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Archives of Pharmacal Research

, Volume 42, Issue 8, pp 712–721 | Cite as

Idelalisib inhibits osteoclast differentiation and pre-osteoclast migration by blocking the PI3Kδ-Akt-c-Fos/NFATc1 signaling cascade

  • Jeong-Tae Yeon
  • Kwang-Jin Kim
  • Young-Jin Son
  • Sang-Joon ParkEmail author
  • Seong Hwan KimEmail author
Research Article
  • 157 Downloads

Abstract

Since increased number of osteoclasts could lead to impaired bone structure and low bone mass, which are common characteristics of bone disorders including osteoporosis, the pharmacological inhibition of osteoclast differentiation is one of therapeutic strategies for preventing and/or treating bone disorders and related facture. However, little data are available regarding the functional relevance of phosphoinositide 3-kinase (PI3K) isoforms in the osteoclast differentiation process. To elucidate the functional involvement of PI3Kδ in osteoclastogenesis, here we investigated how osteoclast differentiation was influenced by idelalisib (also called CAL-101), which is p110δ-selective inhibitor approved for the treatment of specific human B cell malignancies. Here, we found that receptor activator of nuclear factor kappa B ligand (RANKL) induced PI3Kδ protein expression, and idelalisib inhibited RANKL-induced osteoclast differentiation. Next, the inhibitory effect of idelalisib on RANKL-induced activation of the Akt-c-Fos/NFATc1 signaling cascade was confirmed by western blot analysis and real-time PCR. Finally, idelalisib inhibited pre-osteoclast migration in the last stage of osteoclast differentiation through down-regulation of the Akt-c-Fos/NFATc1 signaling cascade. It may be possible to expand the clinical use of idelalisib for controlling osteoclast differentiation. Together, the present results contribute to our understanding of the clinical value of PI3Kδ as a druggable target and the efficacy of related therapeutics including osteoclastogenesis.

Keywords

Phosphoinositide 3-kinases Idelalisib Osteoclast differentiation 

Notes

Acknowledgements

This work was supported by project grants from National Research Foundation of Korea (KN-1331) and Korea Research Institute of Chemical Technology (KK1703-F02, KK1803-F00 & KK1932-20).

Compliance with ethical standards

Conflict of interest

The authors have declared no conflict of interest.

