Phospholipase D2 controls bone homeostasis by modulating M-CSF-dependent osteoclastic cell migration and microtubule stability
2
조회
0
다운로드
1
인용
0
참고문헌
초록
Phospholipase D2 (PLD2), a signaling protein, plays a central role in cellular communication and various biological processes. Here, we show that PLD2 contributes to bone homeostasis by regulating bone resorption through osteoclastic cell migration and microtubule-dependent cytoskeletal organization. Pld2-deficient mice exhibited a low bone mass attributed to increased osteoclast function without altered osteoblast activity. While Pld2 deficiency did not affect osteoclast differentiation, its absence promoted the migration of osteoclast lineage cells through a mechanism involving M-CSF-induced activation of the PI3K–Akt–GSK3β signaling pathway. The absence of Pld2 also boosted osteoclast spreading and actin ring formation, resulting in elevated bone resorption. Furthermore, Pld2 deletion increased microtubule acetylation and stability, which were later restored by treatment with a specific inhibitor of Akt, an essential molecule for microtubule stabilization and osteoclast bone resorption activity. Interestingly, PLD2 interacted with the M-CSF receptor (c-Fms) and PI3K, and the association between PLD2 and c-Fms was reduced in response to M-CSF. Altogether, our findings indicate that PLD2 regulates bone homeostasis by modulating osteoclastic cell migration and microtubule stability via the M-CSF-dependent PI3K–Akt–GSK3β axis.
Abstract
Phospholipase D2 (PLD2), a signaling protein, plays a central role in cellular communication and various biological processes. Here, we show that PLD2 contributes to bone homeostasis by regulating bone resorption through osteoclastic cell migration and microtubule-dependent cytoskeletal organization. Pld2-deficient mice exhibited a low bone mass attributed to increased osteoclast function without altered osteoblast activity. While Pld2 deficiency did not affect osteoclast differentiation, its absence promoted the migration of osteoclast lineage cells through a mechanism involving M-CSF-induced activation of the PI3K–Akt–GSK3β signaling pathway. The absence of Pld2 also boosted osteoclast spreading and actin ring formation, resulting in elevated bone resorption. Furthermore, Pld2 deletion increased microtubule acetylation and stability, which were later restored by treatment with a specific inhibitor of Akt, an essential molecule for microtubule stabilization and osteoclast bone resorption activity. Interestingly, PLD2 interacted with the M-CSF receptor (c-Fms) and PI3K, and the association between PLD2 and c-Fms was reduced in response to M-CSF. Altogether, our findings indicate that PLD2 regulates bone homeostasis by modulating osteoclastic cell migration and microtubule stability via the M-CSF-dependent PI3K–Akt–GSK3β axis.
참고문헌 (43)
- Boyle, W. J., "Osteoclast differentiation and activation", Nature, 423, pp.337~342 (2003)
- 최제용, "Healthy bone tissue homeostasis", Experimental and Molecular Medicine, 52, pp.1~1 (2020), 생화학분자생물학회[DOI]
- Takayanagi, H., "Osteoimmunology : shared mechanisms and crosstalk between the immune and bone systems", Nat. Rev. Immunol, 7, pp.292~304 (2007)
- Teitelbaum, S. L., "Bone resorption by osteoclasts", Science, 289, pp.1504~1508 (2000)
- Kong, Y. Y., "OPGL is a key regulator of osteoclastogenesis, lymphocyte development and lymph-node organogenesis", Nature, 397, pp.315~323 (1999)
- Lacey, D. L., "Osteoprotegerin ligand is a cytokine that regulates osteoclast differentiation and activation", Cell, 93, pp.165~176 (1998)
- -related activation-induced cytokine), a new TNF family member predominantly expressed in T cells, is a dendritic cell-specific survival factor, "J. Exp. Med", 1997, 2075~2080
- Yasuda, H., "Osteoclast differentiation factor is a ligand for osteoprotegerin", osteoclastogenesis-inhibitory factor and is identical to TRANCE, Proc. Natl Acad. Sci. USA, pp.1998, 95[DOI]
- Feng, X., "Osteoclasts : new Insights", Bone Res, 1, pp.11~26 (2013)
- 문세환, "The M-CSF receptor in osteoclasts and beyond", Experimental and Molecular Medicine, 52, pp.1~16 (2020), 생화학분자생물학회[DOI]
- Teitelbaum, S. L., "The osteoclast and its unique cytoskeleton", Ann. N. Y. Acad. Sci, 1240, pp.14~17 (2011)
- Yoshida, H., "The murine mutation osteopetrosis is in the coding region of the macrophage colony stimulating factor gene", Nature, 345, pp.442~444 (1990)
- Destaing, O., "Podosomes display actin turnover and dynamic self-organization in osteoclasts expressing actingreen fluorescent protein", Mol. Biol. Cell, 14, pp.407~416 (2003)
- Jurdic, P., "Podosome and sealing zone : specificity of the osteoclast model", Eur. J. Cell Biol, 85, pp.195~202 (2006)
- Destaing, O., "A novel Rho-mDia2-HDAC6 pathway controls podosome patterning through microtubule acetylation in osteoclasts", J. Cell Sci, 118, pp.2901~2911 (2005)
