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The pathophysiology of immunoporosis: innovative therapeutic targets

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Abstract

Background

The physiological balance between bone resorption and bone formation is now known to be mediated by a cascade of events parallel to the classic osteoblast-osteoclast interaction. Thus, osteoimmunology now encompasses the role played by other cell types, such as cytokines, lymphocytes and chemokines, in immunological responses and how they help modulate bone metabolism. All these factors have an impact on the RANK/RANKL/OPG pathway, which is the major pathway for the maturation and resorption activity of osteoclast precursor cells, responsible for osteoporosis development. Recently, immunoporosis has emerged as a new research area in osteoimmunology dedicated to the immune system’s role in osteoporosis.

Methods

The first part of this review presents theoretical concepts on the factors involved in the skeletal system and osteoimmunology. Secondly, existing treatments and novel therapeutic approaches to treat osteoporosis are summarized. These were selected from to the most recent studies published on PubMed containing the term osteoporosis. All data relate to the results of in vitro and in vivo studies on the osteoimmunological system of humans, mice and rats.

Findings

Treatments for osteoporosis can be classified into two categories. They either target osteoclastogenesis inhibition (denosumab, bisphosphonates), or they aim to restore the number and function of osteoblasts (romozumab, abaloparatide). Even novel therapies, such as resolvins, gene therapy, and mesenchymal stem cell transplantation, fall within this classification system.

Conclusion

This review presents alternative pathways in the pathophysiology of osteoporosis, along with some recent therapeutic breakthroughs to restore bone homeostasis.

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References

  1. O’Donnell S. Screening, prevention and management of osteoporosis among Canadian adults. Health Promot Chronic Dis Prev Can. 2018;38(12):445–54. https://doi.org/10.24095/hpcdp.38.12.02.

    Article  PubMed  Google Scholar 

  2. Office of the Surgeon G. Reports of the Surgeon General. Bone Health and Osteoporosis: A Report of the Surgeon General. Rockville (MD): Office of the Surgeon General (US); 2004.

  3. Burge R, Dawson-Hughes B, Solomon DH, Wong JB, King A, Tosteson A. Incidence and economic burden of osteoporosis-related fractures in the United States, 2005–2025. J Bone Miner Res. 2007;22(3):465–75. https://doi.org/10.1359/jbmr.061113.

    Article  PubMed  Google Scholar 

  4. Johnell O, Kanis J. Epidemiology of osteoporotic fractures. Osteoporos Int. 2005;16(Suppl 2):S3-7. https://doi.org/10.1007/s00198-004-1702-6.

    Article  PubMed  Google Scholar 

  5. Melton LJ. Epidemiology worldwide. Endocrinol Metab Clin North Am. 2003;32(1):1–13.

    Article  Google Scholar 

  6. Takayanagi H. Osteoimmunology: shared mechanisms and crosstalk between the immune and bone systems. Nat Rev Immunol. 2007;7(4):292–304. https://doi.org/10.1038/nri2062.

    Article  CAS  PubMed  Google Scholar 

  7. Suda T, Takahashi N, Udagawa N, Jimi E, Gillespie MT, Martin TJ. Modulation of osteoclast differentiation and function by the new members of the tumor necrosis factor receptor and ligand families. Endocr Rev. 1999;20(3):345–57. https://doi.org/10.1210/edrv.20.3.0367.

    Article  CAS  PubMed  Google Scholar 

  8. Marie P, Debiais F, Cohen-Solal M, de Vernejoul MC. New factors controlling bone remodeling. Joint Bone Spine. 2000;67(3):150–6.

    CAS  PubMed  Google Scholar 

  9. Manolagas SC. Birth and death of bone cells: basic regulatory mechanisms and implications for the pathogenesis and treatment of osteoporosis. Endocr Rev. 2000;21(2):115–37. https://doi.org/10.1210/edrv.21.2.0395.

    Article  CAS  PubMed  Google Scholar 

  10. Khosla S, Amin S, Orwoll E. Osteoporosis in men. Endocr Rev. 2008;29(4):441–64. https://doi.org/10.1210/er.2008-0002.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Manolagas SC, Jilka RL. Bone marrow, cytokines, and bone remodeling Emerging insights into the pathophysiology of osteoporosis. N Engl J Med. 1995;332(5):305–11. https://doi.org/10.1056/nejm199502023320506.

    Article  CAS  PubMed  Google Scholar 

  12. Huang JC, Sakata T, Pfleger LL, Bencsik M, Halloran BP, Bikle DD, et al. PTH differentially regulates expression of RANKL and OPG. J Bone Miner Res. 2004;19(2):235–44. https://doi.org/10.1359/jbmr.0301226.

    Article  CAS  PubMed  Google Scholar 

  13. Feng X, Teitelbaum SL. Osteoclasts: new insights. Bone Res. 2013;1(1):11–26. https://doi.org/10.4248/br201301003.

    Article  PubMed  Google Scholar 

  14. Ge C, Xiao G, Jiang D, Franceschi RT. Critical role of the extracellular signal-regulated kinase-MAPK pathway in osteoblast differentiation and skeletal development. J Cell Biol. 2007;176(5):709–18. https://doi.org/10.1083/jcb.200610046.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Kolch W. Coordinating ERK/MAPK signalling through scaffolds and inhibitors. Nat Rev Mol Cell Biol. 2005;6(11):827–37. https://doi.org/10.1038/nrm1743.

