SnapShot: Osteoimmunology

502 Cell Metabolism 21, March 3, 2015 ©2015 Elsevier Inc. DOI http://dx.doi.org/10.1016/j.cmet.2015.02.001

See online version for legends and references

Input

Treg

Th2

Th1

CCL20

Osteoclasts

Bone destruction

IL-4

IFN-γ

Synovial fibroblasts

Osteoblasts

DKK1

IL-17 IL-6

B cells

Infection

Hematopoiesis

Inflammation

Macrophages, mast cells, neutrophils

Complement

Initiation

Genetic factors, Trauma environmental Microbiota factors Dietary intake

Autoantibodies

TNF, IL-1, IL-6

IL-17

Th17

IL-17

B cells

Autoantigen?

Migration

Th17

RANKL

TGF-β, IL-6, IL-23

Osteoclast precursors

Th0

Bone mass/quality

Osteoclast

Bone remodeling

Immune system

Bone destruction in inflammation

Calcium metabolism

Osteocyte

Hematopoietic cells

Endocrine system

Osteoblast

Macrophages, DCs

Output

Vascular system Neural system

Dietary calcium | Exercise/gravity | Aging, stress | Tumor | Autoimmunity | Infection

Emerging concept of the osteoimmune system

Sema3A

Osteoblast

Jagged 1

Leukemia

CXCL12

Wnts

HSC

SCF

Lepr + perivascular cell

Thrombopoietin Osteopontin Angiopoietin-1

HSC quiescence

Nestin + perivascular cell CAR cell

LRP5/6 frizzeled

Mobilization?

Activated TGF-β

Latent TGF-β

Nonmyelinating Schwann cell

Osteocyte

RANK

NFATc2

IRF-8 MafB BcI6

Syk

DAP12

TREM2

NFATc1

Dcstamp Ocstamp Atp6v0d2 ltgb3 Ctsk Acp5 Oscar

Osteoclast genes

Plexin-A1

Nrp1

Sema3A

Sema6D

Transition phase

Sost DKK1

Osteoblasts

Sema4D

Calcineurin

NFATc1

FcRγ

NFATc1

Ca 2+

Blimp1

NFATc1

Autoamplification

NF-κB

MAPK

Collagen OSCAR PIR-A SIRPβ1

Btk/Tec BLNK/ SLP76 PLCγ

TRAF6

RANKL

AP-1

OPG

Osteocytes

Osteoclast precursors Mechanical loading or microdamages

Osteoclasts

RANKL, M-CSF, ligands for lg-like receptors

Osteocytes

RANKL

Resorption phase RANK

Osteoclastogenic signaling

Osteoclast progenitors

Vessels

Ephrin S1P Wnts

Coupling factors such as IGF-I, TGF-β

PDGF-BB

Osteocytes

Bone-lining cells

Bone cell communication factors

Osteoclast

Osteoblasts

HSC niche Endothelial cell

Formation phase

Osteoblast progenitors

Osteocytes

OPG

Osteoclast precursors

Neuronal cells

Hiroshi Takayanagi Department of Immunology, Graduate School of Medicine and Faculty of Medicine, The University of Tokyo, Hongo 7-3-1, Bunkyo-ku, Tokyo 113-0033, Japan and Japan Science and Technology Agency (JST), Exploratory Research for Advanced Technology (ERATO) Program, Takayanagi Osteonetwork Project, Hongo 7-3-1, Bunkyo-ku, Tokyo 113-0033, Japan