- Gil-Henn, H., "Defective microtubule-dependent podosome organization in osteoclasts leads to increased bone density in Pyk2(-", -)mice, 2007, pp.178, 1053~1064
- Guimbal, S., "Dock5 is a new regulator of microtubule dynamic instability in osteoclasts", Biol. Cell, 111, pp.271~283 (2019)
- Hong, J. M., "Calpain-6, a target molecule of glucocorticoids, regulates osteoclastic bone resorption via cytoskeletal organization and microtubule acetylation", J. Bone Miner. Res, 26, pp.657~665 (2011)
- Matsumoto, T., "Regulation of bone resorption and sealing zone formation in osteoclasts occurs through protein kinase B-mediated microtubule stabilization", J. Bone Miner. Res, 28, pp.1191~1202 (2013)
- Zalli, D., "The actin-binding protein cofilin and its interaction with cortactin are required for podosome patterning in osteoclasts and bone resorption in vivo and in vitro", J. Bone Miner. Res, 31, pp.1701~1712 (2016)
- Brown, H. A., "Targeting phospholipase D in cancer, infection and neurodegenerative disorders", Nat. Rev. Drug Discov, 16, pp.351~367 (2017)
- Ghim, J., "Accumulating insights into the role of phospholipase D2 in human diseases", Adv. Biol. Regul, 61, pp.42~46 (2016)
- Frohman, M. A., "The phospholipase D superfamily as therapeutic targets", Trends Pharmacol. Sci, 36, pp.137~144 (2015)
- Zhu, M., "Differential roles of phospholipase D proteins in FcepsilonRImediated signaling and mast cell function", J. Immunol, 195, pp.4492~4502 (2015)
- Abdallah, D., "Effects of phospholipase D during cultured osteoblast mineralization and bone formation", J. Cell. Biochem, 120, pp.5923~5935 (2019)
- Kang, D. W., "Deletion of phospholipase D1 decreases bone mass and increases fat mass via modulation of Runx2, beta-catenin-osteoprotegerin, PPARgamma and C", EBPalpha signaling axis, 2021, pp.1867, 166084~
- Sylvia, V. L., "Regulation of phospholipase D(PLD)in growth plate chondrocytes by 24R, 25-(OH)2D3 is dependent on cell maturation state(resting zone cells)and is specific to the PLD2 isoform", Biochim. Biophys. Acta, 1499, pp.209~221 (2001)
- Tokuda, H., "Function of Ca2+ in phosphatidylcholine-hydrolyzing phospholipase D activation in osteoblast-like cells", Bone, 19, pp.347~352 (1996)
- Ghim, J., "Endothelial deletion of phospholipase D2 reduces hypoxic response and pathological angiogenesis", Arterioscler. Thromb. Vasc. Biol, 34, pp.1697~1703 (2014)
- Lim, K. E., "Core binding factor beta of osteoblasts maintains cortical bone mass via stabilization of Runx2 in mice", J. Bone Miner. Res, 30, pp.715~722 (2015)
- Takeshita, S., "Identification and characterization of the new osteoclast progenitor with macrophage phenotypes being able to differentiate into mature osteoclasts", J. Bone Miner. Res, 15, pp.1477~1488 (2000)
- Lee, A. W., "Both src-dependent and-independent mechanisms mediate phosphatidylinositol 3-kinase regulation of colony-stimulating factor 1-activated mitogen-activated protein kinases in myeloid progenitors", Mol. Cell. Biol, 20, pp.6779~6798 (2000)
- Xiong, Y., "A CSF-1 receptor phosphotyrosine 559 signaling pathway regulates receptor ubiquitination and tyrosine phosphorylation", J. Biol. Chem, 286, pp.952~960 (2011)
- Ridley, A. J., "Cell migration: integrating signals from front to back", Science, 302, pp.1704~1709 (2003)
- Knapek, K., "The molecular basis of phospholipase D2-induced chemotaxis : elucidation of differential pathways in macrophages and fibroblasts", Mol. Cell. Biol, 30, pp.4492~4506 (2010)
- Lehman, N., "Phagocyte cell migration is mediated by phospholipases PLD1and PLD2", Blood, 108, pp.3564~3572 (2006)
- Wang, Z., "Phosphatidic acid generated by PLD2 promotes the plasma membrane recruitment of IQGAP1 and neointima formation", FASEB J, 33, pp.6713~6725 (2019)
- Munugalavadla, V., "The p85alpha subunit of class IA phosphatidylinositol 3-kinase regulates the expression of multiple genes involved in osteoclast maturation and migration", Mol. Cell. Biol, 28, pp.7182~7198 (2008)
- Hyun-Ju Kim, "Oleoylethanolamide Exhibits GPR119-Dependent Inhibition of Osteoclast Function and GPR119-Independent Promotion of Osteoclast Apoptosis", Molecules and Cells, 43(4), pp.340~349 (2020), 한국분자세포생물학회
- Kim, H. J., "G protein-coupled receptor 120 signaling negatively regulates osteoclast differentiation, survival, and function", J. Cell. Physiol, 231, pp.844~851 (2016)
- Kim, H. J., "Glucocorticoids suppress bone formation via the osteoclast", J. Clin. Invest, 116, pp.2152~2160 (2006)
- McHugh, K. P., "Mice lacking beta3 integrins are osteosclerotic because of dysfunctional osteoclasts", J. Clin. Invest, 105, pp.433~440 (2000)
- Hur, E. M., "GSK3 controls axon growth via CLASP-mediated regulation of growth cone microtubules", Genes Dev, 25, pp.1968~1981 (2011)