    Article  CAS  PubMed  Google Scholar 

  16. Krishnan V, Bryant HU, Macdougald OA. Regulation of bone mass by Wnt signaling. J Clin Invest. 2006;116(5):1202–9. https://doi.org/10.1172/jci28551.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Wong PC, Seiffert D, Bird JE, Watson CA, Bostwick JS, Giancarli M, et al. Blockade of protease-activated receptor-4 (PAR4) provides robust antithrombotic activity with low bleeding. Sci Transl Med. 2017;9(371):eaaf5294. https://doi.org/10.1126/scitranslmed.aaf5294.

    Article  CAS  PubMed  Google Scholar 

  18. Takayanagi H, Kim S, Koga T, Nishina H, Isshiki M, Yoshida H, et al. Induction and activation of the transcription factor NFATc1 (NFAT2) integrate RANKL signaling in terminal differentiation of osteoclasts. Dev Cell. 2002;3(6):889–901.

    Article  CAS  Google Scholar 

  19. Alonso G, Koegl M, Mazurenko N, Courtneidge SA. Sequence requirements for binding of Src family tyrosine kinases to activated growth factor receptors. J Biol Chem. 1995;270(17):9840–8. https://doi.org/10.1074/jbc.270.17.9840.

    Article  CAS  PubMed  Google Scholar 

  20. Xiong Y, Song D, Cai Y, Yu W, Yeung YG, Stanley ER. A CSF-1 receptor phosphotyrosine 559 signaling pathway regulates receptor ubiquitination and tyrosine phosphorylation. J Biol Chem. 2011;286(2):952–60. https://doi.org/10.1074/jbc.M110.166702.

    Article  CAS  PubMed  Google Scholar 

  21. Tanaka K, Yamaguchi Y, Hakeda Y. Isolated chick osteocytes stimulate formation and bone-resorbing activity of osteoclast-like cells. J Bone Miner Metab. 1995;13(2):61–70.

    Article  Google Scholar 

  22. Nakashima T, Hayashi M, Fukunaga T, Kurata K, Oh-Hora M, Feng JQ, et al. Evidence for osteocyte regulation of bone homeostasis through RANKL expression. Nat Med. 2011;17(10):1231–4. https://doi.org/10.1038/nm.2452.

    Article  CAS  PubMed  Google Scholar 

  23. Chen H, Senda T, Kubo KY. The osteocyte plays multiple roles in bone remodeling and mineral homeostasis. Med Mol Morphol. 2015;48(2):61–8. https://doi.org/10.1007/s00795-015-0099-y.

    Article  CAS  PubMed  Google Scholar 

  24. Walsh MC, Choi Y. Biology of the RANKL-RANK-OPG System in Immunity, Bone, and Beyond. Front Immunol. 2014;5:511. https://doi.org/10.3389/fimmu.2014.00511.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Ikeda T, Kasai M, Suzuki J, Kuroyama H, Seki S, Utsuyama M, et al. Multimerization of the receptor activator of nuclear factor-kappaB ligand (RANKL) isoforms and regulation of osteoclastogenesis. J Biol Chem. 2003;278(47):47217–22. https://doi.org/10.1074/jbc.M304636200.

    Article  CAS  PubMed  Google Scholar 

  26. Murakami T, Yamamoto M, Ono K, Nishikawa M, Nagata N, Motoyoshi K, et al. Transforming growth factor-beta1 increases mRNA levels of osteoclastogenesis inhibitory factor in osteoblastic/stromal cells and inhibits the survival of murine osteoclast-like cells. Biochem Biophys Res Commun. 1998;252(3):747–52. https://doi.org/10.1006/bbrc.1998.9723.

    Article  CAS  PubMed  Google Scholar 

  27. Lum L, Wong BR, Josien R, Becherer JD, Erdjument-Bromage H, Schlondorff J, et al. Evidence for a role of a tumor necrosis factor-alpha (TNF-alpha)-converting enzyme-like protease in shedding of TRANCE, a TNF family member involved in osteoclastogenesis and dendritic cell survival. J Biol Chem. 1999;274(19):13613–8. https://doi.org/10.1074/jbc.274.19.13613.

    Article  CAS  PubMed  Google Scholar 

  28. Hikita A, Yana I, Wakeyama H, Nakamura M, Kadono Y, Oshima Y, et al. Negative regulation of osteoclastogenesis by ectodomain shedding of receptor activator of NF-kappaB ligand. J Biol Chem. 2006;281(48):36846–55. https://doi.org/10.1074/jbc.M606656200.

    Article  CAS  PubMed  Google Scholar 

  29. Doedens JR, Black RA. Stimulation-induced down-regulation of tumor necrosis factor-alpha converting enzyme. J Biol Chem. 2000;275(19):14598–607. https://doi.org/10.1074/jbc.275.19.14598.

    Article  CAS  PubMed  Google Scholar 

  30. Chen G, Sircar K, Aprikian A, Potti A, Goltzman D, Rabbani SA. Expression of RANKL/RANK/OPG in primary and metastatic human prostate cancer as markers of disease stage and functional regulation. Cancer. 2006;107(2):289–98. https://doi.org/10.1002/cncr.21978.

    Article  CAS  PubMed  Google Scholar 

  31. Mizukami J, Takaesu G, Akatsuka H, Sakurai H, Ninomiya-Tsuji J, Matsumoto K, et al. Receptor activator of NF-kappaB ligand (RANKL) activates TAK1 mitogen-activated protein kinase kinase kinase through a signaling complex containing RANK, TAB2, and TRAF6. Mol Cell Biol. 2002;22(4):992–1000. https://doi.org/10.1128/mcb.22.4.992-1000.2002.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Walsh MC, Choi Y. Biology of the TRANCE axis. Cytokine Growth Factor Rev. 2003;14(3–4):251–63.

