The role of bone cells in immune regulation during the course of infection


Bone homeostasis depends on a balance between osteoclastic bone resorption and osteoblastic bone formation. Bone cells are regulated by a variety of biochemical factors, such as hormones and cytokines, as well as various types of physical stress. The immune system affects bone, since such factors are dysregulated under pathologic conditions, including infection. The bone marrow, one of the primary lymphoid organs, provides a special microenvironment that supports the function and differentiation of immune cells and hematopoietic stem cells (HSCs). Thus, bone cells contribute to immune regulation by modulating immune cell differentiation and/or function through the maintenance of the bone marrow microenvironment. Although osteoblasts were first reported as the population that supports HSCs, the role of osteoblast-lineage cells in hematopoiesis has been shown to be more limited than previously expected. Osteoblasts are specifically involved in the differentiation of lymphoid cells under physiological and pathological conditions. It is of critical importance how bone cells are modified during inflammation and/or infection and how such modification affects the immune system.

This is a preview of subscription content, log in to check access.

Fig. 1
Fig. 2


  1. 1.

    Takayanagi H (2012) New developments in osteoimmunology. Nat Rev Rheumatol 8:684–689

    CAS  PubMed  Google Scholar 

  2. 2.

    Okamoto K, Nakashima T, Shinohara M, Negishi-Koga T, Komatsu N, Terashima A, Sawa S, Nitta T, Takayanagi H (2017) Osteoimmunology: the conceptual framework unifying the immune and skeletal systems. Physiol Rev 97:1295–1349

    CAS  PubMed  Google Scholar 

  3. 3.

    Takayanagi H (2007) Osteoimmunology: shared mechanisms and crosstalk between the immune and bone systems. Nat Rev Immunol 7:292–304

    CAS  Google Scholar 

  4. 4.

    Terashima A, Takayanagi H (2018) Overview of osteoimmunology. Calcif Tissue Int 102:503–511

    CAS  PubMed  Google Scholar 

  5. 5.

    Morrison SJ, Scadden DT (2014) The bone marrow niche for haematopoietic stem cells. Nature 505:327–334

    CAS  PubMed  PubMed Central  Google Scholar 

  6. 6.

    Lord BI, Testa NG, Hendry JH (1975) The relative spatial distributions of CFUs and CFUc in the normal mouse femur. Blood 46:65–72

    CAS  PubMed  Google Scholar 

  7. 7.

    Gong JK (1978) Endosteal marrow: a rich source of hematopoietic stem cells. Science 199:1443–1445

    CAS  PubMed  Google Scholar 

  8. 8.

    Taichman RS, Emerson SG (1994) Human osteoblasts support hematopoiesis through the production of granulocyte colony-stimulating factor. J Exp Med 179:1677–1682

    CAS  PubMed  Google Scholar 

  9. 9.

    Calvi LM, Adams GB, Weibrecht KW, Weber JM, Olson DP, Knight MC, Martin RP, Schipani E, Divieti P, Bringhurst FR, Milner LA, Kronenberg HM, Scadden DT (2003) Osteoblastic cells regulate the haematopoietic stem cell niche. Nature 425:841–846

    CAS  Google Scholar 

  10. 10.

    Zhang J, Niu C, Ye L, Huang H, He X, Tong WG, Ross J, Haug J, Johnson T, Feng JQ, Harris S, Wiedemann LM, Mishina Y, Li L (2003) Identification of the haematopoietic stem cell niche and control of the niche size. Nature 425:836–841

    CAS  PubMed  Google Scholar 

  11. 11.

    Chan CK, Chen CC, Luppen CA, Kim JB, DeBoer AT, Wei K, Helms JA, Kuo CJ, Kraft DL, Weissman IL (2009) Endochondral ossification is required for haematopoietic stem-cell niche formation. Nature 457:490–494

    CAS  PubMed  Google Scholar 

  12. 12.

    Pinho S, Lacombe J, Hanoun M, Mizoguchi T, Bruns I, Kunisaki Y, Frenette PS (2013) PDGFRα and CD51 mark human Nestin+ sphere-forming mesenchymal stem cells capable of hematopoietic progenitor cell expansion. J Exp Med 210:1351–1367 %1357 2013/1306/1319

    CAS  PubMed  PubMed Central  Google Scholar 

  13. 13.

