Biology subjects

Bouxsein, M. L.

Publications and source records attributed to Bouxsein, M. L..

3 recordsLinked to original sources

bioRxiv2020

Systems genetics analyses in Diversity Outbred mice inform human bone mineral density GWAS and identify Qsox1 as a novel determinant of bone strength

Genome-wide association studies (GWASs) for osteoporotic traits have identified over 1000 associations; however, their impact has been limited by the difficulties of causal gene identification and a strict focus on bone mineral density (BMD). Here, we used Diversity Outbred (DO) mice to directly address these limitations by performing the first systems genetics analysis of 55 complex skeletal phenotypes. We applied a network approach to cortical bone RNA-seq data to discover 72 genes likely to be causal for human BMD GWAS associations, including the novel genes SERTAD4 and GLT8D2. We also performed GWAS in the DO for a wide-range of bone traits and identified Qsox1 as a novel gene influencing cortical bone accrual and bone strength. Our results provide a new perspective on the genetics of osteoporosis and highlight the ability of the mouse to inform human genetics.

genetics↗

bioRxiv2020

Trpm8 modulates thermogenesis in a sex-dependent manner without influencing cold-induced bone loss

Trpm8 (transient receptor potential cation channel, subfamily M, member 8) is expressed by sensory neurons, and it is involved in the detection of cold temperatures. Increased TRPM8 activity triggers an increase in uncoupling protein 1 (Ucp1)-dependent brown adipose tissue (BAT) thermogenesis. Bone density and marrow adipose tissue are regulated by rodent housing temperature and brown adipose tissue, suggesting one mediator of this effect may be TRPM8. In order to test whether TRPM8 was involved in the co-regulation of thermogenesis and bone homeostasis, we examined the bone phenotypes of one-year-old Trpm8 knockout mice (Trpm8-KO) and then exposed them to a 4-week cold temperature challenge. Male Trpm8-KO mice had lower bone mineral density than WT, with smaller bone size (femur length and cross-sectional area) being the most striking finding, and exhibited a delayed cold acclimation with increased BAT expression of Ucp1, Dio2 and Cidea at the end of the study. In contrast to males, female Trpm8-KO mice had low vertebral bone microarchitectural parameters, but no genotype-specific alterations in body temperature. Interestingly, Trpm8 was not required for cold-induced trabecular bone loss in either sex, but may be required for cold-induced changes in marrow adiposity in males. Furthermore, bone marrow adipose tissue accumulation in females was significantly blunted by Trpm8 deletion. In summary, we identified sex differences in the role of TRPM8 in maintaining body temperature, bone density and marrow adipose tissue. Identifying mechanisms through which cold temperature and brown adipose tissue influence bone could help to ameliorate potential bone side effects of obesity treatments designed to stimulate thermogenesis.

physiology↗

bioRxiv2020

Pharmacological inhibition of longevity regulator PAPP-A restrains mesenchymal stromal cell activity

Reducing insulin-like growth factor (IGF) signaling is one of the best conserved and characterized mechanisms to extend longevity. Pregnancy associated plasma protein A (PAPP-A) is a secreted metalloprotease that increases IGF availability by cleaving IGF binding proteins. PAPP-A inhibition reduces local IGF signaling, limits the progression of multiple age-related diseases, and extends lifespan, but the mechanisms behind these pleiotropic effects remains unknown. Here, we developed and utilized a PAPP-A neutralizing antibody to discover that adulthood inhibition of this protease reduced collagen and extracellular matrix (ECM) gene expression in multiple tissues in mice. Using bone marrow to explore this effect, we identified mesenchymal stromal cells (MSCs) as the source of PAPP-A and primary responders to PAPP-A inhibition. Short-term treatment with anti-PAPP-A reduced IGF signaling in MSCs, altered MSC expression of collagen/ECM, and decreased MSC number. This affected MSC-dependent functions, decreasing myelopoiesis and osteogenesis. Our data demonstrate that PAPP-A inhibition reduces the activity and number of IGF-dependent mesenchymal progenitor cells and their differentiated progeny, and that this reduction leads to functional changes at the tissue level. MSC-like cells are present in virtually all tissues, and aberrant collagen and ECM production from mesenchymal cells drives aspects of aging and age-related diseases, thus this may be a mechanism by which PAPP-A deficiency enhances lifespan and healthspan. SummaryInhibition of PAPP-A, a regulator of IGF signaling, decreases multi-tissue collagen and extracellular matrix gene expression and modulates mesenchymal stromal cell activity in murine bone marrow.

physiology↗