”

Section: Bone Matrix-mechanical and Chemicalmentioning

confidence: 99%

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Similarities Between Disuse and Age-Induced Bone Loss

Buettmann

Goldscheitter

Hoppock

et al. 2020

Journal of Bone and Mineral Research

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Disuse and aging are known risk factors associated with low bone mass and quality deterioration, resulting in increased fracture risk. Indeed, current and emerging evidence implicate a large number of shared skeletal manifestations between disuse and aging scenarios. This review provides a detailed overview of current preclinical models of musculoskeletal disuse and the clinical scenarios they seek to recapitulate. We also explore and summarize the major similarities between bone loss after extreme disuse and advanced aging at multiple length scales, including at the organ/tissue, cellular, and molecular level. Specifically, shared structural and material alterations of bone loss are presented between disuse and aging, including preferential loss of bone at cancellous sites, cortical thinning, and loss of bone strength due to enhanced fragility. At the cellular level bone loss is accompanied, during disuse and aging, by increased bone resorption, decreased formation, and enhanced adipogenesis due to altered gap junction intercellular communication, WNT/β‐catenin and RANKL/OPG signaling. Major differences between extreme short‐term disuse and aging are discussed, including anatomical specificity, differences in bone turnover rates, periosteal modeling, and the influence of subject sex and genetic variability. The examination also identifies potential shared mechanisms underlying bone loss in aging and disuse that warrant further study such as collagen cross‐linking, advanced glycation end products/receptor for advanced glycation end products (AGE‐RAGE) signaling, reactive oxygen species (ROS) and nuclear factor κB (NF‐κB) signaling, cellular senescence, and altered lacunar‐canalicular connectivity (mechanosensation). Understanding the shared structural alterations, changes in bone cell function, and molecular mechanisms common to both extreme disuse and aging are paramount to discovering therapies to combat both age‐related and disuse‐induced osteoporosis. © 2022 American Society for Bone and Mineral Research (ASBMR).

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Section: Bone Matrix-mechanical and Chemicalmentioning

confidence: 86%

Section: Cortical and Cancellous Microarchitecturementioning

confidence: 99%

Section: Cortical and Cancellous Microarchitecturementioning

confidence: 99%

Section: Immobilization and Paralysismentioning

confidence: 99%

Section: Bone Matrix-mechanical and Chemicalmentioning

confidence: 99%

See 3 more Smart Citations

Similarities Between Disuse and Age-Induced Bone Loss

Buettmann

Goldscheitter

Hoppock

et al. 2020

Journal of Bone and Mineral Research

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

Friedman

Buettmann

Zeineddine

et al. 2023

Journal Orthopaedic Research

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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.

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