    Arai F, Hirao A, Ohmura M, Sato H, Matsuoka S, Takubo K, Ito K, Koh GY, Suda T (2004) Tie2/angiopoietin-1 signaling regulates hematopoietic stem cell quiescence in the bone marrow niche. Cell 118:149–161

    CAS  PubMed  Google Scholar 

  14. 14.

    Yoshihara H, Arai F, Hosokawa K, Hagiwara T, Takubo K, Nakamura Y, Gomei Y, Iwasaki H, Matsuoka S, Miyamoto K, Miyazaki H, Takahashi T, Suda T (2007) Thrombopoietin/MPL signaling regulates hematopoietic stem cell quiescence and interaction with the osteoblastic niche. Cell Stem Cell 1:685–697

    CAS  PubMed  Google Scholar 

  15. 15.

    Stier S, Ko Y, Forkert R, Lutz C, Neuhaus T, Grunewald E, Cheng T, Dombkowski D, Calvi LM, Rittling SR, Scadden DT (2005) Osteopontin is a hematopoietic stem cell niche component that negatively regulates stem cell pool size. J Exp Med 201:1781–1791

    CAS  PubMed  PubMed Central  Google Scholar 

  16. 16.

    Zhou BO, Ding L, Morrison SJ (2015) Hematopoietic stem and progenitor cells regulate the regeneration of their niche by secreting Angiopoietin-1. Elife 4:e05521

    PubMed  PubMed Central  Google Scholar 

  17. 17.

    Kiel MJ, Radice GL, Morrison SJ (2007) Lack of evidence that hematopoietic stem cells depend on N-cadherin-mediated adhesion to osteoblasts for their maintenance. Cell Stem Cell 1:204–217

    CAS  PubMed  Google Scholar 

  18. 18.

    Lymperi S, Horwood N, Marley S, Gordon MY, Cope AP, Dazzi F (2008) Strontium can increase some osteoblasts without increasing hematopoietic stem cells. Blood 111:1173–1181

    CAS  PubMed  Google Scholar 

  19. 19.

    Bromberg O, Frisch BJ, Weber JM, Porter RL, Civitelli R, Calvi LM (2012) Osteoblastic N-cadherin is not required for microenvironmental support and regulation of hematopoietic stem and progenitor cells. Blood 120:303–313

    CAS  PubMed  PubMed Central  Google Scholar 

  20. 20.

    Ding L, Saunders TL, Enikolopov G, Morrison SJ (2012) Endothelial and perivascular cells maintain haematopoietic stem cells. Nature 481:457–462

    CAS  PubMed  PubMed Central  Google Scholar 

  21. 21.

    Ding L, Morrison SJ (2013) Haematopoietic stem cells and early lymphoid progenitors occupy distinct bone marrow niches. Nature 495:231–235

    CAS  PubMed  PubMed Central  Google Scholar 

  22. 22.

    Greenbaum A, Hsu YM, Day RB, Schuettpelz LG, Christopher MJ, Borgerding JN, Nagasawa T, Link DC (2013) CXCL12 in early mesenchymal progenitors is required for haematopoietic stem-cell maintenance. Nature 495:227–230

    CAS  PubMed  PubMed Central  Google Scholar 

  23. 23.

    Omatsu Y, Seike M, Sugiyama T, Kume T, Nagasawa T (2014) Foxc1 is a critical regulator of haematopoietic stem/progenitor cell niche formation. Nature 508:536–540

    CAS  PubMed  Google Scholar 

  24. 24.

    Omatsu Y, Sugiyama T, Kohara H, Kondoh G, Fujii N, Kohno K, Nagasawa T (2010) The essential functions of adipo-osteogenic progenitors as the hematopoietic stem and progenitor cell niche. Immunity 33:387–399

    CAS  PubMed  Google Scholar 

  25. 25.

    Wu JY, Purton LE, Rodda SJ, Chen M, Weinstein LS, McMahon AP, Scadden DT, Kronenberg HM (2008) Osteoblastic regulation of B lymphopoiesis is mediated by Gsa-dependent signaling pathways. Proc Natl Acad Sci U S A 105:16976–16981

    CAS  PubMed  PubMed Central  Google Scholar 

  26. 26.