SnapShot: Osteoimmunology

Bone marrow

SnapShot: Osteoimmunology Hiroshi Takayanagi Department of Immunology, Graduate School of Medicine and Faculty of Medicine, The University of Tokyo, Hongo 7-3-1, Bunkyo-ku, Tokyo 113-0033, Japan and Japan Science and Technology Agency (JST), Exploratory Research for Advanced Technology (ERATO) Program, Takayanagi Osteonetwork Project, Hongo 7-3-1, Bunkyo-ku, Tokyo 113-0033, Japan Bone marrow, one of the primary lymphoid organs, harbors immune cells including hematopoietic stem cells (HSCs), lymphocytes, monocytes/macrophages, and neutrophils, all of which share microenvironments with bone cells such as osteoblasts, osteoclasts, and osteocytes. Bone cells were previously thought to be involved only in resorbing and forming bone. However, they are closely interacting with immune cells in the bone marrow, constituting the osteoimmune system, which choreographs all the cells in bone to regulate calcium homeostasis, bone mass/quality, and hematopoiesis in response to external stimuli (Takayanagi, 2012). Osteoimmunology started with the studies on bone destruction in rheumatoid arthritis (RA), the typical pathological event at the interface of bone and activated immune system. RANKL, the essential cytokine for osteoclast differentiation, was identified as the crucial link connecting T cell activation and osteoclastogenesis. RANKL signal transduction pathways are unraveled with a surprising similarity to immune cell signaling. In addition, numerous immunomodulatory molecules were shown to be involved in bone metabolism and vice versa (Takayanagi, 2007). Osteoblasts were also shown to be important in immune cell regulation as a part of the HSC niche. Here, I summarize these key subjects in recent advances in osteoimmunology. Bone Cell Differentiation/Function through Bone Cell Communication Factors To maintain the osteoimmune system, all the cells in bone marrow are regulated in a coordinated way through many soluble and membrane proteins, that are only poorly explored. After bone resorption, the same amount of bone should be formed to maintain the bone volume. Therefore, the factors that couple bone formation with resorption were regarded as important. Classical coupling factors included IGF-1 and TGF-β, which are embedded in bone matrix and released at resorption. Ephrins, S1P, Wnt proteins, and PDGF-BB (Xie et al., 2014) were shown to be among them. However, communication among bone cells does not occur only at the switch from resorption to formation. RANKL/OPG are well-known bone cell communication factors. Sost and DKKs are produced by osteocytes to regulate bone formation. Neuronal factors such as semaphorin/plexin emerged as important bone cell communication factors, which work in various phases of bone remodeling (Negishi-Koga and Takayanagi, 2012). Bone Cells in Maintaining HSC Regulation and Oncogenic Transformation Since it was proposed that osteoblasts are the HSC niche, many papers suggested that distinct cell populations fulfill the criteria for the HSC niche, including CXCL12abundant reticular (CAR) cells, Lepr+ perivascular cells, Nestin+ perivascular cells, and nonmyelinating Schwann cells (Morrison and Scadden, 2014). The role of osteoblasts may be more limited than initially proposed, as selective deletion of CXCL12 or SCF, essential for HSC maintenance, in osteoblasts leads to no obvious defects in the HSC number. However, since impairments of osteoblast or osteoclast function affect hematopoiesis or HSC mobilization, it is possible that bone cells provide an appropriate environment for retaining the normal HSCs in adult bone marrow. Osteoblasts are involved in HSC quiescence through secreting angiopoietin-1, osteopontin, or thrombopoietin. Interestingly, high expression of Jagged 1 in osteoblasts causes hematological disorders through an activation of Notch signaling in HSCs, indicating that the osteoblast niche plays a role in inhibiting the oncogenic transformation of the hematopoietic cells (Kode et al., 2014). It is also proposed that the conversion of latent TGF-β into active TGF-β by nonmyelinating Schwann cells regulates quiescence of HSCs. Multiple criteria to characterize