Osteoclasts are the body's primary bone resorbing cells that play a vital role in bone remodeling and bone erosion in conditions such as postmenopausal osteoporosis, rheumatoid arthritis and periodontitis. We have recently discovered that in addition to resorbing bone, osteoclasts also act as antigen-presenting cells that can induce FoxP3 in CD8 T-cells. These novel regulatory T-cells, called TcREG, prevent the activation of TEFF and directly suppress osteoclast activity. Significantly, we have shown that activation of osteoclasts by treatment with low-dose RANKL (receptor-activator of NF-kappa B ligand) maximally induces functional TcREG. These TcREG greatly ameliorate osteoporosis, and indeed lead to increased bone formation. Here we propose to conduct high-throughput screening for drug-like compounds that mimic RANKL's effect. Identification of such compounds will be helpful in three ways: first, they will be used to dissect pathways and mechanisms in mouse models. Second, they may be developed into drugs to treat certain types of osteopetrosis in which patients cannot produce functional RANKL. Finally, because our studies show that low-level stimulation of RANK by RANKL increase the number of regulatory T-cells in bone that suppress inflammation and osteoclast activity, small molecule RANK agonists have the potential to give rise to a new class of drugs for treatment of osteoporosis.
According to the International Osteoporosis Foundation, half of women and 20% of men over age 50 will develop osteoporosis, and 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 (weakened) bone. In 2005, the mortality in the year following fracture in the US was 20- 25%, and is expected to quadruple by 2025. This application will employ screening approaches to find and characterize small molecule compounds that stimulate the RANK receptor to increase regulatory T cells in bone that suppress inflammation and osteoclast activity, potentially giving rise to a an entirely new class of drugs for treatment of bone disorders.
| Shashkova, Elena V; Trivedi, Jahnavi; Cline-Smith, Anna B et al. (2016) Osteoclast-Primed Foxp3+ CD8 T Cells Induce T-bet, Eomesodermin, and IFN-? To Regulate Bone Resorption. J Immunol 197:726-35 |
| Cline-Smith, Anna; Gibbs, Jesse; Shashkova, Elena et al. (2016) Pulsed low-dose RANKL as a potential therapeutic for postmenopausal osteoporosis. JCI Insight 1: |