    Terashima A, Okamoto K, Nakashima T, Akira S, Ikuta K, Takayanagi H (2016) Sepsis-induced osteoblast ablation causes immunodeficiency. Immunity 44:1434–1443

    CAS  PubMed  Google Scholar 

  27. 27.

    Yu VWC, Saez B, Cook C, Lotinun S, Pardo-Saganta A, Wang YH, Lymperi S, Ferraro F, Raaijmakers M, Wu JY, Zhou L, Rajagopal J, Kronenberg HM, Baron R, Scadden DT (2015) Specific bone cells produce DLL4 to generate thymus-seeding progenitors from bone marrow. J Exp Med 212:759–774

    CAS  PubMed  PubMed Central  Google Scholar 

  28. 28.

    Rankin EB, Wu C, Khatri R, Wilson TL, Andersen R, Araldi E, Rankin AL, Yuan J, Kuo CJ, Schipani E, Giaccia AJ (2012) The HIF signaling pathway in osteoblasts directly modulates erythropoiesis through the production of EPO. Cell 149:63–74

    CAS  PubMed  PubMed Central  Google Scholar 

  29. 29.

    Raaijmakers MH, Mukherjee S, Guo S, Zhang S, Kobayashi T, Schoonmaker JA, Ebert BL, Al-Shahrour F, Hasserjian RP, Scadden EO, Aung Z, Matza M, Merkenschlager M, Lin C, Rommens JM, Scadden DT (2010) Bone progenitor dysfunction induces myelodysplasia and secondary leukaemia. Nature 464:852–857

    CAS  PubMed  PubMed Central  Google Scholar 

  30. 30.

    Kode A, Manavalan JS, Mosialou I, Bhagat G, Rathinam CV, Luo N, Khiabanian H, Lee A, Murty VV, Friedman R, Brum A, Park D, Galili N, Mukherjee S, Teruya-Feldstein J, Raza A, Rabadan R, Berman E, Kousteni S (2014) Leukaemogenesis induced by an activating beta-catenin mutation in osteoblasts. Nature 506:240–244

    CAS  PubMed  PubMed Central  Google Scholar 

  31. 31.

    Kode A, Mosialou I, Manavalan SJ, Rathinam CV, Friedman RA, Teruya-Feldstein J, Bhagat G, Berman E, Kousteni S (2015) FoxO1-dependent induction of acute myeloid leukemia by osteoblasts in mice. Leukemia 30:1–13

    PubMed  PubMed Central  Google Scholar 

  32. 32.

    Lowell CA, Niwa M, Soriano P, Varmus HE (1996) Deficiency of the Hck and Src tyrosine kinases results in extreme levels of extramedullary hematopoiesis. Blood 87:1780–1792

    CAS  PubMed  Google Scholar 

  33. 33.

    Dougall WC, Glaccum M, Charrier K, Rohrbach K, Brasel K, De Smedt T, Daro E, Smith J, Tometsko ME, Maliszewski CR, Armstrong A, Shen V, Bain S, Cosman D, Anderson D, Morrissey PJ, Peschon JJ, Schuh J (1999) RANK is essential for osteoclast and lymph node development. Genes Dev 13:2412–2424

    CAS  PubMed  PubMed Central  Google Scholar 

  34. 34.

    Begg SK, Radley JM, Pollard JW, Chisholm OT, Stanley ER, Bertoncello I (1993) Delayed hematopoietic development in osteopetrotic (op/op) mice. J Exp Med 177:237–242

    CAS  PubMed  Google Scholar 

  35. 35.

    Sreehari S, Naik DR, Eapen M (2011) Osteopetrosis: a rare cause of anemia. Hematol Rep 3:e1

    PubMed  PubMed Central  Google Scholar 

  36. 36.

    Gerritsen EJ, Vossen JM, van Loo IH, Hermans J, Helfrich MH, Griscelli C, Fischer A (1994) Autosomal recessive osteopetrosis: variability of findings at diagnosis and during the natural course. Pediatrics 93:247–253

    CAS  PubMed  Google Scholar 

  37. 37.

