Genetic variability affects the skeletal response to immobilization in founder strains of the diversity outbred mouse population
Year: 2021
Type: article
Abstract: Mechanical unloading decreases bone volume and strength. In humans and mice, bone mineral density is highly heritable, and in mice the response to changes in loading varies with genetic background. Thus, genetic variability may affect the response of bone to unloading. As a first step to identify genes involved in bones' response to unloading, we evaluated the effects of unloading in eight inbred mouse strains: C57BL/6J, PWK/PhJ, WSB/EiJ, A/J, 129S1/SvImJ, NOD/ShiLtJ, NZO/HlLtJ, and CAST/EiJ. C57BL/6J and NOD/ShiLtJ mice had the greatest unloading-induced loss of diaphyseal cortical bone volume and strength. NZO/HlLtJ mice had the greatest metaphyseal trabecular bone loss, and C57BL/6J, WSB/EiJ, NOD/ShiLtJ, and CAST/EiJ mice had the greatest epiphyseal trabecular bone loss. Bone loss in the epiphyses displayed the highest heritability. With immobilization, mineral:matrix was reduced, and carbonate:phosphate and crystallinity were increased. A/J mice displayed the greatest unloading-induced loss of mineral:matrix. Changes in gene expression in response to unloading were greatest in NOD/ShiLtJ and CAST/EiJ mice. The most upregulated genes in response to unloading were associated with increased collagen synthesis and extracellular matrix formation. Our results demonstrate a strong differential response to unloading as a function of strain. Diversity outbred (DO) mice are a high-resolution mapping population derived from these eight inbred founder strains. These results suggest DO mice will be highly suited for examining the genetic basis of the skeletal response to unloading.
Source: Bone Reports
Language: English
Subfield: Physiology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $1,900
Funders: National Science Foundation, National Aeronautics and Space Administration, Nuclear Safety and Security Commission, National Institutes of Health, National Institute of Arthritis and Musculoskeletal and Skin Diseases, U.S. National Library of Medicine, Division of Chemical, Bioengineering, Environmental, and Transport Systems
Awards: G1354076642, G2195841744, THIS PROPOSAL FOR A TRANSLATIONAL RESEARCH INSTITUTE IS SUBMITTED ON BEHALF OF A CONSORTIUM OF NON-PROFIT ACADEMIC INSTITUTIONS IN RESPONSE TO NASA C, AIM 1: EXAMINE THE RESPONSE OF WILD-TYPE AND CX43-DEFICIENT (VIA CRISPR GENE EDITING) MURINE OSTEOCYTES (OCY454) TO SIMULATED MICROGRAVITY IN VITRO USING A HIGH ASPECT RATIO VESSEL (HARV). AIM 2: EXAMINE THE EFFECT OF SIMULATED MICROGRAVITY IN VIVO ON BONES FROM OSTEOCYTE-SPECIFIC CX43-DEFICIENT MICE. CX43 WILL BE SELECTIVELY DELETED FROM MICE USING A CRE RECOMBINASE APPROACH SIMILAR TO WHAT WE PREVIOUSLY USED TO DELETE CX43 FROM OSTEOBLASTS AND OSTEOCYTES. USING WELL-ESTABLISHED EXPERIMENTAL PARADIGMS LIKE THE HARV APPARATUS AND HLS GREATLY INCREASES THE PROBABILITY OF SUCCESSFULLY COMPLETING OUR AIMS AND ATTAINING IMPORTANT NOVEL FINDINGS. COLLECTIVELY OUR INFRASTRUCTURE AND EXPERTISE IN COMBINATION WITH MULTIPLE UNIQUE REAGENTS PLACE US IN AN UNPARALLELED POSITION TO RAPIDLY AND SIGNIFICANTLY ADVANCE KNOWLEDGE PERTAINING TO THE MECHANISMS UNDERLYING MICROGRAVITY-INDUCED BONE LOSS. THESE AIMS AND THE EXPERIMENTS DESIGNED THEREIN REPRESENT A SUBSTANTIVE DEPARTURE FROM OUR CURRENT UNDERSTANDING AND WILL REVEAL NOVEL TARGETS FOR COUNTERMEASURES., G4962444584, A Systems Genetics Approach to Identify BMD Genes, MRI Acquisition: An integrated platform for combined multi-scale mechanical and chemical analysis to inform functional materials design, G5470864440, Genetic analysis of bone strength, G6038994698, G9000078547, G9000152935, G9000279430
OpenAlex ID: W3206155477