DESCRIPTION (provided by applicant): Aging is coupled with a decline of immune function, loss of bone mass and accumulation of marrow fat. Peroxisome proliferator-activated receptor-gamma (PPAR?) is a key factor regulating fat and bone cell formation. Studies show that PPAR? insufficiency can increase bone mass, suggesting that targeting PPAR? could be a novel strategy for new anti-osteoporosis therapies. However, it is not clear how PPAR? insufficiency increases bone because deletion of PPAR? gene in fat tissue also increases bone mass, and that global reduction of fat causes severe diabetes and insulin resistance. We hypothesize that bone-specific PPAR? inactivation, which blocks only bone marrow fat formation, will eliminate marrow fat-generated inflammatory responses, including inflammatory cytokines and inflammatory cells, increases the availability and activity of osteoblasts, and improves immune function, thereby reducing the pace of bone loss in aging. This hypothesis is formulated on the basis that marrow fat increases with aging and fat tissue produces large quantities of inflammatory cytokines. In addition to inhibit bone cell development, these cytokines are predicted to degrading the bone marrow microenvironment (causing chronic inflammation) and inhibiting the hematopoiesis resulting in a shift of progenitor cell from a predominant lymphoid to a myeloid proportion (skewing of hematopoiesis) because bone marrow is the place where immune system is originated. We will test our hypothesis using two PPAR? knockout mouse models, one blocks only bone marrow fat cell formation and the other reduces whole body fat mass. Two specific aims are proposed. Aims 1 will test the specific hypothesis that PPAR? controls adult bone homeostasis but not skeletal development or growth, and Aim 2 will test the specific hypothesis that inactivation of PPAR? eliminates fat-generated inflammatory responses, including cytokines and inflammatory cells, and boosts the immune function, which declines with aging and may contribute to age-induced bone loss. Results of this research will shed new light on our current understanding of the mechanisms by which PPAR? regulates bone metabolism and help develop new anti-osteoporosis therapies.
- National Institute on Aging
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