    Lymperi S, Ersek A, Ferraro F, Dazzi F, Horwood NJ (2011) Inhibition of osteoclast function reduces hematopoietic stem cell numbers in vivo. Blood 117:1540–1549

    CAS  PubMed  Google Scholar 

  38. 38.

    Mansour A, Abou-Ezzi G, Sitnicka E, Jacobsen SE, Wakkach A, Blin-Wakkach C (2012) Osteoclasts promote the formation of hematopoietic stem cell niches in the bone marrow. J Exp Med 209:537–549

    CAS  PubMed  PubMed Central  Google Scholar 

  39. 39.

    Adams GB, Chabner KT, Alley IR, Olson DP, Szczepiorkowski ZM, Poznansky MC, Kos CH, Pollak MR, Brown EM, Scadden DT (2006) Stem cell engraftment at the endosteal niche is specified by the calcium-sensing receptor. Nature 439:599–603

    CAS  PubMed  Google Scholar 

  40. 40.

    Yamazaki S, Ema H, Karlsson G, Yamaguchi T, Miyoshi H, Shioda S, Taketo MM, Karlsson S, Iwama A, Nakauchi H (2011) Nonmyelinating Schwann cells maintain hematopoietic stem cell hibernation in the bone marrow niche. Cell 147:1146–1158

    CAS  PubMed  Google Scholar 

  41. 41.

    Kollet O, Dar A, Shivtiel S, Kalinkovich A, Lapid K, Sztainberg Y, Tesio M, Samstein RM, Goichberg P, Spiegel A, Elson A, Lapidot T (2006) Osteoclasts degrade endosteal components and promote mobilization of hematopoietic progenitor cells. Nat Med 12:657–664

    CAS  PubMed  Google Scholar 

  42. 42.

    Miyamoto K, Yoshida S, Kawasumi M, Hashimoto K, Kimura T, Sato Y, Kobayashi T, Miyauchi Y, Hoshi H, Iwasaki R, Miyamoto H, Hao W, Morioka H, Chiba K, Yasuda H, Penninger JM, Toyama Y, Suda T, Miyamoto T (2011) Osteoclasts are dispensable for hematopoietic stem cell maintenance and mobilization. J Exp Med 208:2175–2181

    CAS  PubMed  PubMed Central  Google Scholar 

  43. 43.

    Winkler IG, Sims NA, Pettit AR, Barbier V, Nowlan B, Helwani F, Poulton IJ, van Rooijen N, Alexander KA, Raggatt LJ, Levesque JP (2010) Bone marrow macrophages maintain hematopoietic stem cell (HSC) niches and their depletion mobilizes HSCs. Blood 116:4815–4828

    CAS  PubMed  Google Scholar 

  44. 44.

    Katayama Y, Battista M, Kao WM, Hidalgo A, Peired AJ, Thomas SA, Frenette PS (2006) Signals from the sympathetic nervous system regulate hematopoietic stem cell egress from bone marrow. Cell 124:407–421

    CAS  PubMed  Google Scholar 

  45. 45.

    Asada N, Katayama Y, Sato M, Minagawa K, Wakahashi K, Kawano H, Kawano Y, Sada A, Ikeda K, Matsui T, Tanimoto M (2013) Matrix-embedded osteocytes regulate mobilization of hematopoietic stem/progenitor cells. Cell Stem Cell 12:737–747

    CAS  PubMed  Google Scholar 

  46. 46.

    Bone RC, Sprung CL, Sibbald WJ (1992) Definitions for sepsis and organ failure. Crit Care Med 20:724–726

    CAS  PubMed  Google Scholar 

  47. 47.

    Bone RC, Balk RA, Cerra FB, Dellinger RP, Fein AM, Knaus WA, Schein RM, Sibbald WJ (1992) Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. The ACCP/SCCM Consensus Conference Committee American College of Chest Physicians/Society of Critical Care Medicine. Chest 101:1644–1655

    CAS  PubMed  Google Scholar 

  48. 48.