    Article  CAS  Google Scholar 

  33. Naito A, Azuma S, Tanaka S, Miyazaki T, Takaki S, Takatsu K, et al. Severe osteopetrosis, defective interleukin-1 signalling and lymph node organogenesis in TRAF6-deficient mice. Genes Cells. 1999;4(6):353–62.

    Article  CAS  Google Scholar 

  34. Aliprantis AO, Ueki Y, Sulyanto R, Park A, Sigrist KS, Sharma SM, et al. NFATc1 in mice represses osteoprotegerin during osteoclastogenesis and dissociates systemic osteopenia from inflammation in cherubism. J Clin Invest. 2008;118(11):3775–89. https://doi.org/10.1172/jci35711.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Li Y, Toraldo G, Li A, Yang X, Zhang H, Qian WP, et al. B cells and T cells are critical for the preservation of bone homeostasis and attainment of peak bone mass in vivo. Blood. 2007;109(9):3839–48. https://doi.org/10.1182/blood-2006-07-037994.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Kearns AE, Khosla S, Kostenuik PJ. Receptor activator of nuclear factor kappaB ligand and osteoprotegerin regulation of bone remodeling in health and disease. Endocr Rev. 2008;29(2):155–92. https://doi.org/10.1210/er.2007-0014.

    Article  CAS  PubMed  Google Scholar 

  37. Theoleyre S, Wittrant Y, Tat SK, Fortun Y, Redini F, Heymann D. The molecular triad OPG/RANK/RANKL: involvement in the orchestration of pathophysiological bone remodeling. Cytokine Growth Factor Rev. 2004;15(6):457–75. https://doi.org/10.1016/j.cytogfr.2004.06.004.

    Article  CAS  PubMed  Google Scholar 

  38. Glass DA 2nd, Bialek P, Ahn JD, Starbuck M, Patel MS, Clevers H, et al. Canonical Wnt signaling in differentiated osteoblasts controls osteoclast differentiation. Dev Cell. 2005;8(5):751–64. https://doi.org/10.1016/j.devcel.2005.02.017.

    Article  CAS  PubMed  Google Scholar 

  39. Mancini A, Niedenthal R, Joos H, Koch A, Trouliaris S, Niemann H, et al. Identification of a second Grb2 binding site in the v-Fms tyrosine kinase. Oncogene. 1997;15(13):1565–72. https://doi.org/10.1038/sj.onc.1201518.

    Article  CAS  PubMed  Google Scholar 

  40. Wada T, Nakashima T, Hiroshi N, Penninger JM. RANKL-RANK signaling in osteoclastogenesis and bone disease. Trends Mol Med. 2006;12(1):17–25. https://doi.org/10.1016/j.molmed.2005.11.007.

    Article  CAS  PubMed  Google Scholar 

  41. Udagawa N, Takahashi N, Akatsu T, Tanaka H, Sasaki T, Nishihara T, et al. Origin of osteoclasts: mature monocytes and macrophages are capable of differentiating into osteoclasts under a suitable microenvironment prepared by bone marrow-derived stromal cells. Proc Natl Acad Sci U S A. 1990;87(18):7260–4. https://doi.org/10.1073/pnas.87.18.7260.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Okamoto K, Nakashima T, Shinohara M, Negishi-Koga T, Komatsu N, Terashima A, et al. Osteoimmunology: the conceptual framework unifying the immune and skeletal systems. Physiol Rev. 2017;97(4):1295–349. https://doi.org/10.1152/physrev.00036.2016.

    Article  CAS  PubMed  Google Scholar 

  43. Heinemann C, Heinemann S, Worch H, Hanke T. Development of an osteoblast/osteoclast co-culture derived by human bone marrow stromal cells and human monocytes for biomaterials testing. Eur Cell Mater. 2011;21:80–93.

    Article  CAS  Google Scholar 

  44. Stone MJ, Hayward JA, Huang C, Zil EH, Sanchez J. Mechanisms of Regulation of the Chemokine-Receptor Network. Int J Mol Sci. 2017;18(2):342. https://doi.org/10.3390/ijms18020342.

    Article  CAS  PubMed Central  Google Scholar 

  45. Greenbaum A, Hsu YM, Day RB, Schuettpelz LG, Christopher MJ, Borgerding JN, et al. CXCL12 in early mesenchymal progenitors is required for haematopoietic stem-cell maintenance. Nature. 2013;495(7440):227–30. https://doi.org/10.1038/nature11926.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Binder NB, Niederreiter B, Hoffmann O, Stange R, Pap T, Stulnig TM, et al. Estrogen-dependent and C-C chemokine receptor-2-dependent pathways determine osteoclast behavior in osteoporosis. Nat Med. 2009;15(4):417–24. https://doi.org/10.1038/nm.1945.

    Article  CAS  PubMed  Google Scholar 

  47. Wong BR, Rho J, Arron J, Robinson E, Orlinick J, Chao M, et al. TRANCE is a novel ligand of the tumor necrosis factor receptor family that activates c-Jun N-terminal kinase in T cells. J Biol Chem. 1997;272(40):25190–4. https://doi.org/10.1074/jbc.272.40.25190.

