Analysis for physiological role of Dexras1 as a glucocorticoid mediator

Abstract

Part1. Dexras1 plays a pivotal role in maintaining the equilibrium between adipogenesis and osteogenesis Mesenchymal stem cells (MSCs) have drawn considerable attention because they can differentiate into various cell types including chondrocytes, osteoblasts, and adipocytes. Because the differentiated cells are derived from the same origin, it is widely accepted that adipogenesis counteracts osteoblastogenesis and restricts MSCs from differentiating into osteoblasts. In addition, it is well-known that chronic steroid treatment induces Cushing’s syndrome, which is accompanied by an increase in visceral adiposity and osteoporosis. The balance of differentiation from MSCs to either adipocytes or osteoblasts is critical to prevent Cushing’s syndrome, however, the detailed molecular mechanisms by which chronic steroid treatment disturbs the balance between adipogenesis and osteoblastogenesis from MSCs is unclear. It was previously reported that Dexras1 is a critical factor that potentiates adipogenesis. Here, I report that Dexras1 is the fundamental regulator that maintains the balance between chronic steroid treatment-associated adipogenesis and osteoporosis. Concurrent with reduced adipogenesis, dual-energy x-ray absorptiometry scan and micro-computed tomography analyses in murine femurs revealed that Dexras1 deficiency was associated with increased osteogenesis. Furthermore, I observed that Dexras1 deficiency promoted in vitro osteogenesis of bone marrow-derived stromal cells and mouse embryonic fibroblasts, suggesting that Dexras1 deficiency ameliorates steroid-induced osteoporosis. I also observed that Dexras1 downregulated SMAD signaling pathways, which reduced the osteogenic differentiation capacity of pre-osteoblast MC3T3-E1 cells into mature osteoblasts. I propose that Dexras1 is critical for maintaining the equilibrium between adipogenesis and osteogenesis in bone marrow stromal cells and may be a future therapeutic target for clinical osteoporosis treatments. part2. Dexras1 induces metabolic side effects of iatrogenic Cushing’s syndrome. Glucocorticoids (GCs) are steroid hormones with multiple roles in regulating essential body functions by controlling cell metabolism, growth, differentiation, and apoptosis. While GCs suppress inflammation, they affect various tissues resulting in side effects including central obesity, muscle weakness, and osteoporosis. In my previous study, I established that Dexras1 directly induced by GCs, acts as a regulator of adipogenesis and osteogenesis via its counter-regulating action. Here, I report that Dexras1 mediates the side effects of GCs on tissues related to metabolism incluing adipose tissues and skeletal musclesin corticotropin releasing hormone transgenic mice (CRH Tg) which show similar phenotypes of human iatrogenic Cushing’s syndrome. Expression of Dexras1 was upregulated in GC-related tissues including adipose tissue and muscle of CRH Tg mice, compared to wild type mice. CRH Tg mice had abnormal fat distribution and muscle atrophy, while CRH Tg-Dexras1 KO mice (CRH Tg-DexKO mice) had reduced mesentric fat as well as enhanced muscle mass. Furthermore, CRH Tg-DexKO mice had improved glucose sensitivity with lowered insulin and triglycerides, compared to CRH Tg mice. CRH Tg-DexKO mice were prone to catalyze fatty acids with high-energy consumption which was dependent on adipose tissue but not brown adipose tissue. CRH Tg mice adipocytes showed promoted lipid catabolism and biosynthesis including high levels of adipocyte-specific insulin like growth factor (IGF1) which were normalized by ablation of Dexras1. Similar to CRH Tg-DexKO mice, CRH Tg mice treated with IGF1R specific inhibitor (linsitinib) showed reduced fat mass with improved glucose sensitivity. Thus, Dexras1 is a key mediator of the metabolic side effects of iatrogenic Cushing’s syndrome by linking GCs to metabolism.