ER stress in prediabetes-associated skeletal fragility

Center University of Colorado Denver
Award Year 2021
Pilot Study ER stress in prediabetes-associated skeletal fragility
Awardee Srividhya Iyer PhD ORCiD

People with diabetes who are obese and people with prediabetes are predisposed to higher fracture incidence and poor bone healing outcomes, but the basis of impaired osteogenesis remains unclear. Accumulation of misfolded proteins results in ER stress and mediates progression of multiple diabetic comorbidities. In preliminary studies, we found that the hyperglycemic obese mice had reduced bone mass and diminished bone healing following fracture. Osteoblast cultures obtained from marrow of obese mice exhibited elevated bioenergetics concomitant with higher respiratory complex V protein levels. Additionally, obese mice had dilated ER in the osteoblasts as well as elevated PERK and ATF6 activity in cortical bone. These findings suggest that impaired osteogenic response partly due to disruption of ER homeostasis could impede fracture repair in the setting of obesity. Studies in Aim 1 will examine the effect of obesity-associated diabetes on osteoprogenitors that contributes to delayed healing in vivo, using reporter mice by flow sorting and histologic imaging. Additional bioenergetic and transcriptomic studies will reveal changes to pathways affected by obesity in osteoblast progenitors. In Aim 2 we will test the therapeutic efficacy of the ER stress inhibitor TUDCA in improving fracture deficits of the obese mice.