    Article  CAS  PubMed  Google Scholar 

  48. Arron JR, Choi Y. Bone versus immune system. Nature. 2000;408(6812):535–6. https://doi.org/10.1038/35046196.

    Article  CAS  PubMed  Google Scholar 

  49. Horwood NJ, Kartsogiannis V, Quinn JM, Romas E, Martin TJ, Gillespie MT. Activated T lymphocytes support osteoclast formation in vitro. Biochem Biophys Res Commun. 1999;265(1):144–50. https://doi.org/10.1006/bbrc.1999.1623.

    Article  CAS  PubMed  Google Scholar 

  50. Choi Y, Woo KM, Ko SH, Lee YJ, Park SJ, Kim HM, et al. Osteoclastogenesis is enhanced by activated B cells but suppressed by activated CD8(+) T cells. Eur J Immunol. 2001;31(7):2179–88. https://doi.org/10.1002/1521-4141(200107)31:7%3c2179::AID-IMMU2179gt;3.0.CO;2-X.

    Article  CAS  PubMed  Google Scholar 

  51. Waterhouse P, Penninger JM, Timms E, Wakeham A, Shahinian A, Lee KP, et al. Lymphoproliferative disorders with early lethality in mice deficient in Ctla-4. Science. 1995;270(5238):985–8. https://doi.org/10.1126/science.270.5238.985.

    Article  CAS  PubMed  Google Scholar 

  52. Axmann R, Herman S, Zaiss M, Franz S, Polzer K, Zwerina J, et al. CTLA-4 directly inhibits osteoclast formation. Ann Rheum Dis. 2008;67(11):1603–9. https://doi.org/10.1136/ard.2007.080713.

    Article  CAS  PubMed  Google Scholar 

  53. Kong YY, Yoshida H, Sarosi I, Tan HL, Timms E, Capparelli C, et al. OPGL is a key regulator of osteoclastogenesis, lymphocyte development and lymph-node organogenesis. Nature. 1999;397(6717):315–23. https://doi.org/10.1038/16852.

    Article  CAS  PubMed  Google Scholar 

  54. Dougall WC, Glaccum M, Charrier K, Rohrbach K, Brasel K, De Smedt T, et al. RANK is essential for osteoclast and lymph node development. Genes Dev. 1999;13(18):2412–24. https://doi.org/10.1101/gad.13.18.2412.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Yun TJ, Tallquist MD, Aicher A, Rafferty KL, Marshall AJ, Moon JJ, et al. Osteoprotegerin, a crucial regulator of bone metabolism, also regulates B cell development and function. J Immunol. 2001;166(3):1482–91. https://doi.org/10.4049/jimmunol.166.3.1482.

    Article  CAS  PubMed  Google Scholar 

  56. Srivastava RK, Dar HY, Mishra PK. Immunoporosis: Immunology of Osteoporosis-Role of T Cells. Front Immunol. 2018;9:657. https://doi.org/10.3389/fimmu.2018.00657.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Zhao R. Immune regulation of osteoclast function in postmenopausal osteoporosis: a critical interdisciplinary perspective. Int J Med Sci. 2012;9(9):825–32. https://doi.org/10.7150/ijms.5180.

    Article  PubMed  PubMed Central  Google Scholar 

  58. Chen J, Yang J, Qiao Y, Li X. Understanding the regulatory roles of natural killer T Cells in rheumatoid arthritis: t helper cell differentiation dependent or independent? Scand J Immunol. 2016;84(4):197–203. https://doi.org/10.1111/sji.12460.

    Article  CAS  PubMed  Google Scholar 

  59. Tilkeridis K, Kiziridis G, Ververidis A, Papoutselis M, Kotsianidis I, Kitsikidou G, et al. Immunoporosis: a new role for invariant natural killer T (NKT) cells through overexpression of Nuclear Factor-κB Ligand (RANKL). Med Sci Monit. 2019;25:2151–8. https://doi.org/10.12659/msm.912119.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Spanoudakis E, Papoutselis M, Terpos E, Dimopoulos MA, Tsatalas C, Margaritis D, et al. Overexpression of RANKL by invariant NKT cells enriched in the bone marrow of patients with multiple myeloma. Blood Cancer J. 2016;6(11): e500. https://doi.org/10.1038/bcj.2016.108.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Kanzaki H, Makihira S, Suzuki M, Ishii T, Movila A, Hirschfeld J, et al. Soluble RANKL cleaved from activated lymphocytes by TNF-alpha-converting enzyme contributes to Osteoclastogenesis in periodontitis. J Immunol. 2016;197(10):3871–83. https://doi.org/10.4049/jimmunol.1601114.

    Article  CAS  PubMed  Google Scholar 

  62. Hooper NM, Karran EH, Turner AJ. Membrane protein secretases. Biochem J. 1997;321(Pt 2):265–79. https://doi.org/10.1042/bj3210265.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Loechel F, Overgaard MT, Oxvig C, Albrechtsen R, Wewer UM. Regulation of human ADAM 12 protease by the prodomain. Evidence for a functional cysteine switch. J Biol Chem. 1999;274(19):13427–33.

    Article  CAS  Google Scholar 

  64. Arai F, Miyamoto T, Ohneda O, Inada T, Sudo T, Brasel K, et al. Commitment and differentiation of osteoclast precursor cells by the sequential expression of c-Fms and receptor activator of nuclear factor kappaB (RANK) receptors. J Exp Med. 1999;190(12):1741–54. https://doi.org/10.1084/jem.190.12.1741.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Humphrey EL, Williams JH, Davie MW, Marshall MJ. Effects of dissociated glucocorticoids on OPG and RANKL in osteoblastic cells. Bone. 2006;38(5):652–61. https://doi.org/10.1016/j.bone.2005.10.004.

