DOI QR코드

DOI QR Code

Selective regulation of osteoclast adhesion and spreading by PLCγ/PKCα-PKCδ/RhoA-Rac1 signaling

  • Kim, Jin-Man (Department of Microbiology, Laboratory of Bone Metabolism and Control, Yeungnam University College of Medicine) ;
  • Lee, Kyunghee (Department of Microbiology, Laboratory of Bone Metabolism and Control, Yeungnam University College of Medicine) ;
  • Jeong, Daewon (Department of Microbiology, Laboratory of Bone Metabolism and Control, Yeungnam University College of Medicine)
  • Received : 2017.10.17
  • Accepted : 2017.12.04
  • Published : 2018.05.31

Abstract

Bone resorption by multinucleated osteoclasts is a multistep process involving adhesion to the bone matrix, migration to resorption sites, and formation of sealing zones and ruffled borders. Macrophage colony-stimulating factor (M-CSF) and osteopontin (OPN) have been shown to be involved in the bone resorption process by respective activation of integrin ${\alpha}v{\beta}3$ via "inside-out" and "outside-in" signaling. In this study, we investigated the link between signal modulators known to M-CSF- and OPN-induced osteoclast adhesion and spreading. M-CSF- and OPN-induced osteoclast adhesion was achieved via activation of stepwise signals, including integrin ${\alpha}v{\beta}3$, $PLC{\gamma}$, $PKC{\delta}$, and Rac1. Osteoclast spreading induced by M-CSF and OPN was shown to be controlled via sequential activation, consistent with the osteoclast adhesion processes. In contrast to osteoclast adhesion, osteoclast spreading induced by M-CSF and OPN was blocked via activation of $PLC{\gamma}/PKC{\alpha}/RhoA$ signaling. The combined results indicate that osteoclast adhesion and spreading are selectively regulated via $PLC{\gamma}/PKC{\alpha}-PKC{\delta}/RhoA-Rac1$ signaling.

