title: Distinctive and selective route of PI3K/PKCα-PKCδ/RhoA-Rac1 signaling in osteoclastic cell migration.
abstract: Cell migration during specialized stages of osteoclast precursors, mononuclear preosteoclasts, and multinucleated mature osteoclasts remain uncertain. M-CSF- and osteopontin-induced osteoclastic cell migration was inhibited by function-blocking monoclonal antibodies specific to the integrin αv and β3 subunits, suggesting that integrin αvβ3 mediates migratory signaling induced by M-CSF and osteopontin. M-CSF and osteopontin stimulation was shown to regulate two branched signaling processes, PI3K/PKCα/RhoA axis and PI3K/PKCδ/Rac1 axis. Interestingly, inactivation of RhoA or Rac1 blocked preosteoclast and mature osteoclast migration but not osteoclast precursor migration in a transwell-based cell migration assay. Moreover, the inhibitory effect on preosteoclast and mature osteoclast migration induced by Rac1 inactivation was more effective than that by RhoA inactivation. Collectively, our findings suggest that osteoclast precursor migration depends on PI3K/PKCα-PKCδ signaling mediated via integrin αvβ3 bypassing RhoA and Rac1, whereas preosteoclast and mature osteoclast migration relies on PI3K/PKCα-PKCδ/RhoA-Rac1 axis signaling mediated via integrin αvβ3 with increased dependency on PKCδ/Rac1 signaling route as differentiation progresses.
authors: Department of Microbiology, Laboratory of Bone Metabolism and Control, Yeungnam University College of Medicine, Daegu, 42415, South Korea.
authors: Jin-Man
authors: JM
authors: Kim
authors: Department of Microbiology, Laboratory of Bone Metabolism and Control, Yeungnam University College of Medicine, Daegu, 42415, South Korea.
authors: Mi Yeong
authors: MY
authors: Kim
authors: Department of Microbiology, Laboratory of Bone Metabolism and Control, Yeungnam University College of Medicine, Daegu, 42415, South Korea. Electronic address: kyungheelee@ynu.ac.kr.
authors: Kyunghee
authors: K
authors: Lee
authors: Department of Microbiology, Laboratory of Bone Metabolism and Control, Yeungnam University College of Medicine, Daegu, 42415, South Korea. Electronic address: dwjeong@ynu.ac.kr.
authors: Daewon
authors: D
authors: Jeong
mesh_terms: D000818:Animals; D002465:Cell Movement / Q000187:drug effects; D039302:Integrin alphaVbeta3 / Q000378:metabolism; D016173:Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D008297:Male; D008810:Mice, Inbred C57BL; D010010:Osteoclasts / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D053495:Osteopontin / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D051571:Protein Kinase C-alpha / Q000378:metabolism; D051745:Protein Kinase C-delta / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D020830:rac1 GTP-Binding Protein / Q000378:metabolism*; D020742:rhoA GTP-Binding Protein / Q000378:metabolism*; D019061:src-Family Kinases / Q000378:metabolism
chemical_list: D039302:Integrin alphaVbeta3; D053495:Osteopontin; D016173:Macrophage Colony-Stimulating Factor; D019869:Phosphatidylinositol 3-Kinases; D019061:src-Family Kinases; D051571:Protein Kinase C-alpha; D051745:Protein Kinase C-delta; D020830:rac1 GTP-Binding Protein; D020742:rhoA GTP-Binding Protein
keywords: M-CSF; Osteoclastic cell migration; Osteopontin; PI3K; PKC; Small GTPase RhoA and Rac1