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.
Keywords:
(R)-TEMOSPho; antiresorptive drugs; bone destruction; osteoclast; osteoclast maturation.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Actin Cytoskeleton / drug effects
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Actin Cytoskeleton / ultrastructure
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Animals
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Apoptosis / drug effects
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Bone Density Conservation Agents / pharmacology*
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Bone Resorption / prevention & control*
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Cell Differentiation
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Cell Survival / drug effects
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Femur / cytology
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Femur / drug effects
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Femur / metabolism
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Gene Expression Regulation
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Macrophage Colony-Stimulating Factor / antagonists & inhibitors*
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Macrophage Colony-Stimulating Factor / pharmacology
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Macrophages / cytology
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Macrophages / drug effects
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Macrophages / metabolism
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Male
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Mice
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Mice, Inbred C57BL
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Neuropeptides / genetics
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Neuropeptides / metabolism
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Organophosphates / pharmacology*
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Osteoblasts / cytology
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Osteoblasts / drug effects*
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Osteoblasts / metabolism
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Osteoclasts / cytology
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Osteoclasts / drug effects*
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Osteoclasts / metabolism
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Phosphatidylinositol 3-Kinases / genetics
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Phosphatidylinositol 3-Kinases / metabolism
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Proto-Oncogene Proteins c-cbl / genetics
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Proto-Oncogene Proteins c-cbl / metabolism
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Proto-Oncogene Proteins c-vav / genetics
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Proto-Oncogene Proteins c-vav / metabolism
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RANK Ligand / antagonists & inhibitors
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RANK Ligand / pharmacology
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Receptor, Macrophage Colony-Stimulating Factor / genetics
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Receptor, Macrophage Colony-Stimulating Factor / metabolism
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Signal Transduction / drug effects*
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Skull / cytology
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Skull / drug effects
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Skull / metabolism
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Tibia / cytology
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Tibia / drug effects
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Tibia / metabolism
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rac1 GTP-Binding Protein / genetics
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rac1 GTP-Binding Protein / metabolism
Substances
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2-(trimethylammonium)ethyl 3-methoxy-3-oxo-2-stearamidopropyl phosphate
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Bone Density Conservation Agents
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Neuropeptides
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Organophosphates
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Proto-Oncogene Proteins c-vav
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RANK Ligand
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Rac1 protein, mouse
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Tnfsf11 protein, mouse
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Vav3 protein, mouse
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Macrophage Colony-Stimulating Factor
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Proto-Oncogene Proteins c-cbl
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Phosphatidylinositol 3-Kinases
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Receptor, Macrophage Colony-Stimulating Factor
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rac1 GTP-Binding Protein
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Cbl protein, mouse