References

  1. Asagiri M, Takayanagi H (2007) The molecular understanding of osteoclast differentiation. Bone 40(2):251–264Google Scholar
  2. Boudot C, Saidak Z, Boulanouar AK, Petit L, Gouilleux F, Massy Z, Brazier M, Mentaverri R, Kamel S (2010) Implication of the calcium sensing receptor and the Phosphoinositide 3-kinase/Akt pathway in the extracellular calcium-mediated migration of RAW 264.7 osteoclast precursor cells. Bone 46:1416–1423Google Scholar
  3. Cantley LC (2002) The phosphoinositide 3-kinase pathway. Science 296(5573):1655–1657Google Scholar
  4. Choi SW, Yeon JT, Ryu BJ, Kim KJ, Moon SH, Lee H, Lee MS, Lee SY, Heo JC, Park SJ, Kim SH (2015) Repositioning potential of PAK4 to osteoclastic bone resorption. J Bone Miner Res 30(8):1494–1507Google Scholar
  5. Feng X (2005) RANKing intracellular signaling in osteoclasts. IUBMB Life 57(6):389–395Google Scholar
  6. Foster FM, Traer CJ, Abraham SM, Fry MJ (2003) The phosphoinositide (PI) 3-kinase family. J Cell Sci 116(Pt 15):3037–3040Google Scholar
  7. Fruman DA, Rommel C (2011) PI3 Kδ inhibitors in cancer: rationale and serendipity merge in the clinic. Cancer Discov 1(7):562–572Google Scholar
  8. Grey A, Chaussade C, Empson V, Lin JM, Watson M, O’Sullivan S, Rewcastle G, Naot D, Cornish J, Shepherd P (2010) Evidence for a role for the p110-alpha isoform of PI3 K in skeletal function. Biochem Biophys Res Commun 391(1):564–569Google Scholar
  9. Győri D, Csete D, Benkő S, Kulkarni S, Mandl P, Dobó-Nagy C, Vanhaesebroeck B, Stephens L, Hawkins PT, Mócsai A (2014) The phosphoinositide 3-kinase isoform PI3 Kβ regulates osteoclast-mediated bone resorption in humans and mice. Arthritis Rheumatol 66(8):2210–2221Google Scholar
  10. Hawkins PT (1851) Stephens LR (2015) PI3 K signalling in inflammation. Biochim Biophys Acta 6:882–897Google Scholar
  11. Herman SE, Gordon AL, Wagner AJ, Heerema NA, Zhao W, Flynn JM, Jones J, Andritsos L, Puri KD, Lannutti BJ, Giese NA, Zhang X, Wei L, Byrd JC, Johnson AJ (2010) Phosphatidylinositol 3-kinase-δ inhibitor CAL-101 shows promising preclinical activity in chronic lymphocytic leukemia by antagonizing intrinsic and extrinsic cellular survival signals. Blood 116(12):2078–2088Google Scholar
  12. Huang H, Chang EJ, Ryu J, Lee ZH, Lee Y, Kim HH (2006) Induction of c-Fos and NFATc1 during RANKL-stimulated osteoclast differentiation is mediated by the p38 signaling pathway. Biochem Biophys Res Commun 351(1):99–105Google Scholar
  13. Ikeda H, Hideshima T, Fulciniti M, Perrone G, Miura N, Yasui H, Okawa Y, Kiziltepe T, Santo L, Vallet S, Cristea D, Calabrese E, Gorgun G, Raje NS, Richardson P, Munshi NC, Lannutti BJ, Puri KD, Giese NA, Anderson KC (2010) PI3 K/p110δ is a novel therapeutic target in multiple myeloma. Blood 116(9):1460–1468Google Scholar
  14. Juss JK, Hayhoe RP, Owen CE, Bruce I, Walmsley SR, Cowburn AS, Kulkarni S, Boyle KB, Stephens L, Hawkins PT, Chilvers ER, Condliffe AM (2012) Functional redundancy of class I phosphoinositide 3-kinase (PI3 K) isoforms in signaling growth factor-mediated human neutrophil survival. PLoS ONE 7(9):e45933Google Scholar
  15. Khosla S, Riggs BL (2005) Pathophysiology of age-related bone loss and osteoporosis. Endocrinol Metab Clin North Am 34(4):1015–1030Google Scholar
  16. Kikuta J, Ishii M (2013) Osteoclast migration, differentiation and function: novel therapeutic targets for rheumatic diseases. Rheumatology 52(2):226–234Google Scholar
  17. Kim HH, Shin HS, Kwak HJ, Ahn KY, Kim JH, Lee HJ, Lee MS, Lee ZH, Koh GY (2003) RANKL regulates endothelial cell survival through the phosphatidylinositol 3′-kinase/Akt signal transduction pathway. FASEB J 17(14):2163–2165Google Scholar
  18. Kim K, Lee SH, Ha Kim J, Choi Y, Kim N (2008) NFATc1 induces osteoclast fusion via up-regulation of Atp6v0d2 and the dendritic cell-specific transmembrane protein (DC-STAMP). Mol Endocrinol 22(1):176–185Google Scholar