    Levy MM, Fink MP, Marshall JC, Abraham E, Angus D, Cook D, Cohen J, Opal SM, Vincent JL, Ramsay G, SCCM/ESICM/ACCP/ATS/SIS (2003) 2001 SCCM/ESICM/ACCP/ATS/SIS international sepsis definitions conference. Crit Care Med 31:1250–1256

    PubMed  Google Scholar 

  49. 49.

    Singer M, Deutschman CS, Seymour CW, Shankar-Hari M, Annane D, Bauer M, Bellomo R, Bernard GR, Chiche JD, Coopersmith CM, Hotchkiss RS, Levy MM, Marshall JC, Martin GS, Opal SM, Rubenfeld GD, van der Poll T, Vincent JL, Angus DC (2016) The third international consensus definitions for sepsis and septic shock (sepsis-3). JAMA 315:801–810

    CAS  PubMed  PubMed Central  Google Scholar 

  50. 50.

    Delano MJ, Scumpia PO, Weinstein JS, Coco D, Nagaraj S, Kelly-Scumpia KM, O’Malley KA, Wynn JL, Antonenko S, Al-Quran SZ, Swan R, Chung CS, Atkinson MA, Ramphal R, Gabrilovich DI, Reeves WH, Ayala A, Phillips J, Laface D, Heyworth PG, Clare-Salzler M, Moldawer LL (2007) MyD88-dependent expansion of an immature GR-1+CD11b+ population induces T cell suppression and Th2 polarization in sepsis. J Exp Med 204:1463–1474

    CAS  PubMed  PubMed Central  Google Scholar 

  51. 51.

    Davey MS, Morgan MP, Liuzzi AR, Tyler CJ, Khan MWA, Szakmany T, Hall JE, Moser B, Eberl M (2014) Microbe-specific unconventional T cells induce human neutrophil differentiation into antigen cross-presenting cells. J Immunol 193:3704–3716

    CAS  PubMed  PubMed Central  Google Scholar 

  52. 52.

    Monserrat J, de Pablo R, Reyes E, Díaz D, Barcenilla H, Zapata MR, De la Hera A, Prieto A, Alvarez-Mon M (2009) Clinical relevance of the severe abnormalities of the T cell compartment in septic shock patients. Crit Care 13:R26

    PubMed  PubMed Central  Google Scholar 

  53. 53.

    Chaudhry H, Zhou J, Zhong Y, Ali MM, McGuire F, Nagarkatti PS, Nagarkatti M (2013) Role of cytokines as a double-edged sword in sepsis. In Vivo 27:669–684

    CAS  PubMed  PubMed Central  Google Scholar 

  54. 54.

    Bo L, Wang F, Zhu J, Li J, Deng X (2011) Granulocyte-colony stimulating factor (G-CSF) and granulocyte-macrophage colony stimulating factor (GM-CSF) for sepsis: a meta-analysis. Crit Care 15:R58

    PubMed  PubMed Central  Google Scholar 

  55. 55.

    Mohammad RA (2010) Use of granulocyte colony-stimulating factor in patients with severe sepsis or septic shock. Am J Health Syst Pharm 67:1238–1245

    CAS  PubMed  Google Scholar 

  56. 56.

    Lee MSJ, Maruyama K, Fujita Y, Konishi A, Lelliott PM, Itagaki S, Horii T, Lin JW, Khan SM, Kuroda E, Akira S, Ishii KJ, Coban C (2017) Products persist in the bone marrow and promote chronic bone loss. Sci Immunol 2:eaam8093

  57. 57.

    Gibellini D, Borderi M, De Crignis E, Cicola R, Vescini F, Caudarella R, Chiodo F, Re MC (2007) RANKL/OPG/TRAIL plasma levels and bone mass loss evaluation in antiretroviral naive HIV-1-positive men. J Med Virol 79:1446–1454

    CAS  PubMed  Google Scholar 

  58. 58.

    Clouse KA, Cosentino LM, Weih KA, Pyle SW, Robbins PB, Hochstein HD, Natarajan V, Farrar WL (1991) The HIV-1 gp120 envelope protein has the intrinsic capacity to stimulate monokine secretion. J Immunol 147:2892–2901

    CAS  PubMed  Google Scholar 

  59. 59.

