Osteoclasts are the body's sole bone resorbing cells. Pro-inflammatory T-cells, commonly called effector T-cells (TEFF), produce cytokines that stimulate bone resorption by osteoclasts. Prolonged exposure to the inflammatory cytokines leads to osteoporosis. Normally, regulatory T-cells, TREG, counteract the activity of TEFF. TREG suppress TEFF, suppress inflammation and promote healing. We have recently discovered that osteoclasts can induce a novel class of TREG, belonging to the CD8 lineage. These regulatory CD8+ T-cells, termed TcREG, like the more extensively studied TREG of the CD4 lineage, also express the transcription factor FoxP3. We have demonstrated that TcREG can negatively regulate bone turnover and production of TEFF in a mouse model of postmenopausal osteoporosis. Osteoclasts induce TcREG from naive CD8 T-cells, which then negatively regulate osteoclast numbers and activity, to form a negative feedback loop. TcREG could potentially be very important for maintaining and restoring skeletal and immune homeostasis. We propose, in the application to study the mechanisms underlying the negative feedback loop. We propose to first uncover the mechanism by which osteoclasts induce FoxP3 in CD8 T-cells. Knowledge of these mechanisms could be used to induce TcREG locally to treat chronic inflammation. Second, additional proposed experiments will reveal how TcREG negatively regulate osteoclasts. Insights into how TcREG suppress bone turnover in osteoporosis is likely to lead to new treatment modalities, with relevance to other bone erosion diseases. This approach would represent an entirely new and mechanistically distinct avenue than those currently in use or development.
According to the International Osteoporosis Foundation half the women and 20% of men over age 50 will develop osteoporosis. Of these a quarter of men and a third of women will experience fracture of the hip, forearm or spine by age 60 due to effete bone. In 2005, the mortality in the year following fracture in the US was 20 to 25% and is expected to quadruple by 2025. Therapies such as hormone replacement and bisphophonates are problematic, such that osteoporosis remains a leading cause of morbidity and mortality in the elderly. Bone formation by osteoblasts and bone resorption by osteoclasts are normally coupled. Thus, old or weakened bone can be removed and replaced with strong new bone. Loss of estrogen at menopause leads to increased osteoclast numbers, and activation of pro-inflammatory T-cells in the bone marrow. The proposed studies will examine the role and mechanism used to counterbalance the activity of regulatory T-cells in inhibiting osteoporosis. PUBLIC HEALTH RELEVANCE: We have shown that regulatory T-cells of the CD8 lineage, called TcREG, can ameliorate osteoporosis in a mouse where menopause is initiated by ovariectomy. Here we propose experiments to understand how these cells are induced in vivo and how they limit bone loss. Insights from these experiments are likely to lead to new treatment modalities representing an entirely new and mechanistically distinct avenue than those currently in use or development for osteoporosis and other bone erosion diseases.
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