  19. Lakkakorpi PT, Wesolowski G, Zimolo Z, Rodan GA, Rodan SB (1997) Phosphatidylinositol 3-kinase association with the osteoclast cytoskeleton, and its involvement in osteoclast attachment and spreading. Exp Cell Res 237(2):296–306Google Scholar
  20. Lannutti BJ, Meadows SA, Herman SE, Kashishian A, Steiner B, Johnson AJ, Byrd JC, Tyner JW, Loriaux MM, Deininger M, Druker BJ, Puri KD, Ulrich RG, Giese NA (2011) CAL-101, a p110delta selective phosphatidylinositol-3-kinase inhibitor for the treatment of B-cell malignancies, inhibits PI3 K signaling and cellular viability. Blood 117(2):591–594Google Scholar
  21. Lee SE, Woo KM, Kim SY, Kim HM, Kwack K, Lee ZH, Kim HH (2002) The phosphatidylinositol 3-kinase, p38, and extracellular signal-regulated kinase pathways are involved in osteoclast differentiation. Bone 30(1):71–77Google Scholar
  22. Livak KJ, Schmittgen TD (2001) Analysis of relative gene expression data using real-time quantitative PCR and the 2-ΔΔCT method. Methods 25(4):402–408Google Scholar
  23. Manolagas SC, Parfitt AM (2010) What old means to bone. Trends Endocrinol Metab 21(6):369–374Google Scholar
  24. Marie PJ, Kassem M (2011) Osteoblasts in osteoporosis: past, emerging, and future anabolic targets. Eur J Endocrinol 165(1):1–10Google Scholar
  25. Marini C, Bruno S, Fiz F, Campi C, Piva R, Cutrona G, Matis S, Nieri A, Miglino M, Ibatici A, Maria Orengo A, Maria Massone A, Neumaier CE, Totero D, Giannoni P, Bauckneht M, Pennone M, Tenca C, Gugiatti E, Bellini A, Borra A, Tedone E, Efetürk H, Rosa F, Emionite L, Cilli M, Bagnara D, Brucato V, Bruzzi P, Piana M, Fais F, Sambuceti G (2017) Functional activation of osteoclast commitment in chronic lymphocytic leukaemia: a possible role for RANK/RANKL pathway. Sci Rep 7(1):14159Google Scholar
  26. Meadows SA, Vega F, Kashishian A, Johnson D, Diehl V, Miller LL, Younes A, Lannutti BJ (2012) PI3 Kδ inhibitor, GS-1101 (CAL-101), attenuates pathway signaling, induces apoptosis, and overcomes signals from the microenvironment in cellular models of Hodgkin lymphoma. Blood 119(8):1897–1900Google Scholar
  27. Millar FR, Janes SM, Giangreco A (2017) Epithelial cell migration as a potential therapeutic target in early lung cancer. Eur Respir Rev 26(143):160069Google Scholar
  28. Moon JB, Kim JH, Kim K, Youn BU, Ko A, Lee SY, Kim N (2012) Akt induces osteoclast differentiation through regulating the GSK3β/NFATc1 signaling cascade. J Immunol 188(1):163–169Google Scholar
  29. Mukherjee A, Rotwein P (2012) Selective signaling by Akt1 controls osteoblast differentiation and osteoblast-mediated osteoclast development. Mol Cell Biol 32(2):490–500Google Scholar
  30. Munugalavadla V, Vemula S, Sims EC, Krishnan S, Chen S, Yan J, Li H, Niziolek PJ, Takemoto C, Robling AG, Yang FC, Kapur R (2008) 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(23):7182–7198Google Scholar
  31. Nakamura I, Takahashi N, Jimi E, Udagawa N, Suda T (2012) Regulation of osteoclast function. Mod Rheumatol 22(2):167–177Google Scholar
  32. Nakamura I, Takahashi N, Sasaki T, Tanaka S, Udagawa N, Murakami H, Kimura K, Kabuyama Y, Kurokawa T, Suda T, Fukui Y (1995) Wortmannin, a specific inhibitor of phosphatidylinositol-3 kinase, blocks osteoclastic bone resorption. FEBS Lett 361(1):79–84Google Scholar
  33. Norman P (2011) Selective PI3 Kδ inhibitors, a review of the patent literature. Expert Opin Ther Pat 21(11):1773–1790Google Scholar
  34. Papakonstanti EA, Zwaenepoel O, Bilancio A, Burns E, Nock GE, Houseman B, Shokat K, Ridley AJ, Vanhaesebroeck B (2008) Distinct roles of class IA PI3 K isoforms in primary and immortalised macrophages. J Cell Sci 121(Pt 24):4124–4133Google Scholar
  35. Pauls SD, Lafarge ST, Landego I, Zhang T, Marshall AJ (2012) The phosphoinositide 3-kinase signaling pathway in normal and malignant B cells: activation mechanisms, regulation and impact on cellular functions. Front Immunol 3:224Google Scholar
  36. Pilkington MF, Sims SM, Dixon SJ (1998) Wortmannin inhibits spreading and chemotaxis of rat osteoclasts in vitro. J Bone Miner Res 13(4):688–694Google Scholar
