Prompted by our observations and those of others, the av?3 integrin is a current therapeutic anti-resorptive target for diseases such as osteoporosis and inflammatory osteolysis. The purpose of this grant, from its inception, has been to expand the potential of therapeutically targeting the integrin by characterizing its associated molecules and the bone-degrading signals they transmit. The success of this exercise is underscored by the fact that in addition to those inhibiting av?3, drugs targeting signaling molecules, such as c-Src and Syk, which are effectors of the integrin, in OCs, are in clinical trial for osteolytic diseases. We have, in the past funding period, fulfilled our specific aims. While our efforts continue to define the mechanisms by which av?3 regulates the OC, particularly in the context of derivative signals which organize its cytoskeleton, our current attention turns to the integrin, itself. We address the mechanisms by which the integrin assumes an activated conformation which permits it to recognize ligand and transmit its bone-resorptive signals. Our findings and those of others, indicate M-CSF plays a central role in this regard. We have established that av?3 and M-CSF collaborate in organizing the OC cytoskeleton. Our data indicate, however, that the principal means by which M-CSF exerts its cytoskeletal effect is to prompt its receptor c-Fms to transmit intracellular signals to the cytoplasmic domain of the ?3 integrin subunit. These signals, in turn, transit the integrin from its default, resting state, to its activated conformation, permitting ligand recognition and cytoskeleton-organizing events. Our findings also suggest that talin activates OC av?3 and the signals derived thereof, by interacting with specific residues in the ?3 integrin cytoplasmic domain. We hypothesize, therefore that 1) M-CSF, liganding its receptor, c-Fms, transmits intracellular signals which activate the av?3 integrin in OCs;2) talin and its recognition sequences in the ?3 cyoplasmic domain mediate M-CSF-induced OC cytoskeletal organization and function and 3) inhibiting av?3 activation, in vivo, diminishes pathological bone resorption.
Our specific aims are therefore to determine 1) the mechanism by which M-CSF, interacting with its receptor c-Fms, transmits intracellular signals which activate the av?3 integrin in OCs;2) the role of talin and its recognition sequences in the ?3 integrin cytoplasmic domain in mediating M-CSF-induced OC cytoskeletal organization and function and 3) the impact of inhibiting av?3 activation, in vivo, on pathological bone resorption.
Most patients at risk for osteoporotic fractures are treated with bisphosphonates, which are increasingly associated with complications such as atypical fractures. The present grant, from its inception, has focused on discovering new therapeutic targets for these patients, specifically addressing molecules, known as integrins, which mediate the attachment of bone resorbing cells to skeletal matrix. The success of our efforts is underscored by the fact that integrin-targeting drugs are in clinical trial for the treatment of osteoporosis.
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|Rohatgi, Nidhi; Zou, Wei; Collins, Patrick L et al. (2018) ASXL1 impairs osteoclast formation by epigenetic regulation of NFATc1. Blood Adv 2:2467-2477|
|Mbalaviele, Gabriel; Novack, Deborah V; Schett, Georg et al. (2017) Inflammatory osteolysis: a conspiracy against bone. J Clin Invest 127:2030-2039|
|Zou, Wei; Rohatgi, Nidhi; Chen, Timothy Hung-Po et al. (2016) PPAR-? regulates pharmacological but not physiological or pathological osteoclast formation. Nat Med 22:1203-1205|
|Su, Xinming; Esser, Alison K; Amend, Sarah R et al. (2016) Antagonizing Integrin ?3 Increases Immunosuppression in Cancer. Cancer Res 76:3484-95|
|Izawa, Takashi; Rohatgi, Nidhi; Fukunaga, Tomohiro et al. (2015) ASXL2 Regulates Glucose, Lipid, and Skeletal Homeostasis. Cell Rep 11:1625-37|
|Warren, Julia T; Zou, Wei; Decker, Corinne E et al. (2015) Correlating RANK ligand/RANK binding kinetics with osteoclast formation and function. J Cell Biochem 116:2476-83|
|Zou, Wei; Teitelbaum, Steven L (2015) Absence of Dap12 and the ?v?3 integrin causes severe osteopetrosis. J Cell Biol 208:125-36|
|Fukunaga, Tomohiro; Zou, Wei; Rohatgi, Nidhi et al. (2015) An insulin-sensitizing thiazolidinedione, which minimally activates PPAR?, does not cause bone loss. J Bone Miner Res 30:481-8|
|Zhu, Tingting; Chappel, Jean C; Hsu, Fong-Fu et al. (2013) Type I phosphotidylinosotol 4-phosphate 5-kinase ? regulates osteoclasts in a bifunctional manner. J Biol Chem 288:5268-77|
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