Osteoimmunology: Meeting Report from the 31St Annual Meeting of the American Society for Bone and Mineral Research

IBMS BoneKEy. 2009 November;6(11):446-449 http://www.bonekey-ibms.org/cgi/content/full/ibmske;6/11/446 doi: 10.1138/20090411

MEETING REPORTS Osteoimmunology: Meeting Report from the 31st Annual Meeting of the American Society for Bone and Mineral Research

September 11-15, 2009 in Denver, Colorado Roberto Pacifici1 and M. Neale Weitzmann1,2 1Emory University School of Medicine, Atlanta, Georgia, USA 2Atlanta Veterans Affairs Medical Center, Decatur, Georgia, USA

Osteoimmunology is a new discipline that that further attract T cells, thus facilitating studies the crosstalk between the immune their interaction with osteoclasts. While T system and bone. This definition can be cell-to-osteoclast communication is well- broad or narrow. While many accepted, these data also demonstrate the osteoimmunologists focus on RANKL/RANK potential for osteoclast-to-T cell signaling. signaling pathways in monocytes, cells integral to immunity, this report will present a The role of another important T cell sampling of the broader aspect of the role of costimulatory molecule, the receptor CD40 immune cells and immune mechanisms in ligand (CD40L), was investigated in the the regulation of bone turnover in health and context of estrogen deficiency (2). This work disease. A number of these interesting new showed that ovariectomy (ovx) fails to directions and developments in induce bone loss in CD40L(-/-) mice as a osteoimmunology were unveiled at the 31st consequence of a dual function of CD40L in Annual Meeting of the American Society for this system. First, CD40L is required for ovx Bone and Mineral Research in Denver, and to induce T cell activation and T cell are briefly summarized below. production of TNF. Second, CD40L upregulates the production of RANKL by T and B Cell Function stromal cells, further enhancing osteoclastogenesis. In inflammation and estrogen deficiency, antigen-presenting cells (APCs) activate T Regulatory T cells (Tregs) are a specialized cells leading to increased subpopulation of immune cells that suppress osteoclastogenesis and bone loss through immune responses. A study reported that a production of RANKL and TNF. An deficiency in Tregs leads to osteosclerosis interesting study showed for the first time by a mechanism involving increased that osteoclasts themselves can function as production of anti-resorptive cytokines APCs and thus regulate T cell function (1). including IFNγ, IL-4, and GM-CSF by CD4+ This was not entirely surprising given the T cells formed in the absence of Tregs (3). heritage of osteoclasts that derives from The study was conducted using Scurfy mice, cells of the monocyte/macrophage lineage, a complex model characterized by multiple and the fact that macrophages represent a immune alterations and poor health. major subset of APCs. The data showed Therefore, the findings of this study await that HLA-DR molecules are expressed by confirmation in one of the available unstimulated mature osteoclasts, a unique alternative models of Treg deficiency. property of APCs, and are readily upregulated by IFNγ. Upon differentiation B cells play important roles in basal and from CD11b+ monocytes, osteoclasts pathological osteoclastogenesis as they upregulate the expression of the key produce large amounts of pro- and anti- costimulatory molecules CD40 and CD80, osteoclastogenic cytokines. MicroRNAs which are central to the process of APC- (miRNAs) are short noncoding RNA driven T cell activation. Finally, osteoclasts molecules that regulate gene expression by were found to secrete several chemokines targeting the 3’ UTR of mRNAs and causing

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Copyright 2009 International Bone & Mineral Society IBMS BoneKEy. 2009 November;6(11):446-449 http://www.bonekey-ibms.org/cgi/content/full/ibmske;6/11/446 doi: 10.1138/20090411 mRNA destabilization and/or translation through the production of TNF (9). This was blockage. One study screened for evidenced by the fact that PTH failed to differentially expressed miRNAs in the induce bone loss and stimulate bone circulating B cells of postmenopausal resorption in TNF(-/-) mice, and mice lacking women exhibiting high and low bone mineral the TNF receptor p55. The relevance of T density (BMD) (4). One species of cell-produced TNF was further microRNA, miR-181b, was upregulated in demonstrated using adoptive transfer high BMD groups and revealed a negative experiments in which PTH induced bone correlation with FGFR1 and MECP2 genes, loss in nude mice reconstituted with wild predicted targets of miR-181b. These data type T cells, but failed to cause bone loss in suggest that human miR-181b may be nude mice reconstituted with TNF(-/-) T involved in B cell-related functions pertinent cells. to bone metabolism and osteoporosis. IFNγ, a cytokine secreted at high Another study focused on receptor for concentrations by Th1 T cells, directly advanced glycation end products (RAGE), a inhibits osteoclast formation in vitro, but multiligand receptor of the immunoglobulin functions as a pro-osteoclastogenic cytokine superfamily, best known as the receptor for in vivo through indirect actions on APCs. Its advanced glycation end products (AGEs) effects on osteoblastogenesis, however, are (5). The data show that RAGE(-/-) mice at 8- less well-studied. It was reported that IFNγ 17 weeks displayed reduced bone mineral inhibits the differentiation of osteoblasts by content (BMC), and an enhancement in the upregulating the expression of DKK3, a gain of percent body fat. Furthermore, these WNT antagonist (10). In inflammatory mice had a blunted anabolic response to conditions, IFNγ may reduce the number of intermittent PTH treatment. The mature osteoblasts, thus widening the gap mechanisms and target cells involved in between bone resorption and bone RAGE action remain to be determined. formation.