Keywords

References

  1. Boyle WJ, Simonet WS and Lacey DL (2003) Osteoclast differentiation and activation. Nature 423, 337-342 https://doi.org/10.1038/nature01658
  2. Touaitahuata H, Blangy A and Vives V (2014) Modulation of osteoclast differentiation and bone resorption by Rho GTPases. Small GTPases 5, e28119 https://doi.org/10.4161/sgtp.28119
  3. Georgess D, Machuca-Gayet I, Blangy A and Jurdic P (2014) Podosome organization drives osteoclast-mediated bone resorption. Cell Adh Migr 8, 191-204
  4. Raggatt LJ and Partridge NC (2010) Cellular and molecular mechanisms of bone remodeling. J Biol Chem 285, 25103-25108 https://doi.org/10.1074/jbc.R109.041087
  5. Faccio R, Novack DV, Zallone A, Ross FP and Teitelbaum SL (2003) Dynamic changes in the osteoclast cytoskeleton in response to growth factors and cell attachment are controlled by beta3 integrin. J Cell Biol 162, 499-509 https://doi.org/10.1083/jcb.200212082
  6. Ross FP, Chappel J, Alvarez JI et al (1993) Interactions between the bone matrix proteins osteopontin and bone sialoprotein and the osteoclast integrin alpha v beta 3 potentiate bone resorption. J Biol Chem 268, 9901-9907
  7. Ross FP and Teitelbaum SL (2005) alphavbeta3 and macrophage colony-stimulating factor: partners in osteoclast biology. Immunol Rev 208, 88-105 https://doi.org/10.1111/j.0105-2896.2005.00331.x
  8. Pfaff M and Jurdic P (2001) Podosomes in osteoclast-like cells: structural analysis and cooperative roles of paxillin, proline-rich tyrosine kinase 2 (Pyk2) and integrin alphaVbeta3. J Cell Sci 114, 2775-2786
  9. Lakkakorpi PT, Wesolowski G, Zimolo Z, Rodan GA and Rodan SB (1997) Phosphatidylinositol 3-kinase association with the osteoclast cytoskeleton, and its involvement in osteoclast attachment and spreading. Exp Cell Res 237, 296-306 https://doi.org/10.1006/excr.1997.3797
  10. Nakamura I, Lipfert L, Rodan GA and Le TD (2001) Convergence of alpha(v)beta(3) integrin- and macrophage colony stimulating factor-mediated signals on phospholipase Cgamma in prefusion osteoclasts. J Cell Biol 152, 361-373 https://doi.org/10.1083/jcb.152.2.361
  11. Zhang D, Udagawa N, Nakamura I et al (1995) The small GTP-binding protein, rho p21, is involved in bone resorption by regulating cytoskeletal organization in osteoclasts. J Cell Sci 108 (Pt 6), 2285-2292
  12. Rucci N, DiGiacinto C, Orru L, Millimaggi D, Baron R and Teti A (2005) A novel protein kinase C alphadependent signal to ERK1/2 activated by alphaVbeta3 integrin in osteoclasts and in Chinese hamster ovary (CHO) cells. J Cell Sci 118, 3263-3275 https://doi.org/10.1242/jcs.02436
  13. Horne WC, Sanjay A, Bruzzaniti A and Baron R (2005) The role(s) of Src kinase and Cbl proteins in the regulation of osteoclast differentiation and function. Immunol Rev 208, 106-125 https://doi.org/10.1111/j.0105-2896.2005.00335.x
  14. Tanabe N, Wheal BD, Kwon J et al (2011) Osteopontin signals through calcium and nuclear factor of activated T cells (NFAT) in osteoclasts: a novel RGD-dependent pathway promoting cell survival. J Biol Chem 286, 39871-39881 https://doi.org/10.1074/jbc.M111.295048
  15. Epple H, Cremasco V, Zhang K, Mao D, Longmore GD and Faccio R (2008) Phospholipase Cgamma2 modulates integrin signaling in the osteoclast by affecting the localization and activation of Src kinase. Mol Cell Biol 28, 3610-3622 https://doi.org/10.1128/MCB.00259-08
  16. Berridge MJ (1993) Inositol trisphosphate and calcium signalling. Nature 361, 315-325 https://doi.org/10.1038/361315a0
  17. Tatin F, Varon C, Genot E and Moreau V (2006) A signalling cascade involving PKC, Src and Cdc42 regulates podosome assembly in cultured endothelial cells in response to phorbol ester. J Cell Sci 119, 769-781 https://doi.org/10.1242/jcs.02787
  18. Jung SY, Kim OB, Kang HK, Jang DH, Min BM and Yu FH (2013) Protein kinase Calpha/beta inhibitor Go6976 promotes PC12 cell adhesion and spreading through membrane recruitment and activation of protein kinase Cdelta. Exp Cell Res 319, 153-160 https://doi.org/10.1016/j.yexcr.2012.10.003
  19. Ory S, Munari-Silem Y, Fort P and Jurdic P (2000) Rho and Rac exert antagonistic functions on spreading of macrophage-derived multinucleated cells and are not required for actin fiber formation. J Cell Sci 113 (Pt 7), 1177-1188
  20. Teti A, Taranta A, Migliaccio S et al (1998) Colony stimulating factor-1-induced osteoclast spreading depends on substrate and requires the vitronectin receptor and the c-src proto-oncogene. J Bone Miner Res 13, 50-58 https://doi.org/10.1359/jbmr.1998.13.1.50
  21. Miranti CK, Ohno S and Brugge JS (1999) Protein kinase C regulates integrin-induced activation of the extracellular regulated kinase pathway upstream of Shc. J Biol Chem 274, 10571-10581 https://doi.org/10.1074/jbc.274.15.10571
  22. Kim JM, Kim MY, Lee K and Jeong D (2016) Distinctive and selective route of PI3K/PKCalpha-PKCdelta/RhoA-Rac1 signaling in osteoclastic cell migration. Mol Cell Endocrinol 437, 261-267 https://doi.org/10.1016/j.mce.2016.08.042
  23. Allen WE, Jones GE, Pollard JW and Ridley AJ (1997) Rho, Rac and Cdc42 regulate actin organization and cell adhesion in macrophages. J Cell Sci 110 (Pt 6), 707-720
  24. Wells CM, Walmsley M, Ooi S, Tybulewicz V and Ridley AJ (2004) Rac1-deficient macrophages exhibit defects in cell spreading and membrane ruffling but not migration. J Cell Sci 117, 1259-1268 https://doi.org/10.1242/jcs.00997
  25. Kandabashi T, Shimokawa H, Miyata K et al (2003) Evidence for protein kinase C-mediated activation of Rho-kinase in a porcine model of coronary artery spasm. Arterioscler Thromb Vasc Biol 23, 2209-2214 https://doi.org/10.1161/01.ATV.0000104010.87348.26
  26. Hotokezaka H, Sakai E, Kanaoka K et al (2002) U0126 and PD98059, specific inhibitors of MEK, accelerate differentiation of RAW264.7 cells into osteoclast-like cells. J Biol Chem 277, 47366-47372 https://doi.org/10.1074/jbc.M208284200
  27. Lee K, Chung YH, Ahn H, Kim H, Rho J and Jeong D (2016) Selective Regulation of MAPK Signaling Mediates RANKL-dependent Osteoclast Differentiation. Int J Biol Sci 12, 235-245 https://doi.org/10.7150/ijbs.13814
  28. Nakamura I, Pilkington MF, Lakkakorpi PT et al (1999) Role of alpha(v)beta(3) integrin in osteoclast migration and formation of the sealing zone. J Cell Sci 112 (Pt 22), 3985-3993
  29. Jung SY, Kim JM, Kang HK, Jang DH and Min BM (2009) A biologically active sequence of the laminin alpha2 large globular 1 domain promotes cell adhesion through syndecan-1 by inducing phosphorylation and membrane localization of protein kinase Cdelta. J Biol Chem 284, 31764-31775 https://doi.org/10.1074/jbc.M109.038547