    Article  CAS  PubMed  Google Scholar 

  66. Bekker PJ, Holloway D, Nakanishi A, Arrighi M, Leese PT, Dunstan CR. The effect of a single dose of osteoprotegerin in postmenopausal women. J Bone Miner Res. 2001;16(2):348–60. https://doi.org/10.1359/jbmr.2001.16.2.348.

    Article  CAS  PubMed  Google Scholar 

  67. Lewiecki EM, Miller PD, McClung MR, Cohen SB, Bolognese MA, Liu Y, et al. Two-year treatment with denosumab (AMG 162) in a randomized phase 2 study of postmenopausal women with low BMD. J Bone Miner Res. 2007;22(12):1832–41. https://doi.org/10.1359/jbmr.070809.

    Article  CAS  PubMed  Google Scholar 

  68. Rauch F, Munns C, Land C, Glorieux FH. Pamidronate in children and adolescents with osteogenesis imperfecta: effect of treatment discontinuation. J Clin Endocrinol Metab. 2006;91(4):1268–74. https://doi.org/10.1210/jc.2005-2413.

    Article  CAS  PubMed  Google Scholar 

  69. Iranikhah M, Deas C, Murphy P, Freeman MK. Effects of denosumab after treatment discontinuation : a review of the literature. Consult Pharm. 2018;33(3):142–51. https://doi.org/10.4140/TCP.n.2018.142.

    Article  PubMed  Google Scholar 

  70. Hansel TT, Kropshofer H, Singer T, Mitchell JA, George AJ. The safety and side effects of monoclonal antibodies. Nat Rev Drug Discovery. 2010;9(4):325–38. https://doi.org/10.1038/nrd3003.

    Article  CAS  PubMed  Google Scholar 

  71. Lotinun S, Sibonga JD, Turner RT. Differential effects of intermittent and continuous administration of parathyroid hormone on bone histomorphometry and gene expression. Endocrine. 2002;17(1):29–36. https://doi.org/10.1385/endo:17:1:29.

    Article  CAS  PubMed  Google Scholar 

  72. Lindsay R, Krege JH, Marin F, Jin L, Stepan JJ. Teriparatide for osteoporosis: importance of the full course. Osteoporos Int. 2016;27(8):2395–410. https://doi.org/10.1007/s00198-016-3534-6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Cheng C, Wentworth K, Shoback DM. New frontiers in osteoporosis therapy. Annu Rev Med. 2019. https://doi.org/10.1146/annurev-med-052218-020620.

    Article  PubMed  Google Scholar 

  74. Rauner M, Rachner TD, Hofbauer LC. Bone formation and the wnt signaling pathway. N Engl J Med. 2016;375(19):1902. https://doi.org/10.1056/NEJMc1609768.

    Article  PubMed  Google Scholar 

  75. Bandeira L, Lewiecki EM, Bilezikian JP. Romosozumab for the treatment of osteoporosis. Expert Opin Biol Ther. 2017;17(2):255–63. https://doi.org/10.1080/14712598.2017.1280455.

    Article  CAS  PubMed  Google Scholar 

  76. Cosman F, Crittenden DB, Adachi JD, Binkley N, Czerwinski E, Ferrari S, et al. Romosozumab treatment in postmenopausal women with osteoporosis. N Engl J Med. 2016;375(16):1532–43. https://doi.org/10.1056/NEJMoa1607948.

    Article  CAS  PubMed  Google Scholar 

  77. Markham A. Romosozumab: first global approval. Drugs. 2019;79(4):471–6. https://doi.org/10.1007/s40265-019-01072-6.

    Article  CAS  PubMed  Google Scholar 

  78. Abou-Samra AB, Juppner H, Force T, Freeman MW, Kong XF, Schipani E, et al. Expression cloning of a common receptor for parathyroid hormone and parathyroid hormone-related peptide from rat osteoblast-like cells: a single receptor stimulates intracellular accumulation of both cAMP and inositol trisphosphates and increases intracellular free calcium. Proc Natl Acad Sci U S A. 1992;89(7):2732–6. https://doi.org/10.1073/pnas.89.7.2732.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Stewart AF, Cain RL, Burr DB, Jacob D, Turner CH, Hock JM. Six-month daily administration of parathyroid hormone and parathyroid hormone-related protein peptides to adult ovariectomized rats markedly enhances bone mass and biomechanical properties: a comparison of human parathyroid hormone 1–34, parathyroid hormone-related protein 1–36, and SDZ-parathyroid hormone 893. J Bone Miner Res. 2000;15(8):1517–25. https://doi.org/10.1359/jbmr.2000.15.8.1517.

    Article  CAS  PubMed  Google Scholar 

  80. Sahbani K, Cardozo CP, Bauman WA, Tawfeek HA. Abaloparatide exhibits greater osteoanabolic response and higher cAMP stimulation and β-arrestin recruitment than teriparatide. Physiol Rep. 2019;7(19): e14225. https://doi.org/10.14814/phy2.14225.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Serhan CN, Clish CB, Brannon J, Colgan SP, Chiang N, Gronert K. Novel functional sets of lipid-derived mediators with antiinflammatory actions generated from omega-3 fatty acids via cyclooxygenase 2-nonsteroidal antiinflammatory drugs and transcellular processing. J Exp Med. 2000;192(8):1197–204. https://doi.org/10.1084/jem.192.8.1197.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Lacativa PG, Farias ML. Osteoporosis and inflammation. Arq Bras Endocrinol Metabol. 2010;54(2):123–32. https://doi.org/10.1590/s0004-27302010000200007.

