Osteoimmunology is an interdisciplinary research field focused on the molecular understanding of the interplay between the immune and skeletal systems. Although osteoimmunology started with the study of the immune regulation of osteoclasts, its scope has been extended to encompass a wide range of molecular and cellular interactions, including those between osteoblasts and osteoclasts, lymphocytes and osteoclasts, and osteoblasts and haematopoietic cells. Therefore, the two systems should be understood to be integrated and operating in the context of the 'osteoimmune' system, a heuristic concept that provides not only a framework for obtaining new insights by basic research, but also a scientific basis for the discovery of novel treatments for diseases related to both systems.

Rheumatoid arthritis (RA) remains a significant unmet medical need despite significant therapeutic advances. The pathogenesis of RA is complex and includes many cell types, including T cells, B cells, and macrophages. Fibroblast-like synoviocytes (FLS) in the synovial intimal lining also play a key role by producing cytokines that perpetuate inflammation and proteases that contribute to cartilage destruction. Rheumatoid FLS develop a unique aggressive phenotype that increases invasiveness into the extracellular matrix and further exacerbates joint damage. Recent advances in understanding the biology of FLS, including their regulation regulate innate immune responses and activation of intracellular signaling mechanisms that control their behavior, provide novel insights into disease mechanisms. New agents that target FLS could potentially complement the current therapies without major deleterious effect on adaptive immune responses.

TNF and TNFR family proteins play important roles in the control of cell death, proliferation, autoimmunity, the function of immune cells, or the organogenesis of lymphoid organs. Recently, novel members of this large family have been identified that have critical functions in immunity and that couple lymphoid cells with other organ systems such as bone morphogenesis and mammary gland formation in pregnancy. The TNF-family molecule RANK-L (RANK-L, TRANCE, ODF) and its receptor RANK are key regulators of bone remodeling, and they are essential for the development and activation of osteoclasts. Intriguingly, RANK-L/RANK interactions also regulate T cell/dendritic cell communications, dendritic cell survival, and lymph node formation; T cell-derived RANK-L can mediate bone loss in arthritis and periodontal disease. Moreover, RANK-L and RANK are expressed in mammary gland epithelial cells, and they control the development of a lactating mammary gland during pregnancy and the propagation of mammalian species. Modulation of these systems provides us with a unique opportunity to design novel therapeutics to inhibit bone loss in arthritis, periodontal disease, and osteoporosis.

BACKGROUND

The interaction between the immune and skeletal systems has long been acknowledged, but investigation into rheumatoid arthritis (RA) as well as the various bone phenotypes found in immunocompromised gene-deficient mice has highlighted the importance of the dynamic interplay between the two systems. This has led to the recent emergence and subsequent rapid evolution of the field of osteoimmunology. BONE DESTRUCTION WITH ARTHRITIS AS A RANKL DISEASE: In the bone destruction associated with RA, IL-17-producing helper T cells (T(H)17) play a major role by inducing receptor activator of nuclear factor-kappaB ligand (RANKL). RANKL stimulates osteoclastogenesis through nuclear factor of activated T cells cytoplasmic 1 (NFATc1), which is well known as a crucial regulator of immunity.

UNASSIGNED

In addition to cellular interactions via cytokines, the immune and skeletal systems share various molecules, including transcription factors, signaling molecules, and membrane receptors.

CONCLUSIONS

The scope of osteoimmunology has grown to encompass a wide range of molecular and cellular interactions, the elucidation of which will provide a scientific basis for future therapeutic approaches to diseases of both the immune and skeletal systems.

Interferons (IFNs) play crucial roles in the regulation of a wide variety of innate and adaptive immune responses. Type I interferons (IFN-alpha/beta) are central to the host defense against pathogens such as viruses, whereas type II interferon (IFN-gamma) mainly contributes to the T-cell-mediated regulation of the immune responses. Studies of bone destruction associated with rheumatoid arthritis have highlighted the importance of the interaction between the immune and skeletal systems. Recently, a new research area, termed osteoimmunology, has been spawned by a series of studies focusing on the signaling networks between IFN and other cytokines in bone metabolisms. It has been revealed that IFN-gamma interferes with the osteoclast differentiation induced by receptor activator of nuclear factor-kappaB ligand (RANKL), and this mechanism is critical for the suppression of pathological bone resorption associated with inflammation. In addition, RANKL induces the IFN-beta gene in osteoclast precursor cells, and this induction constitutes a critical aspect of the negative feedback regulation mechanisms of RANKL signaling to suppress excessive osteoclastogenesis. Furthermore, a novel function of signal transducer and activator of transcription 1 (Stat1), the essential transcription factor for both type I and type II IFN responses, was revealed in the regulation of osteoblast differentiation. Collectively, these studies unveil novel aspects of the IFN system and indicate the operation of the intricate signaling network among IFN and other cytokine systems in bone remodeling, which might offer a molecular basis for the treatment of bone diseases.