    Fakruddin JM, Laurence J (2003) HIV envelope gp120-mediated regulation of osteoclastogenesis via receptor activator of nuclear factor kappa B ligand (RANKL) secretion and its modulation by certain HIV protease inhibitors through interferon-gamma/RANKL cross-talk. J Biol Chem 278:48251–48258

    CAS  PubMed  Google Scholar 

  60. 60.

    Fakruddin JM, Laurence J (2005) HIV-1 Vpr enhances production of receptor of activated NF-kappaB ligand (RANKL) via potentiation of glucocorticoid receptor activity. Arch Virol 150:67–78

    CAS  PubMed  Google Scholar 

  61. 61.

    Lee JW, Hoshino A, Inoue K, Saitou T, Uehara S, Kobayashi Y, Ueha S, Matsushima K, Yamaguchi A, Imai Y, Iimura T (2017) The HIV co-receptor CCR5 regulates osteoclast function. Nat Commun 8:2226

    PubMed  PubMed Central  Google Scholar 

  62. 62.

    Gibellini D, De Crignis E, Ponti C, Cimatti L, Borderi M, Tschon M, Giardino R, Re MC (2008) HIV-1 triggers apoptosis in primary osteoblasts and HOBIT cells through TNFalpha activation. J Med Virol 80:1507–1514

    CAS  PubMed  Google Scholar 

  63. 63.

    Cotter EJ, Malizia AP, Chew N, Powderly WG, Doran PP (2007) HIV proteins regulate bone marker secretion and transcription factor activity in cultured human osteoblasts with consequent potential implications for osteoblast function and development. AIDS Res Hum Retrovir 23:1521–1530

    CAS  PubMed  Google Scholar 

  64. 64.

    Beaupere C, Garcia M, Larghero J, Fève B, Capeau J, Lagathu C (2015) The HIV proteins Tat and Nef promote human bone marrow mesenchymal stem cell senescence and alter osteoblastic differentiation. Aging Cell 14:534–546

    CAS  PubMed  PubMed Central  Google Scholar 

  65. 65.

    Lew DP, Waldvogel FA (2004) Osteomyelitis. Lancet 364:369–379

    CAS  PubMed  Google Scholar 

  66. 66.

    Cassat JE, Hammer ND, Campbell JP, Benson MA, Perrien DS, Mrak LN, Smeltzer MS, Torres VJ, Skaar EP (2013) A secreted bacterial protease tailors the Staphylococcus aureus virulence repertoire to modulate bone remodeling during osteomyelitis. Cell Host Microbe 13:759–772

    CAS  PubMed  PubMed Central  Google Scholar 

  67. 67.

    Loughran AJ, Gaddy D, Beenken KE, Meeker DG, Morello R, Zhao H, Byrum SD, Tackett AJ, Cassat JE, Smeltzer MS (2016) Impact of sarA and phenol-soluble modulins on the pathogenesis of osteomyelitis in diverse clinical isolates of Staphylococcus aureus. Infect Immun 84:2586–2594

    CAS  PubMed  PubMed Central  Google Scholar 

  68. 68.

    Yoshii T, Magara S, Miyai D, Nishimura H, Kuroki E, Furudoi S, Komori T, Ohbayashi C (2002) Local levels of interleukin-1β, -4, -6 and tumor necrosis factor alpha in an experimental model of murine osteomyelitis due to staphylococcus aureus. Cytokine 19:59–65

    CAS  PubMed  Google Scholar 

  69. 69.

    Zwerina J, Hayer S, Tohidast-Akrad M, Bergmeister H, Redlich K, Feige U, Dunstan C, Kollias G, Steiner G, Smolen J, Schett G (2004) Single and combined inhibition of tumor necrosis factor, interleukin-1, and RANKL pathways in tumor necrosis factor-induced arthritis: effects on synovial inflammation, bone erosion, and cartilage destruction. Arthritis Rheum 50:277–290

    CAS  PubMed  Google Scholar 

  70. 70.

    Dapunt U, Maurer S, Giese T, Gaida MM, Hänsch GM (2014) The macrophage inflammatory proteins MIP1α (CCL3) and MIP2α (CXCL2) in implant-associated osteomyelitis: linking inflammation to bone degradation. Mediat Inflamm 2014:728619

    Google Scholar 

  71. 71.

