Abstract
The postmenopausal period in women is associated with decreased circulating estrogen levels, which accelerate bone loss and increase the risk of fracture. Here, we gained novel insight into the molecular mechanisms mediating bone loss in ovariectomized (OVX) mice, a model of human menopause, using co-expression network analysis. Specifically, we generated a co-expression network consisting of 53 gene modules using expression profiles from intact and OVX mice from a panel of inbred strains. The expression of four modules was altered by OVX, including module 23 whose expression was decreased by OVX across all strains. Module 23 was enriched for genes involved in the response to oxidative stress, a process known to be involved in OVX-induced bone loss. Additionally, module 23 homologs were co-expressed in human bone marrow. Alpha synuclein (Snca) was one of the most highly connected “hub” genes in module 23. We characterized mice deficient in Snca and observed a 40% reduction in OVX-induced bone loss. Furthermore, protection was associated with the altered expression of specific network modules, including module 23. In summary, the results of this study suggest that Snca regulates bone network homeostasis and ovariectomy-induced bone loss.
Highlights
Osteoporosis is a condition characterized by low bone mineral density (BMD) and an increased risk of fracture[1]
Based on the enrichment for genes involved in the response to oxidative stress, which has been linked to ovariectomy-induced bone loss, we focused on module 23
In the U.S, 80% of the total osteoporotic population is comprised of postmenopausal women, 50% of which will experience a fracture during their lifetime
Summary
Osteoporosis is a condition characterized by low bone mineral density (BMD) and an increased risk of fracture[1]. Osteoporosis primarily affects postmenopausal women due to decreased estrogen levels[4], which accelerate bone loss. In states of estrogen deficiency, both bone formation and resorption are increased; resorption outpaces formation resulting in lower BMD and higher rates of fracture. To make this situation worse, women experiencing the most rapid postmenopausal bone loss are at an even higher risk for fracture independent of BMD6. We identified a module of genes whose expression is associated with OVX-induced bone loss. We demonstrated that the hub gene of this module, alpha-synuclein (Snca), is a key mediator of the expression of specific network modules and the skeletal response to estrogen deficiency
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