Abstract
Investigations into interactions between the skeletal and immune systems were developed during research into arthritis, with characterization of T-cell-mediated regulation of osteoclastogenesis. A new interdisciplinary field—osteoimmunology—was created, and has since expanded to encompass disciplines including signal transduction, stem cell niches and fundamental immunology. We have witnessed rapid progress in understanding the mechanisms of bone damage in arthritis and the roles of immune molecules in bone, but comparatively less evidence has been provided for the role of bone-derived factors in the immune system. Nevertheless, regulation of immune cells, including haematopoietic stem cells, by bone cells is now a hot topic in this field. Here, I discuss recent advances in osteoimmunology and emerging avenues of basic and clinical investigation.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Buy this article
- Purchase on SpringerLink
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Takayanagi, H. Osteoimmunology: shared mechanisms and crosstalk between the immune and bone systems. Nat. Rev. Immunol. 7, 292–304 (2007).
Seeman, E. & Delmas, P. D. Bone quality—the material and structural basis of bone strength and fragility. N. Engl. J. Med. 354, 2250–2261 (2006).
Lorenzo, J., Horowitz, M. & Choi, Y. Osteoimmunology: interactions of the bone and immune system. Endocr. Rev. 29, 403–440 (2008).
Nakashima, T. & Takayanagi, H. Osteoimmunology: crosstalk between the immune and bone systems. J. Clin. Immunol. 29, 555–567 (2009).
Nagasawa, T. Microenvironmental niches in the bone marrow required for B-cell development. Nat. Rev. Immunol. 6, 107–116 (2006).
Kiel, M. J. & Morrison, S. J. Uncertainty in the niches that maintain haematopoietic stem cells. Nat. Rev. Immunol. 8, 290–301 (2008).
Takayanagi, H. Osteoimmunology and the effects of the immune system on bone. Nat. Rev. Rheumatol. 5, 667–676 (2009).
Takayanagi, H. et al. T cell-mediated regulation of osteoclastogenesis by signalling cross-talk between RANKL and IFN-γ. Nature 408, 600–605 (2000).
Chiang, E. Y. et al. Targeted depletion of lymphotoxin-α-expressing TH1 and TH17 cells inhibits autoimmune disease. Nat. Med. 15, 766–773 (2009).
Cohen, S. B. et al. Denosumab treatment effects on structural damage, bone mineral density, and bone turnover in rheumatoid arthritis: a twelve-month, multicenter, randomized, double-blind, placebo-controlled, phase II clinical trial. Arthritis Rheum. 58, 1299–1309 (2008).
Nakashima, T. et al. Evidence for osteocyte regulation of bone homeostasis through RANKL expression. Nat. Med. 17, 1231–1234 (2011).
Onal, M. et al. RANKL expression by B lymphocytes contributes to ovariectomy-induced bone loss. J. Biol. Chem. 287, 29851–29860 (2012).
Chan, A. C. & Carter, P. J. Therapeutic antibodies for autoimmunity and inflammation. Nat. Rev. Immunol. 10, 301–316 (2012).
Xiong, J. et al. Matrix-embedded cells control osteoclast formation. Nat. Med. 17, 1235–1241 (2011).
Green, E. A., Choi, Y. & Flavell, R. A. Pancreatic lymph node-derived CD4+CD25+ Treg cells: highly potent regulators of diabetes that require TRANCE-RANK signals. Immunity 16, 183–191 (2002).
Totsuka, T. et al. RANK-RANKL signaling pathway is critically involved in the function of CD4+CD25+ regulatory T cells in chronic colitis. J. Immunol. 182, 6079–6087 (2009).
Loser, K. et al. Epidermal RANKL controls regulatory T-cell numbers via activation of dendritic cells. Nat. Med. 12, 1372–1379 (2006).
Tan, W. et al. Tumour-infiltrating regulatory T cells stimulate mammary cancer metastasis through RANKL-RANK signalling. Nature 470, 548–553 (2011).
Rossi, S. W. et al. RANK signals from CD4+3− inducer cells regulate development of Aire-expressing epithelial cells in the thymic medulla. J. Exp. Med. 204, 1267–1272 (2007).
Akiyama, T. et al. The tumor necrosis factor family receptors RANK and CD40 cooperatively establish the thymic medullary microenvironment and self-tolerance. Immunity 29, 423–437 (2008).
Hikosaka, Y. et al. The cytokine RANKL produced by positively selected thymocytes fosters medullary thymic epithelial cells that express autoimmune regulator. Immunity 29, 438–450 (2008).
Lacey, D. L. et al. Bench to bedside: elucidation of the OPG–RANK–RANKL pathway and the development of denosumab. Nat. Rev. Drug Discov. 11, 401–419 (2012).
Mercier, F. E., Ragu, C. & Scadden, D. T. The bone marrow at the crossroads of blood and immunity. Nat. Rev. Immunol. 12, 49–60 (2011).
Calvi, L. M. et al. Osteoblastic cells regulate the haematopoietic stem cell niche. Nature 425, 841–846 (2003).
Zhang, J. et al. Identification of the haematopoietic stem cell niche and control of the niche size. Nature 425, 836–841 (2003).