niche cells, such as localization or molecular markers, increase the complexity of understanding bone marrow microenvironments. Further studies are required to clearly delineate the role of bone cells in HSC regulation under physiological and pathological settings. Inflammation and T Cells in Bone Destruction in RA Bone erosion in arthritis occurs at the interface of activated immune system and bone. Much has been done to understand how activated T cells induce bone erosion (Takayanagi, 2012). Th17 cells were found to be exclusively responsible for osteoclastogenesis in the synovium. IL-17 upregulates RANKL expression on synovial fibroblasts and induces inflammatory cytokines such as TNF-α, IL-6, and IL-1 from innate immune cells. These inflammatory cytokines further upregulate RANKL expression on synovial fibroblasts and activate osteoclast precursors. It was recently shown that Th17 cells derived from Foxp3+ T cells represent the most pathogenic T cells in arthritis (Komatsu et al., 2014). The role of immune cells is extended to other diseases like ankylosing spondylitis and bone formation in fracture repair and ectopic bone formation (Sherlock et al., 2012). Shared Molecules between Bone and Immune Cells in Osteoclastogenic Signaling The osteoclastogenic signal transduction is mainly dependent on RANKL/RANK and Ig-like receptor (OSCAR, PIR-A, SIRPb1, and TREM2)-ITAM-bearing molecules (FcRγ and DAP12) signaling (Takayanagi, 2007). OPG is a decoy receptor for RANKL to modulate osteoclastogenesis. RANKL stimulates NF-κB and MAPKs through TRAF6, leading to the initial induction of NFATc1, the master transcription factor of osteoclastogenesis. In response to ITAM signal, NFATc1 translocates to the nucleus, makes a complex with AP-1, and binds to its own promoter, thus enabling a robust induction (autoamplification) of NFATc1. NFATc1 activity is negatively regulated by several transcription factors, including IRF-8, MafB, and Bcl6. The expression of these negative regulators is blocked by Blimp1, a transcriptional target of NFATc1. NFATc1 induces most of the osteoclast genes directly in cooperation with other transcription factors. Ig-like receptor cooperates with RANKL signal and activates PLCγ-mediated calcium signaling through the Syk-Btk/Tec/BLNK/SLP76 complex. Ligands of Ig-like receptor are not well defined, but OSCAR was shown to be a receptor for collagen (Barrow et al., 2011). TREM2 is activated through the association with Plexin-A1/Sema6D. The binding of the Sema3A to Nrp1/Plexin-A1 complex blocked the interaction between Plexin-A1 and the TREM2/DAP12 complex (Hayashi et al., 2012). Surprisingly, most of the signaling molecules were originally identified and studied in the immune system. Shared molecules are not limited to osteoclastogenic genes but now extended to various genes related to bone cell differentiation/function regulators and communication factors. References Barrow, A.D., Raynal, N., Andersen, T.L., Slatter, D.A., Bihan, D., Pugh, N., Cella, M., Kim, T., Rho, J., Negishi-Koga, T., et al. (2011). J. Clin. Invest. 121, 3505–3516. Hayashi, M., Nakashima, T., Taniguchi, M., Kodama, T., Kumanogoh, A., and Takayanagi, H. (2012). Nature 485, 69–74. Kode, A., Manavalan, J.S., Mosialou, I., Bhagat, G., Rathinam, C.V., Luo, N., Khiabanian, H., Lee, A., Murty, V.V., Friedman, R., et al. (2014). Nature 506, 240–244. Komatsu, N., Okamoto, K., Sawa, S., Nakashima, T., Oh-hora, M., Kodama, T., Tanaka, S., Bluestone, J.A., and Takayanagi, H. (2014). Nat. Med. 20, 62–68. Morrison, S.J., and Scadden, D.T. (2014). Nature 505, 327–334. Negishi-Koga, T., and Takayanagi, H. (2012). Bonekey Rep 1, 183. Sherlock, J.P., Joyce-Shaikh, B., Turner, S.P., Chao, C.C., Sathe, M., Grein, J., Gorman, D.M., Bowman, E.P., McClanahan, T.K., Yearley, J.H., et al. (2012). Nat. Med. 18, 1069–1076. Takayanagi, H. (2007). Nat. Rev. Immunol. 7, 292–304. Takayanagi, H. (2012). Nat. Rev. Rheumatol. 8, 684–689. Xie, H., Cui, Z., Wang, L., Xia, Z., Hu, Y., Xian, L., Li, C., Xie, L., Crane, J., Wan, M., et al. (2014). Nat. Med. 20, 1270–1278.

502.e1  Cell Metabolism 21, March 3, 2015 ©2015 Elsevier Inc.  DOI http://dx.doi.org/10.1016/j.cmet.2015.02.001