PTH and Hemopoietic Stem Cells IL-12 and IL-18 are macrophage-secreted cytokines that potently regulate T cell Several studies investigated the effects of differentiation, but also have direct effects PTH on hemopoietic stem cells (HSCs). One on osteoclasts. It was reported that IL-18 such study showed that PTH increases the inhibits TNF-induced osteoclastogenesis in number of HSCs (Lin-/CD117-/Sca-1-) (6). synergy with IL-12 in vivo (11). This This effect correlates with the capacity of conclusion was reached because in vivo PTH to increase the number of osteoclast treatment with suboptimal doses of IL-12 precursors. These findings were confirmed and IL-18 blocked TNF-induced bone by another study (7) showing that PTH resorption and osteoclast formation. Another increases hemopoietic progenitor cells and study (12) further corroborated the T cell- bone mass in an IL-6-dependent manner. A independent action of IL-12 in suppressing key finding of the study was that PTH failed TNF-induced osteoclastogenesis while it to increase HSCs and bone volume in adult was also shown that IL-12 and IL-18 IL-6(-/-) mice. It was further shown (8) that synergistically induced nitric oxide (NO) bone marrow calcium levels correlate with production in bone marrow cells in the bone marrow hemopoietic progenitor cells. presence of TNF and that NO mediates the pro-apoptotic activity of TNF in bone marrow Cytokines Made by Immune Cells cells (13). Several studies dealt with cytokines IL-27 is an anti-inflammatory factor that produced by immune cells. T cells are inhibits the development of the Th17 pro- potent mediators of ovariectomy and osteoclastogenic subset of T cells and inflammatory bone loss as they secrete attenuates experimental autoimmune osteoclastogenic cytokines including TNF encephalomyelitis and collagen-induced and RANKL. It was shown that bone marrow arthritis. Data were presented showing that T cells are also complicit in the bone loss IL-27 suppresses RANKL expression by associated with continuous PTH treatment, CD4+ T cells in part through a STAT3- 447

Copyright 2009 International Bone & Mineral Society IBMS BoneKEy. 2009 November;6(11):446-449 http://www.bonekey-ibms.org/cgi/content/full/ibmske;6/11/446 doi: 10.1138/20090411 mediated pathway (14). IL-27 might be a mediated T cell activation is required for potential therapeutic agent against bone estrogen deficiency to induce bone loss. destructive autoimmune diseases such as J Bone Miner Res. 2009;24(Suppl 1). rheumatoid arthritis. [Abstract]

