title: Regulation of osteoclasts by membrane-derived lipid mediators.
abstract: Osteoclasts are bone-resorbing cells of monocytic origin. An imbalance between bone formation and resorption can lead to osteoporosis or osteopetrosis. Osteoclastogenesis is triggered by RANKL- and IP3-induced Ca(2+) influx followed by activation of NFATc1, a master transcription factor for osteoclastogenic gene regulation. During differentiation, osteoclasts undergo cytoskeletal remodeling to migrate and attach to the bone surface. Simultaneously, they fuse with each other to form multinucleated cells. These processes require PI3-kinase-dependent cytoskeletal protein activation to initiate cytoskeletal remodeling, resulting in the formation of circumferential podosomes and fusion-competent protrusions. In multinucleated osteoclasts, circumferential podosomes mature into stabilized actin rings, which enables the formation of a ruffled border where intensive membrane trafficking is executed. Membrane lipids, especially phosphoinositides, are key signaling molecules that regulate osteoclast morphology and act as second messengers and docking sites for multiple important effectors. We examine the critical roles of phosphoinositides in the signaling cascades that regulate osteoclast functions.
authors.affiliation: Laboratory of Cell and Tissue Biology, School of Medicine, Keio University, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan. oikawa@z8.keio.jp
authors.forename: Tsukasa
authors.initials: T
authors.lastname: Oikawa
authors.forename: Yukiko
authors.initials: Y
authors.lastname: Kuroda
authors.forename: Koichi
authors.initials: K
authors.lastname: Matsuo
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002462:Cell Membrane / Q000378:metabolism*; D002465:Cell Movement; D003599:Cytoskeleton / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D008563:Membrane Lipids / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D010010:Osteoclasts / Q000166:cytology*; D010022:Osteopetrosis / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010716:Phosphatidylinositols / Q000378:metabolism; D010766:Phosphorylation; D053245:RANK Ligand / Q000378:metabolism; D015398:Signal Transduction; D014158:Transcription, Genetic; D015854:Up-Regulation; D019061:src-Family Kinases / Q000378:metabolism
chemical_list: D000199:Actins; D008563:Membrane Lipids; D010716:Phosphatidylinositols; D053245:RANK Ligand; D019869:Phosphatidylinositol 3-Kinases; D019061:src-Family Kinases; D002118:Calcium