title: 2-(trimethylammonium) ethyl (R)-3-methoxy-3-oxo-2-stearamidopropyl phosphate suppresses osteoclast maturation and bone resorption by targeting macrophage-colony stimulating factor signaling.
abstract: 2-(Trimethylammonium) ethyl (R)-3-methoxy-3-oxo-2-stearamidopropyl phosphate [(R)-TEMOSPho], a derivative of an organic chemical identified from a natural product library, promotes highly efficient megakaryopoiesis. Here, we show that (R)-TEMOSPho blocks osteoclast maturation from progenitor cells of hematopoietic origin, as well as blocking the resorptive function of mature osteoclasts. The inhibitory effect of (R)-TEMOSPho on osteoclasts was due to a disruption of the actin cytoskeleton, resulting from impaired downstream signaling of c-Fms, a receptor for macrophage-colony stimulating factor linked to c-Cbl, phosphoinositol-3-kinase (PI3K), Vav3, and Rac1. In addition, (R)-TEMOSPho blocked inflammation-induced bone destruction by reducing the numbers of osteoclasts produced in mice. Thus, (R)-TEMOSPho may represent a promising new class of antiresorptive drugs for the treatment of bone loss associated with increased osteoclast maturation and activity.
authors.affiliation: Department of Life Science and the Research Center for Cellular Homeostasis, Ewha Womans University, Seoul 120-750, Korea.
authors.forename: So Jeong
authors.initials: SJ
authors.lastname: Park
authors.affiliation: Department of Life Science and the Research Center for Cellular Homeostasis, Ewha Womans University, Seoul 120-750, Korea.
authors.forename: Doo Ri
authors.initials: DR
authors.lastname: Park
authors.forename: Deepak
authors.initials: D
authors.lastname: Bhattarai
authors.forename: Kyeong
authors.initials: K
authors.lastname: Lee
authors.affiliation: Department of Life Science and the Research Center for Cellular Homeostasis, Ewha Womans University, Seoul 120-750, Korea.
authors.forename: Jaesang
authors.initials: J
authors.lastname: Kim
authors.affiliation: Department of Life Science and the Research Center for Cellular Homeostasis, Ewha Womans University, Seoul 120-750, Korea.
authors.forename: Yun Soo
authors.initials: YS
authors.lastname: Bae
authors.affiliation: Department of Life Science and the Research Center for Cellular Homeostasis, Ewha Womans University, Seoul 120-750, Korea.
authors.forename: Soo Young
authors.initials: SY
authors.lastname: Lee
mesh_terms: D008841:Actin Cytoskeleton / Q000187:drug effects / Q000648:ultrastructure; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D050071:Bone Density Conservation Agents / Q000494:pharmacology*; D001862:Bone Resorption / Q000517:prevention & control*; D002454:Cell Differentiation; D002470:Cell Survival / Q000187:drug effects; D005269:Femur / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D005786:Gene Expression Regulation; D016173:Macrophage Colony-Stimulating Factor / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009479:Neuropeptides / Q000235:genetics / Q000378:metabolism; D010755:Organophosphates / Q000494:pharmacology*; D010006:Osteoblasts / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D010010:Osteoclasts / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D050721:Proto-Oncogene Proteins c-cbl / Q000235:genetics / Q000378:metabolism; D051567:Proto-Oncogene Proteins c-vav / Q000235:genetics / Q000378:metabolism; D053245:RANK Ligand / Q000037:antagonists & inhibitors / Q000494:pharmacology; D016186:Receptor, Macrophage Colony-Stimulating Factor / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D012886:Skull / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D013977:Tibia / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D020830:rac1 GTP-Binding Protein / Q000235:genetics / Q000378:metabolism
chemical_list: C000598171:2-(trimethylammonium)ethyl 3-methoxy-3-oxo-2-stearamidopropyl phosphate; D050071:Bone Density Conservation Agents; D009479:Neuropeptides; D010755:Organophosphates; D051567:Proto-Oncogene Proteins c-vav; D053245:RANK Ligand; C484602:Rac1 protein, mouse; C505689:Tnfsf11 protein, mouse; C496622:Vav3 protein, mouse; D016173:Macrophage Colony-Stimulating Factor; D050721:Proto-Oncogene Proteins c-cbl; D019869:Phosphatidylinositol 3-Kinases; D016186:Receptor, Macrophage Colony-Stimulating Factor; D020830:rac1 GTP-Binding Protein; C493849:Cbl protein, mouse
keywords: (R)-TEMOSPho; antiresorptive drugs; bone destruction; osteoclast; osteoclast maturation