MHC Class II TransActivator (CIITA) is a 3. Furukawa M, Takaishi H, Yoda M, master switch for MHC Class II expression Tohmonda T, Hikata T, Hakozaki A, and antigen presentation in APCs. CIITA is Uchikawa S, Mori T, Matsumoto M, upregulated by IFNγ and has been Chiba K, Ono M, Sakaguchi S, Toyama implicated in ovariectomy-induced bone loss Y. Foxp3+ regulatory T cell deficiency in animal models. The role of CIITA in basal induces osteosclerosis via bone homeostasis was investigated using hyperactivation of osteoclast- transgenic mice lines that overexpress suppressive CD4+ T cell subsets. J CIITA (15). CIITA transgenic mice display a Bone Miner Res. 2009;24(Suppl 1). dramatic decrease in trabecular structure, a [Abstract] consequence of significantly elevated osteoclast formation and activity. The data 4. Gao G, Chen X, Deng H, Recker R, suggest that CIITA may regulate basal bone Xiao P. Human microRNA miR-181b in homeostasis by promoting osteoclast B cells was related with the etiology of differentiation. osteoporosis. J Bone Miner Res. 2009;24(Suppl 1). [Abstract] The Immune Response and Cancer Growth/Metastasis 5. Philip B, Childress P, Robling A, Heller A, Bierhaus A, Nawroth P, Bidwell J. A tight association between bone turnover Ablation of the RAGE receptor and cancer growth and metastases has long attenuates parathyroid hormone- been recognized. However, the role of the induced increases in femoral trabecular immune response in this phenomenon has bone. J Bone Miner Res. 2009;24(Suppl received scant attention. It was 1). [Abstract] demonstrated that cancer metastases and growth are significantly diminished in the 6. Jacome-Galarza C, Lee S, Kalinowski J, context of a hyperactive immune response Lorenzo J, Aguila H. Parathyroid but significantly elevated in the context of hormone regulates specific populations immunodeficiency (16). CD4+ and CD8+ T of osteoclast and hematopoietic cells are reported to be critical to the progenitors in the bone marrow of mice. regulation of bone metastasis, while CD8 T J Bone Miner Res. 2009;24(Suppl 1). cells are involved in repressing tumor growth [Abstract] in bone. These data expand the current vicious cycle model to include immune cells 7. Pirih F, Michalski M, Koh A, Sorah K, as critical regulators of tumor growth and Ross C, McCauley L. PTH increases metastases in bone. hematopoietic progenitor cells and bone Conflict of Interest: None reported. mass in an IL-6 dependent manner. J Bone Miner Res. 2009;24(Suppl 1). Peer Review: This article has been peer-reviewed. [Abstract]

References 8. Li X, Koh A, McCauley L. Bone marrow calcium levels correlate with bone 1. Grassi F, Manferdini C, Gabusi E, marrow hemopoietic progenitor cells. J Cattini L, Facchini A, Lisignoli G. Bone Miner Res. 2009;24(Suppl 1). Regulation of T cells' function by [Abstract] osteoclast-secreted factors in vitro. J Bone Miner Res. 2009;24(Suppl 1). 9. Bedi B, Tawfeek H, Li J, Baek K, [Abstract] Weitzmann M, Pacifici R. Continuous PTH treatment causes cortical bone loss 2. Li J, Baek K, Bedi B, Adam J, Yang X, Weitzman M, Pacifici R. CD40L 448

through T cell produced TNF. J Bone 18-mediated nitric oxide induces Miner Res. 2009;24(Suppl 1). [Abstract] apoptosis in TNF-α-induced osteoclastogenesis of bone marrow 10. Terauchi M, Sakamoto K, Tamamura Y, cells. J Bone Miner Res. 2009;24(Suppl Obayashi S, Kubota T, Yamaguchi A. 1). [Abstract] Interferon-gamma inhibits the differentiation of osteoblasts through 14. Wada S, Chiba Y, Nimura N, Yoshimoto Wnt signaling. J Bone Miner Res. T, Nakamura C, Kamiya S, Okumura M, 2009;24(Suppl 1). [Abstract] Mizuguchi J, Fukawa T. IL-27 suppresses RANKL expression in CD4+ 11. Morita Y, Kitaura H, Fujimura Y, T cells partly through STAT3. J Bone Yoshimatsu M, Kohara H, Eguchi T, Miner Res. 2009;24(Suppl 1). [Abstract] Takano-Yamamoto T, Yoshida N. IL-18 inhibits TNF-α-induced 15. Benasciutti E, Mariani E, Perilli E, osteoclastogenesis in synergy with IL-12 Faccio R, Barras E, Fazzalari N, Reith in vivo. J Bone Miner Res. W, Cenci S. MHC class II transactivator 2009;24(Suppl 1). [Abstract] (CIITA) as a novel regulator of osteoclastogenesis. J Bone Miner Res. 12. Yoshimatsu M, Kitaura H, Fujimura Y, 2009;24(Suppl 1). [Abstract] Kohara H, Morita Y, Eguchi T, Takano- Yamamoto T, Yoshida N. IL-12 inhibits 16. Zhang K, Weilbaecher K, Novack D, TNF-α-mediated osteoclastogenesis via Faccio R. Adaptive immune cells a T-cell-independent mechanism. J regulate the bone/tumor vicious cycle in Bone Miner Res. 2009;24(Suppl 1). mice. J Bone Miner Res. 2009;24(Suppl [Abstract] 1). [Abstract]

13. Kitaura H, Fujimura Y, Yoshimatsu M, Kohara H, Morita Y, Eguchi T, Yoshida N, Takano-Yamamoto T. IL-12- and IL-

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