Arai, F. et al. Tie2/angiopoietin-1 signaling regulates hematopoietic stem cell quiescence in the bone marrow niche. Cell 118, 149–161 (2004).
Kiel, M. J., Radice, G. L. & Morrison, S. J. Lack of evidence that hematopoietic stem cells depend on N-cadherin-mediated adhesion to osteoblasts for their maintenance. Cell Stem Cell 1, 204–217 (2007).
Lymperi, S. et al. Strontium can increase some osteoblasts without increasing hematopoietic stem cells. Blood 111, 1173–1181 (2008).
Ding, L., Saunders, T. L., Enikolopov, G. & Morrison, S. J. Endothelial and perivascular cells maintain haematopoietic stem cells. Nature 481, 457–462 (2012).
Omatsu, Y. et al. The essential functions of adipo-osteogenic progenitors as the hematopoietic stem and progenitor cell niche. Immunity 33, 387–399 (2010).
Yamazaki, S. et al. Nonmyelinating Schwann cells maintain hematopoietic stem cell hibernation in the bone marrow niche. Cell 147, 1146–1158 (2012).
Mendez-Ferrer, S. et al. Mesenchymal and haematopoietic stem cells form a unique bone marrow niche. Nature 466, 829–834 (2010).
Kollet, O. et al. Osteoclasts degrade endosteal components and promote mobilization of hematopoietic progenitor cells. Nat. Med. 12, 657–664 (2006).
Miyamoto, K. et al. Osteoclasts are dispensable for hematopoietic stem cell maintenance and mobilization. J. Exp. Med. 208, 2175–2181 (2011).
Geffroy-Luseau, A., Jego, G., Bataille, R., Campion, L. & Pellat-Deceunynck, C. Osteoclasts support the survival of human plasma cells in vitro. Int. Immunol. 20, 775–782 (2008).
Li, H. et al. Cross talk between the bone and immune systems: osteoclasts function as antigen-presenting cells and activate CD4+ and CD8+ T cells. Blood 116, 210–217 (2010).
Borrero, C. G., Mountz, J. M. & Mountz, J. D. Emerging MRI methods in rheumatoid arthritis. Nat. Rev. Rheumatol. 7, 85–95 (2011).
Li, P. et al. Systemic tumor necrosis factor α mediates an increase in peripheral CD11bhigh osteoclast precursors in tumor necrosis factor α-transgenic mice. Arthritis Rheum. 50, 265–276 (2004).
Proulx, S. T. et al. Elucidating bone marrow edema and myelopoiesis in murine arthritis using contrast-enhanced magnetic resonance imaging. Arthritis Rheum. 58, 2019–2029 (2008).
Cain, C. J. et al. Absence of sclerostin adversely affects B cell survival. J. Bone Miner. Res. 27, 1451–1461 (2012).
Xian, L. et al. Matrix IGF-1 maintains bone mass by activation of mTOR in mesenchymal stem cells. Nat. Med. 18, 1095–1101 (2012).
Tang, Y. et al. TGF-β1-induced migration of bone mesenchymal stem cells couples bone resorption with formation. Nat. Med. 15, 757–765 (2009).
Matsuo, K. & Irie, N. Osteoclast-osteoblast communication. Arch. Biochem. Biophys. 473, 201–209 (2008).
Negishi-Koga, T. et al. Suppression of bone formation by osteoclastic expression of semaphorin 4D. Nat. Med. 17, 1473–1480 (2011).
Hayashi, M. et al. Osteoprotection by semaphorin 3A. Nature 485, 69–74 (2012).
Acknowledgements
The author would like to thank T. Nakashima, A. Terashima, N. Komatsu, M. Guerrini and K. Okamoto for providing helpful discussions and assistance during preparation of this manuscript. This work was supported in part by a grant for ERATO, the Takayanagi Osteonetwork Project from the Japan Science and Technology Agency.
Author information
Authors and Affiliations
Ethics declarations
Competing interests
The author declares no competing financial interests.
Supplementary information
Supplementary Table 1
Skeletal phenotypes caused by genetic deficiencies in immunomodulatory molecules in mice (DOC 66 kb)
Supplementary Table 2
Immunological phenotypes relevant to rheumatic diseases caused by genetic deficiencies in bone-regulatory molecules (DOC 54 kb)
Rights and permissions
About this article
Cite this article
Takayanagi, H. New developments in osteoimmunology. Nat Rev Rheumatol 8, 684–689 (2012). https://doi.org/10.1038/nrrheum.2012.167
Published:
Issue Date:
DOI: https://doi.org/10.1038/nrrheum.2012.167
This article is cited by
-
SARS-CoV-2 and its Multifaceted Impact on Bone Health: Mechanisms and Clinical Evidence
Current Osteoporosis Reports (2024)
-
COVID-19 and Bone Loss: A Review of Risk Factors, Mechanisms, and Future Directions
Current Osteoporosis Reports (2024)
-
Development of a composite hydrogel incorporating anti-inflammatory and osteoinductive nanoparticles for effective bone regeneration
Biomaterials Research (2023)
-
The potential role of osteoporosis in unspecific [18F]PSMA-1007 bone uptake
European Journal of Nuclear Medicine and Molecular Imaging (2023)
-
Review of potential medical treatments for middle ear cholesteatoma
Cell Communication and Signaling (2022)