    Young AB, Cooley ID, Chauhan VS, Marriott I (2011) Causative agents of osteomyelitis induce death domain-containing TNF-related apoptosis-inducing ligand receptor expression on osteoblasts. Bone 48:857–863

    CAS  PubMed  Google Scholar 

  72. 72.

    Singer FR (2015) Paget’s disease of bone-genetic and environmental factors. Nat Rev Endocrinol 11:662–671

    CAS  PubMed  Google Scholar 

  73. 73.

    Sambandam Y, Sundaram K, Saigusa T, Balasubramanian S, Reddy SV (2017) NFAM1 signaling enhances osteoclast formation and bone resorption activity in Paget’s disease of bone. Bone 101:236–244

    CAS  PubMed  PubMed Central  Google Scholar 

  74. 74.

    Moutsopoulos NM, Madianos PN (2006) Low-grade inflammation in chronic infectious diseases: paradigm of periodontal infections. Ann N Y Acad Sci 1088:251–264

    CAS  PubMed  Google Scholar 

  75. 75.

    Sokos D, Everts V, de Vries TJ (2015) Role of periodontal ligament fibroblasts in osteoclastogenesis: a review. J Periodontal Res 50:152–159

    CAS  PubMed  Google Scholar 

  76. 76.

    Wada N, Maeda H, Yoshimine Y, Akamine A (2004) Lipopolysaccharide stimulates expression of osteoprotegerin and receptor activator of NF-kappa B ligand in periodontal ligament fibroblasts through the induction of interleukin-1 beta and tumor necrosis factor-α. Bone 35:629–635

    CAS  PubMed  Google Scholar 

  77. 77.

    Morandini AC, Sipert CR, Gasparoto TH, Greghi SL, Passanezi E, Rezende ML, Sant’ana AP, Campanelli AP, Garlet GP, Santos CF (2010) Differential production of macrophage inflammatory protein-1alpha, stromal-derived factor-1, and IL-6 by human cultured periodontal ligament and gingival fibroblasts challenged with lipopolysaccharide from P. gingivalis. J Periodontol 81:310–317

    CAS  PubMed  Google Scholar 

  78. 78.

    Tsukasaki M, Komatsu N, Nagashima K, Nitta T, Pluemsakunthai W, Shukunami C, Iwakura Y, Nakashima T, Okamoto K, Takayanagi H (2018) Host defense against oral microbiota by bone-damaging T cells. Nat Commun 9:701

    PubMed  PubMed Central  Google Scholar 

  79. 79.

    Komatsu N, Okamoto K, Sawa S, Nakashima T, Oh-hora M, Kodama T, Tanaka S, Bluestone JA, Takayanagi H (2013) Pathogenic conversion of Foxp3+ T cells into TH17 cells in autoimmune arthritis. Nat Med 20:62–68

    PubMed  Google Scholar 

  80. 80.

    Woo SB, Hellstein JW, Kalmar JR (2006) Narrative [corrected] review: bisphosphonates and osteonecrosis of the jaws. Ann Intern Med 144:753–761

    CAS  PubMed  Google Scholar 

Download references


This work was supported in part by a grant for Practical Research Project for Rare/Intractable Diseases (JP19ek0109379) from the Japan Agency for Medical Research and Development.

Author information




AT and HT wrote the manuscript. HT also edited it.

Corresponding author

Correspondence to Hiroshi Takayanagi.

Ethics declarations

Conflict of interest

AT declare that she belongs to an endowment department, Department of Osteoimmunology, supported with an unrestricted grant from AYUMI Pharmaceutical Corporation, Chugai Pharmaceutical Co., Ltd., MIKI HOUSE Co., Ltd., and Noevir Co., Ltd.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

This article is a contribution to the special issue on Osteoimmunology - Guest Editor: Mary Nakamura

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Terashima, A., Takayanagi, H. The role of bone cells in immune regulation during the course of infection. Semin Immunopathol 41, 619–626 (2019).

Download citation


  • Bone marrow microenvironment
  • Osteoblast
  • Lymphopoiesis
  • Sepsis
  • Infection