    Article  PubMed  Google Scholar 

  83. El Kholy K, Freire M, Chen T, Van Dyke TE. Resolvin E1 promotes bone preservation under inflammatory conditions. Front Immunol. 2018;9:1300. https://doi.org/10.3389/fimmu.2018.01300.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Zhu M, Van Dyke TE, Gyurko R. Resolvin E1 regulates osteoclast fusion via DC-STAMP and NFATc1. FASEB J. 2013;27(8):3344–53. https://doi.org/10.1096/fj.12-220228.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Yagi M, Miyamoto T, Sawatani Y, Iwamoto K, Hosogane N, Fujita N, et al. DC-STAMP is essential for cell-cell fusion in osteoclasts and foreign body giant cells. J Exp Med. 2005;202(3):345–51. https://doi.org/10.1084/jem.20050645.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Benabdoun HA, Kulbay M, Rondon EP, Vallieres F, Shi Q, Fernandes J, et al. In vitro and in vivo assessment of the proresolutive and antiresorptive actions of resolvin D1: relevance to arthritis. Arthritis Res Ther. 2019;21(1):72. https://doi.org/10.1186/s13075-019-1852-8.

    Article  PubMed  PubMed Central  Google Scholar 

  87. Wei J, Li Y, Liu Q, Lan Y, Wei C, Tian K, et al. Betulinic acid protects from bone loss in ovariectomized mice and Suppresses RANKL-Associated Osteoclastogenesis by Inhibiting the MAPK and NFATc1 Pathways. Front Pharmacol. 2020;11:1025. https://doi.org/10.3389/fphar.2020.01025.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Jeong DH, Kwak SC, Lee MS, Yoon KH, Kim JY, Lee CH. Betulinic acid inhibits RANKL-induced osteoclastogenesis via Attenuating Akt, NF-κB, and PLCγ2-Ca(2+) signaling and prevents inflammatory bone loss. J Nat Prod. 2020;83(4):1174–82. https://doi.org/10.1021/acs.jnatprod.9b01212.

    Article  CAS  PubMed  Google Scholar 

  89. Khan N, Mukhtar H. Tea polyphenols for health promotion. Life Sci. 2007;81(7):519–33. https://doi.org/10.1016/j.lfs.2007.06.011.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Lim S, Kim TH, Ihn HJ, Lim J, Kim GY, Choi YH, et al. Inhibitory effect of oolonghomobisflavan B on osteoclastogenesis by suppressing p38 MAPK activation. Bioorg Med Chem Lett. 2020;30(18): 127429. https://doi.org/10.1016/j.bmcl.2020.127429.

    Article  CAS  PubMed  Google Scholar 

  91. Wang W, Li W, Ma N, Steinhoff G. Non-viral gene delivery methods. Curr Pharm Biotechnol. 2013;14(1):46–60.

    CAS  PubMed  Google Scholar 

  92. Stone D. Novel viral vector systems for gene therapy. Viruses. 2010;2(4):1002–7. https://doi.org/10.3390/v2041002.

    Article  PubMed  PubMed Central  Google Scholar 

  93. Fahid FS, Jiang J, Zhu Q, Zhang C, Filbert E, Safavi KE, et al. Application of small interfering RNA for inhibition of lipopolysaccharide-induced osteoclast formation and cytokine stimulation. J Endod. 2008;34(5):563–9. https://doi.org/10.1016/j.joen.2008.01.024.

    Article  PubMed  Google Scholar 

  94. Sundaram K, Nishimura R, Senn J, Youssef RF, London SD, Reddy SV. RANK ligand signaling modulates the matrix metalloproteinase-9 gene expression during osteoclast differentiation. Exp Cell Res. 2007;313(1):168–78. https://doi.org/10.1016/j.yexcr.2006.10.001.

    Article  CAS  PubMed  Google Scholar 

  95. Selinger CI, Day CJ, Morrison NA. Optimized transfection of diced siRNA into mature primary human osteoclasts: inhibition of cathepsin K mediated bone resorption by siRNA. J Cell Biochem. 2005;96(5):996–1002. https://doi.org/10.1002/jcb.20575.

    Article  CAS  PubMed  Google Scholar 

  96. Schiffelers RM, Xu J, Storm G, Woodle MC, Scaria PV. Effects of treatment with small interfering RNA on joint inflammation in mice with collagen-induced arthritis. Arthritis Rheum. 2005;52(4):1314–8. https://doi.org/10.1002/art.20975.

    Article  CAS  PubMed  Google Scholar 

  97. Hoffmann DB, Gruber J, Böker KO, Deppe D, Sehmisch S, Schilling AF, et al. Effects of RANKL knockdown by Virus-like particle-mediated RNAi in a rat model of osteoporosis. Mol Ther Nucleic Acids. 2018;12:443–52. https://doi.org/10.1016/j.omtn.2018.06.001.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Katas H, Alpar HO. Development and characterisation of chitosan nanoparticles for siRNA delivery. J Control Release. 2006;115(2):216–25. https://doi.org/10.1016/j.jconrel.2006.07.021.

