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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 use Diversity Outbred (DO) mice to directly address these limitations by performing a systems genetics analysis of 55 complex skeletal phenotypes. We apply a network approach to cortical bone RNA-seq data to discover 66 genes likely to be causal for human BMD GWAS associations, including the genes SERTAD4 and GLT8D2. We also perform GWAS in the DO for a wide-range of bone traits and identify Qsox1 as a gene influencing cortical bone accrual and bone strength. In this work, we advance our understanding of the genetics of osteoporosis and highlight the ability of the mouse to inform human genetics., Osteoporosis GWAS faces two challenges, causal gene discovery and a lack of phenotypic diversity. Here, the authors use the Diversity Outbred mouse population to inform human GWAS using networks and map genetic loci for 55 bone traits, identifying new potential bone strength genes.

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.

Objectives Stromal interacting molecule-1 (STIM1) plays a role in coordinating calcium signaling in different cell types. The increase or deletion of STIM1 expression in cardiomyocyte causes cardiac complication. Moreover, the deletion of STIM1 in endothelial cell causes vascular endothelial dysfunction. However, the disruption of STIM1 in smooth muscle cells (SMC) has no effect on endothelial function but protects vascular function when mice are infused with angiotensin-II. Nevertheless, the role of SMC-STIM1 in acute and chronic myocardial infarction (MI) induced by acute ischemia-reperfusion injury and permanent coronary artery occlusion is unknown. Methods and results Stim1 were generated and crossed into the SM22α-Cre backgrounds. SM22α-Cre causes deletion of STIM1 floxed genes in adult SMC (Stim1). Control and Stim1 mice were subjected to acute ischemia-reperfusion injury. Hearts were then harvested and incubated with triphenyltetrazolium chloride to determine the infarct size. In control mice which are subjected to ischemia-reperfusion, the heart developed a significant infarct associated with an increase in STIM1 expression. Interestingly, the infarct size was substantially reduced in Stim1 mice. The protection in Stim1 mice against ischemia-reperfusion injury involves the modulation of endoplasmic reticulum stress, apoptosis, oxidative stress, protein kinase B, and mitogen-activated protein (MAP) kinase (ERK1/2 and p38) signaling, and inflammation. Furthermore, in another model of chronic MI induced by permanent coronary artery occlusion, SMC-STIM1 disruption significantly reduced myocardial infarct size and improved cardiac function. Conclusion Our results provide new evidence that SMC-STIM1 disruption is a novel mechanism that protects the heart from MI through reduction of endoplasmic reticulum stress, oxidative stress, MAP-Kinase, apoptosis, and inflammation.

Objectives— Chronic hypertension is the most critical risk factor for cardiovascular disease, heart failure, and stroke. Approach and Results— Here we show that wild-type mice infused with angiotensin II develop hypertension, cardiac hypertrophy, perivascular fibrosis, and endothelial dysfunction with enhanced stromal interaction molecule 1 (STIM1) expression in heart and vessels. All these pathologies were significantly blunted in mice lacking STIM1 specifically in smooth muscle (Stim1 SMC−/− ). Mechanistically, STIM1 upregulation during angiotensin II–induced hypertension was associated with enhanced endoplasmic reticulum stress, and smooth muscle STIM1 was required for endoplasmic reticulum stress–induced vascular dysfunction through transforming growth factor-β and nicotinamide adenine dinucleotide phosphate oxidase–dependent pathways. Accordingly, knockout mice for the endoplasmic reticulum stress proapoptotic transcriptional factor, CCAAT-enhancer–binding protein homologous protein (CHOP −/− ), were resistant to hypertension-induced cardiovascular pathologies. Wild-type mice infused with angiotensin II, but not Stim1 SMC−/− or CHOP −/− mice showed elevated vascular nicotinamide adenine dinucleotide phosphate oxidase activity and reduced phosphorylated endothelial nitric oxide synthase, cGMP, and nitrite levels. Conclusions— Thus, smooth muscle STIM1 plays a crucial role in the development of hypertension and associated cardiovascular pathologies and represents a promising target for cardiovascular therapy.

Background: Stromal interacting molecule 1 (STIM1) is a calcium sensor in the endoplasmic reticulum (ER). We previously reported that STIM1 plays opposing roles in vascular smooth muscle cells (SMC) vs. endothelial cell in the regulation of vascular reactivity. However, the role of SMC STIM1 in heart failure is yet to be determined. Methods and Results: We utilize control (C57/Bl6) and mice lacking STIM1 specifically in SMC (Stim1 SMC-/- ). We subjected all mice to left anterior descending coronary artery (LAD) permanent occlusion for 3 weeks. We performed echocardiography before the LAD ligation and 3 week after. In the end, we sacrificed mice and harvested the heart for biochemical and histology studies. The heart weight, collagen, and infarct area were significantly augmented in control mice subjected to LAD occlusion. The diastolic (Ejection fraction) and systolic functions (fractional shortening) were significantly compromised in control mice subjected to LAD occlusion. Interestingly, the cardiac hypertrophy, the collagen content, the infarct area, the ejection fraction, and the fraction shortening were protected in Stim1 SMC-/- mice subjected to LAD occlusion. The protective effect of STIM1 disruption in SMC involved the reduction in ER stress activation, the autophagy, and apoptosis mechanisms. Conclusion: Our results indicate that the disruption of STIM1 in SMC protects the heart against chronic ischemia through the inhibition of ER stress, autophagy, and apoptosis.