  37. Rodan GA, Martin TJ (2000) Therapeutic approaches to bone diseases. Science 289(5484):1508–1514Google Scholar
  38. Rossi JF, Chappard D, Marcelli C, Laplante J, Commes T, Baldet P, Janbon C, Jourdan J, Alexandre C, Bataille R (1990) Micro-osteoclast resorption as a characteristic feature of B-cell malignancies other than multiple myeloma. Br J Haematol 76(4):469–475Google Scholar
  39. Rozen S, Skaletsky H (2000) Primer3 on the WWW for general users and for biologist programmers. Methods Mol Biol 132:365–386Google Scholar
  40. Shugg RP, Thomson A, Tanabe N, Kashishian A, Steiner BH, Puri KD, Pereverzev A, Lannutti BJ, Jirik FR, Dixon SJ, Sims SM (2013) Effects of isoform-selective phosphatidylinositol 3-kinase inhibitors on osteoclasts: actions on cytoskeletal organization, survival, and resorption. J Biol Chem 288(49):35346–35357Google Scholar
  41. Song I, Kim JH, Kim K, Jin HM, Youn BU, Kim N (2009) Regulatory mechanism of NFATc1 in RANKL-induced osteoclast activation. FEBS Lett 583(14):2435–2440Google Scholar
  42. Stark AK, Sriskantharajah S, Hessel EM, Okkenhaug K (2015) PI3 K inhibitors in inflammation, autoimmunity and cancer. Curr Opin Pharmacol 23:82–91Google Scholar
  43. Takayanagi H (2005) Inflammatory bone destruction and osteoimmunology. J Periodontal Res 40(4):287–293Google Scholar
  44. Takayanagi H (2007a) Osteoimmunology: shared mechanisms and crosstalk between the immune and bone systems. Nat Rev Immunol 7(4):292–304Google Scholar
  45. Takayanagi H (2007b) The role of NFAT in osteoclast formation. Ann N Y Acad Sci 1116:227–237Google Scholar
  46. Takeshita S, Kaji K, Kudo A (2000) Identification and characterization of the new osteoclast progenitor with macrophage phenotypes being able to differentiate into mature osteoclasts. J Bone Miner Res 15(8):1477–1488Google Scholar
  47. Vanhaesebroeck B, Jones GE, Allen WE, Zicha D, Hooshmand-Rad R, Sawyer C, Wells C, Waterfield MD, Ridley AJ (1999) Distinct PI(3)Ks mediate mitogenic signalling and cell migration in macrophages. Nat Cell Biol 1(1):69–71Google Scholar
  48. Vanhaesebroeck B, Leevers SJ, Ahmadi K, Timms J, Katso R, Driscoll PC, Woscholski R, Parker PJ, Waterfield MD (2001) Synthesis and function of 3-phosphorylated inositol lipids. Annu Rev Biochem 70:535–602Google Scholar
  49. Vanhaesebroeck B, Whitehead MA, Piñeiro R (2016) Molecules in medicine mini-review: isoforms of PI3 K in biology and disease. J Mol Med 94(1):5–11Google Scholar
  50. Xing R, Zhang Y, Li C, Sun L, Yang L, Zhao J, Liu X (2016) Interleukin-21 promotes osteoclastogenesis in RAW264.7 cells through the PI3 K/AKT signaling pathway independently of RANKL. Int J Mol Med 38(4):1125–1134Google Scholar
  51. Yamanaka Y, Clohisy JC, Ito H, Matsuno T, Abu-Amer Y (2013) Blockade of JNK and NFAT pathways attenuates orthopedic particle-stimulated osteoclastogenesis of human osteoclast precursors and murine calvarial osteolysis. J Orthop Res 31(1):67–72Google Scholar
  52. Yap TA, Bjerke L, Clarke PA, Workman P (2015) Drugging PI3 K in cancer: refining targets and therapeutic strategies. Curr Opin Pharmacol 23:98–107Google Scholar
  53. Yeon JT, Ryu BJ, Choi SW, Heo JC, Kim KJ, Son YJ, Kim SH (2014) Natural polyamines inhibit the migration of preosteoclasts by attenuating Ca2 + -PYK2-Src-NFATc1 signaling pathways. Amino Acids 46(11):2605–2614Google Scholar

Copyright information

© The Pharmaceutical Society of Korea 2019

Authors and Affiliations

  1. 1.Research Institute of Basic ScienceSunchon National UniversitySuncheonRepublic of Korea
  2. 2.Department of PharmacySunchon National UniversitySuncheonRepublic of Korea
  3. 3.Department of Histology, College of Veterinary MedicineKyungpook National UniversityDaeguRepublic of Korea
  4. 4.Innovative Target Research Center, Bio & Drug Discovery DivisionKorea Research Institute of Chemical TechnologyDaejeonRepublic of Korea

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