Abstract
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.
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Takayanagi H (2012) New developments in osteoimmunology. Nat Rev Rheumatol 8:684–689
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
Takayanagi H (2007) Osteoimmunology: shared mechanisms and crosstalk between the immune and bone systems. Nat Rev Immunol 7:292–304
Terashima A, Takayanagi H (2018) Overview of osteoimmunology. Calcif Tissue Int 102:503–511
Morrison SJ, Scadden DT (2014) The bone marrow niche for haematopoietic stem cells. Nature 505:327–334
Lord BI, Testa NG, Hendry JH (1975) The relative spatial distributions of CFUs and CFUc in the normal mouse femur. Blood 46:65–72
Gong JK (1978) Endosteal marrow: a rich source of hematopoietic stem cells. Science 199:1443–1445
Taichman RS, Emerson SG (1994) Human osteoblasts support hematopoiesis through the production of granulocyte colony-stimulating factor. J Exp Med 179:1677–1682
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
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
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
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
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
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
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
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
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
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
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
Ding L, Saunders TL, Enikolopov G, Morrison SJ (2012) Endothelial and perivascular cells maintain haematopoietic stem cells. Nature 481:457–462
Ding L, Morrison SJ (2013) Haematopoietic stem cells and early lymphoid progenitors occupy distinct bone marrow niches. Nature 495:231–235
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
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
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
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
Terashima A, Okamoto K, Nakashima T, Akira S, Ikuta K, Takayanagi H (2016) Sepsis-induced osteoblast ablation causes immunodeficiency. Immunity 44:1434–1443
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
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
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
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
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
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
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
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
Sreehari S, Naik DR, Eapen M (2011) Osteopetrosis: a rare cause of anemia. Hematol Rep 3:e1
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
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
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
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
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
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
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
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
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
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
Bone RC, Sprung CL, Sibbald WJ (1992) Definitions for sepsis and organ failure. Crit Care Med 20:724–726
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
Lew DP, Waldvogel FA (2004) Osteomyelitis. Lancet 364:369–379
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
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
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
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
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
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
Singer FR (2015) Paget’s disease of bone-genetic and environmental factors. Nat Rev Endocrinol 11:662–671
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
Moutsopoulos NM, Madianos PN (2006) Low-grade inflammation in chronic infectious diseases: paradigm of periodontal infections. Ann N Y Acad Sci 1088:251–264
Sokos D, Everts V, de Vries TJ (2015) Role of periodontal ligament fibroblasts in osteoclastogenesis: a review. J Periodontal Res 50:152–159
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
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
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
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
Woo SB, Hellstein JW, Kalmar JR (2006) Narrative [corrected] review: bisphosphonates and osteonecrosis of the jaws. Ann Intern Med 144:753–761
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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.
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AT and HT wrote the manuscript. HT also edited it.
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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.
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This article is a contribution to the special issue on Osteoimmunology - Guest Editor: Mary Nakamura
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Terashima, A., Takayanagi, H. The role of bone cells in immune regulation during the course of infection. Semin Immunopathol 41, 619–626 (2019). https://doi.org/10.1007/s00281-019-00755-2
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DOI: https://doi.org/10.1007/s00281-019-00755-2