M directly contribute to aging. But the itochondrial succinate dehydrogenase (SDH) deficiency was reported to underlying mechanism is unknown. The d eficient SDH activity unavoidably leads to the accumulation of succinate, an intermediate metabolite in tricarboxylic acid cycle. Indeed, w e observed a significant elevation of succinate, in bone cells from old subjects and sera from aged mice. The elevated succinate can be released to act as an extracellular signaling mediator through the succinate specific receptor (SUCNR1). SUCNR1 is a G protein-coupled receptor and Succinate/ SUCNR1 signaling has provided a new paradigm for the mechanism of cell stress response in organs. However, there are no studies on the role of elevated succinate and SUCNR1 activation in age-related bone loss. Our preliminary work proves that succinate directly stimulates osteoclastogenesis and osteoclast activity through SUCNR1 in vitro and in vivo. Based on these data, we hypothesize that targeting succinate receptor activation will attenuate the accelerated bone loss in aging. To test our hypothesis, in aim 1 we will rescue age-related bone loss in vivo by targeting succinate receptor.
In aim 2, we will reveal the signaling pathways stimulated by succinate and SUCNR1 activation to enhance osteoclastogenesis. This proposed study will delineate novel mechanistic pathways by which succinate/SUCNR1 regulates osteoclastogenesis. Unravelling the way this metabolite signals will provide a potential therapeutic target to counteract bone loss in aging. The study will be significantly rewarding because of its potential to identify specific protection mechanisms against age-related osteoporosis and fractures.
Age-related osteoporosis and osteoporotic fracture has become a major public health issue in the US with more than 1.5 million age-related osteoporotic fractures occur annually. This study is based on a novel finding on an intrinsic metabolic change in aged-bone and will identify a novel and specific signaling pathway in regulating osteoclasts in aging. Therefore this study will be significant to improve the bone health and life quality in the elderly population.