    Article  CAS  PubMed  Google Scholar 

  99. Rinaudo M. Chitin and chitosan: properties and applications. Prog Polym Sci. 2006;31(7):603–32.

    Article  CAS  Google Scholar 

  100. Lavertu M, Methot S, Tran-Khanh N, Buschmann MD. High efficiency gene transfer using chitosan/DNA nanoparticles with specific combinations of molecular weight and degree of deacetylation. Biomaterials. 2006;27(27):4815–24. https://doi.org/10.1016/j.biomaterials.2006.04.029.

    Article  CAS  PubMed  Google Scholar 

  101. de Souza R, Picola IPD, Shi Q, Petronio MS, Benderdour M, Fernandes JC, et al. Diethylaminoethyl- chitosan as an efficient carrier for siRNA delivery: Improving the condensation process and the nanoparticles properties. Int J Biol Macromol. 2018;119:186–97. https://doi.org/10.1016/j.ijbiomac.2018.07.072.

    Article  CAS  PubMed  Google Scholar 

  102. Fernandes JC, Wang H, Jreyssaty C, Benderdour M, Lavigne P, Qiu X, et al. Bone-protective effects of nonviral gene therapy with folate-chitosan DNA nanoparticle containing interleukin-1 receptor antagonist gene in rats with adjuvant-induced arthritis. Mol Ther. 2008;16(7):1243–51. https://doi.org/10.1038/mt.2008.99.

    Article  CAS  PubMed  Google Scholar 

  103. Shi Q, Rondon-Cavanzo EP, Dalla Picola IP, Tiera MJ, Zhang X, Dai K, et al. In vivo therapeutic efficacy of TNFalpha silencing by folate-PEG-chitosan-DEAE/siRNA nanoparticles in arthritic mice. Int J Nanomed. 2018;13:387–402. https://doi.org/10.2147/ijn.S146942.

    Article  CAS  Google Scholar 

  104. Schnoke M, Midura SB, Midura RJ. Parathyroid hormone suppresses osteoblast apoptosis by augmenting DNA repair. Bone. 2009;45(3):590–602. https://doi.org/10.1016/j.bone.2009.05.006.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Narayanan D, Anitha A, Jayakumar R, Chennazhi KP. In vitro and in vivo evaluation of osteoporosis therapeutic peptide PTH 1–34 loaded pegylated chitosan nanoparticles. Mol Pharm. 2013;10(11):4159–67. https://doi.org/10.1021/mp400184v.

    Article  CAS  PubMed  Google Scholar 

  106. Prego C, Torres D, Fernandez-Megia E, Novoa-Carballal R, Quiñoá E, Alonso MJ. Chitosan-PEG nanocapsules as new carriers for oral peptide delivery effect of chitosan pegylation degree. J Control Release. 2006;111(3):299–308.

    Article  CAS  Google Scholar 

  107. Borchard G, Lueβen HL, de Boer AG, Verhoef JC, Lehr C-M, Junginger HE. The potential of mucoadhesive polymers in enhancing intestinal peptide drug absorption. III: Effects of chitosan-glutamate and carbomer on epithelial tight junctions in vitro. J Control Release. 1996;39(2):131–8. https://doi.org/10.1016/0168-3659(95)00146-8.

    Article  CAS  Google Scholar 

  108. Narayanan D, Anitha A, Jayakumar R, Chennazhi KP. PTH 1–34 Loaded Thiolated Chitosan Nanoparticles for Osteoporosis: Oral Bioavailability and Anabolic Effect on Primary Osteoblast Cells (Journal of Biomedical Nanotechnology, Vol. 10(1), pp. 166–178 (2014)). J Biomed Nanotechnol. 2019;15(6): 1354. https://doi.org/10.1166/jbn.2019.2753.

  109. Kast CE, Bernkop-Schnürch A. Thiolated polymers–thiomers: development and in vitro evaluation of chitosan-thioglycolic acid conjugates. Biomaterials. 2001;22(17):2345–52. https://doi.org/10.1016/s0142-9612(00)00421-x.

    Article  CAS  PubMed  Google Scholar 

  110. Hong DX, Yun YL, Guan YX, Yao SJ. Preparation of micrometric powders of parathyroid hormone (PTH1-34)-loaded chitosan oligosaccharide by supercritical fluid assisted atomization. Int J Pharm. 2018;545(1–2):389–94. https://doi.org/10.1016/j.ijpharm.2018.05.022.

    Article  CAS  PubMed  Google Scholar 

  111. Russo E, Villa C. Poloxamer hydrogels for biomedical applications. Pharmaceutics. 2019;11(12):671. https://doi.org/10.3390/pharmaceutics11120671.

    Article  CAS  PubMed Central  Google Scholar 

  112. Erten Taysi A, Cevher E, Sessevmez M, Olgac V, Mert Taysi N, Atalay B. The efficacy of sustained-release chitosan microspheres containing recombinant human parathyroid hormone on MRONJ. Braz Oral Res. 2019;33:e086. https://doi.org/10.1590/1807-3107bor-2019.vol33.0086.

    Article  PubMed  Google Scholar 

  113. Cheng C, Wentworth K, Shoback DM. New frontiers in osteoporosis therapy. Annu Rev Med. 2020;71:277–88. https://doi.org/10.1146/annurev-med-052218-020620.

    Article  CAS  PubMed  Google Scholar 

  114. Kiernan J, Hu S, Grynpas MD, Davies JE, Stanford WL. Systemic Mesenchymal stromal cell transplantation prevents functional bone loss in a mouse model of age-related osteoporosis. Stem Cells Transl Med. 2016;5(5):683–93. https://doi.org/10.5966/sctm.2015-0231.

