Stromal regulation of pathological bone remodeling - PROJECT SUMMARY Bone disease is a major type of complication of diabetes. Fracture risk in patients with type 1 diabetes (T1D) and T2D can be six-fold and four-fold higher than those without diabetes. The impact of diabetes on bone health is becoming more evident because of the obesity epidemic and the aging of the population. Understanding how diabetes increase bone fragility is important to identify therapeutic targets and treat patients at risk. To treat diabetes, multifactorial approaches including lifestyle modifications and medications are required. However, some dietary regimens and antidiabetic drugs may negatively affect bone health. On the other hand, anti- osteoporosis drugs may affect glucose metabolism. In this project, we propose to test if genetic and pharmacological elevation of O-linked N-Acetylglucosamine (O-GlcNAc) signaling prevents diabetic osteoporosis in preclinical models. The enzymes O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA) mediate the addition and removal of the O-GlcNAc modification to/from serine and threonine residues on intracellular proteins. We and others have established the pivotal role of protein O-GlcNAcylation in physiological homeostasis, as well as disease conditions including diabetes, neurodegeneration, and aging. In the bone, we found that O-GlcNAc is enriched in the multipotent bone marrow stromal cells (BMSCs) that can become either bone-forming osteoblasts or adipocytes. While O-GlcNAc is dispensable for homeostatic turnover of the bone, we found that ablating OGT in adult Lepr+ BMSCs accelerates bone loss specifically in diabetic animals. We will test the central hypothesis that protein O-GlcNAcylation modulates the differentiation fate, metabolic fitness, and niche function of Lepr+ BMSCs, thus impeding diabetic osteopathy and inflammation. Aim 1 will define the functional effects of O-GlcNAcylation on BMSCs and bone health. We expect to find that declined protein O- GlcNAcylation in BMSCs drives maladaptive bone remodeling in diabetic mice. Aim 2 will determine the mechanisms by which O-GlcNAcylation links diabetes to BMSC dysfunction. Specifically, OGT is required for hormonal regulation of BMSC metabolism, proliferation, and differentiation. Aim 3 will characterize O-GlcNAc- dependent stromal-myeloid interactions. We anticipate that stromal O-GlcNAc signaling inhibits bone resorption by limiting BMSC-derived osteoclastogenic niche factors. The completion of the proposed study will establish O- GlcNAcylation as a potential molecular target of future interventions to treat osteoporosis in patients with diabetes.