    Article  PubMed  PubMed Central  Google Scholar 

  115. Houlihan DD, Mabuchi Y, Morikawa S, Niibe K, Araki D, Suzuki S, et al. Isolation of mouse mesenchymal stem cells on the basis of expression of Sca-1 and PDGFR-α. Nat Protoc. 2012;7(12):2103–11. https://doi.org/10.1038/nprot.2012.125.

    Article  CAS  PubMed  Google Scholar 

  116. Sui B, Hu C, Zhang X, Zhao P, He T, Zhou C, et al. Allogeneic mesenchymal stem cell therapy promotes osteoblastogenesis and prevents glucocorticoid-induced osteoporosis. Stem Cells Transl Med. 2016;5(9):1238–46. https://doi.org/10.5966/sctm.2015-0347.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Musiał-Wysocka A, Kot M, Majka M. The pros and cons of mesenchymal stem cell-based therapies. Cell Transplant. 2019;28(7):801–12. https://doi.org/10.1177/0963689719837897.

    Article  PubMed  PubMed Central  Google Scholar 

  118. Phinney DG, Pittenger MF. Concise review: MSC-derived exosomes for cell-free therapy. Stem Cells. 2017;35(4):851–8. https://doi.org/10.1002/stem.2575.

    Article  CAS  PubMed  Google Scholar 

  119. Samir ELA, Mäger I, Breakefield XO, Wood MJ. Extracellular vesicles: biology and emerging therapeutic opportunities. Nat Rev Drug Discov. 2013;12(5):347–57. https://doi.org/10.1038/nrd3978.

    Article  CAS  Google Scholar 

  120. Zuo R, Liu M, Wang Y, Li J, Wang W, Wu J, et al. BM-MSC-derived exosomes alleviate radiation-induced bone loss by restoring the function of recipient BM-MSCs and activating Wnt/β-catenin signaling. Stem Cell Res Ther. 2019;10(1):30. https://doi.org/10.1186/s13287-018-1121-9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. D’Oronzo S, Stucci S, Tucci M, Silvestris F. Cancer treatment-induced bone loss (CTIBL): pathogenesis and clinical implications. Cancer Treat Rev. 2015;41(9):798–808. https://doi.org/10.1016/j.ctrv.2015.09.003.

    Article  CAS  PubMed  Google Scholar 

  122. Zhao P, Xiao L, Peng J, Qian YQ, Huang CC. Exosomes derived from bone marrow mesenchymal stem cells improve osteoporosis through promoting osteoblast proliferation via MAPK pathway. Eur Rev Med Pharmacol Sci. 2018;22(12):3962–70. https://doi.org/10.26355/eurrev_201806_15280.

    Article  CAS  PubMed  Google Scholar 

  123. Kordelas L, Rebmann V, Ludwig AK, Radtke S, Ruesing J, Doeppner TR, et al. MSC-derived exosomes: a novel tool to treat therapy-refractory graft-versus-host disease. Leukemia. 2014;28(4):970–3. https://doi.org/10.1038/leu.2014.41.

    Article  CAS  PubMed  Google Scholar 

  124. Pongchaiyakul C, Nanagara R, Songpatanasilp T, Unnanuntana A. Cost-effectiveness of denosumab for high-risk postmenopausal women with osteoporosis in Thailand. J Med Econ. 2020;23:776–85. https://doi.org/10.1080/13696998.2020.1730381.

    Article  PubMed  Google Scholar 

  125. Shoback D, Rosen CJ, Black DM, Cheung AM, Murad MH, Eastell R. Pharmacological management of osteoporosis in postmenopausal women: an endocrine society guideline update. J Clin Endocrinol Metab. 2020;105(3):048. https://doi.org/10.1210/clinem/dgaa048.

    Article  Google Scholar 

  126. Heuchemer L, Emmert D, Bender T, Rasche T, Marinova M, Kasapovic A, et al. Pain management in osteoporosis. Schmerz. 2020;34:91–104. https://doi.org/10.1007/s00482-020-45-1.

    Article  CAS  PubMed  Google Scholar 

  127. Levis S, Lagari VS. The role of diet in osteoporosis prevention and management. Curr Osteoporos Rep. 2012;10(4):296–302. https://doi.org/10.1007/s11914-012-0119-y.

    Article  PubMed  Google Scholar 

  128. Quattrini S, Pampaloni B, Gronchi G, Giusti F, Brandi ML. The mediterranean diet in osteoporosis prevention: an insight in a peri- and post-menopausal population. Nutrients. 2021;13(2):531. https://doi.org/10.3390/nu13020531.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Cano A, Marshall S, Zolfaroli I, Bitzer J, Ceausu I, Chedraui P, et al. The Mediterranean diet and menopausal health: an EMAS position statement. Maturitas. 2020;139:90–7. https://doi.org/10.1016/j.maturitas.2020.07.001.

    Article  CAS  PubMed  Google Scholar 

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  1. Orthopedics Research Laboratory, Research Center, Hôpital du Sacré-Cœur de Montréal, Université de Montréal, 5400 boul. Gouin ouest, Montréal, Québec, H4J 1C5, Canada

    Mouna Ferbebouh, Francis Vallières, Mohamed Benderdour & Julio Fernandes

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Ferbebouh, M., Vallières, F., Benderdour, M. et al. The pathophysiology of immunoporosis: innovative therapeutic targets. Inflamm. Res. 70, 859–875 (2021). https://doi.org/10.1007/s00011-021-01484-9

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