OBJECTIVE

Angiogenesis is the formation of new capillaries from pre-existing vessels, whereas vasculogenesis is de-novo capillary formation from endothelial precursor cells (EPCs). Current understanding of the role of angiogenesis and vasculogenesis in rheumatoid arthritis (RA) and possibilities of therapeutic intervention should be summarized.

RESULTS

There have been many recent studies on the role of the hypoxia and hypoxia-inducible factor (HIF)-vascular endothelial growth factor (VEGF)-angiopoietin axis in angiogenesis associated with RA. The role of additional growth factors, chemokines, cytokines, matrix components and adhesion molecules has been further characterized. Macrophage migration inhibitory factor (MIF) may link inflammation, angiogenesis and atherosclerosis. Junctional adhesion molecules (JAMs) and focal adhesion kinases (FAKs) have recently been implicated in inflammatory angiogenesis. Novel information regarding the role of serum amyloid A (SAA) and sphingosine kinase has become available. Most of these angiogenic factors have recently been targeted using various techniques and arthritis models. Whereas angiogenesis is abundant in RA, there is defective EPC function and vasculogenesis leading to atherosclerosis and vascular disease in arthritis. Treatment with EPCs already under investigation in vascular diseases may also be attempted in RA.

CONCLUSIONS

Targeting angiogenesis and restoration of vasculogenesis may be beneficial for the therapy and outcome of RA.

During the past decade biologic therapies such as monoclonal antibodies and fusion proteins have revolutionized the management of rheumatic disease. By targeting key cytokines and immune cells biologics have provided more specific therapeutic interventions with less immunosuppression. Clinical use, however, has revealed that their theoretical simplicity hides a more complex reality. Efficacy, toxicity and even pharmacodynamic effects can deviate from those predicted, as poignantly illustrated by the catastrophic effects witnessed during the first-into-human administration of TGN1412. This review summarizes lessons gleaned from practical experience and discusses how these can inform future discovery and development of new biologic therapies for rheumatology.

Chemokines are involved in leukocyte recruitment to inflammatory sites, such as the synovial tissue in rheumatoid arthritis (RA). There is a structural and a functional classification of chemokines. The former includes four groups: CXC, CC, C and CX3C chemokines. Chemokines may also be either inflammatory or homeostatic, however, these functions often overlap. Anti-chemokine and anti-chemokine receptor targeting may be therapeutically used in the future biological therapy of arthritis. Most data in this field have been obtained from animal models of arthritis as only very few human RA trials have been completed. However, it is very likely that various specific chemokine and chemokine receptor antagonists will be developed and administered to RA patients.

Although considerable progress has been made by adequate treatment with traditional disease-modifying antirheumatic drugs (DMARDs), therapy of rheumatoid arthritis (RA) still remains difficult. The discovery of the importance of cytokines such as tumor necrosis factor (TNF), interleukin-1 (IL-1), interleukin-6 (IL-6), and interleukin-15 (IL-15), which are also stimulated by consequences of autoimmune responses, has led to the development of anticytokine therapies ("biologicals"). Blocking TNF or also, to some extent, IL-1 has proved beneficial in DMARD-resistant RA patients in multiple clinical trials. Along with clinical improvement, TNF blockade has been shown to halt radiographic disease progression, a major risk factor for disability. Recently, clinical trials have shown a significant therapeutic benefit of biological inhibitors of IL-6, and also of IL-15, with an efficacy comparable to that of TNF blockers. All these agents are particularly efficacious when combined with methotrexate. Although clinical remission is difficult to achieve even with anticytokine treatment, these drugs offer the potential to decrease disease activity and improve quality of life in a majority of RA patients, and it is conceivable that combinations of biological therapies may pave the path to even better success, which ultimately is remission or even cure.

Bone is a dynamic tissue that provides mechanical support, physical protection, and enables movement. Bone also serves as a storage site for minerals and is where blood cells are produced. Bone homeostasis is regulated by the balance between bone formation and resorption, and involves the coordinated action of osteoblasts and osteoclasts. Osteoblasts are bone-forming cells that secrete organic matrix molecules, while osteoclasts are derived from hematopoietic precursors and resorb bone matrix. Although osteoblasts and osteoclasts are the major regulators of bone metabolism and are regulated by the local microenvironment, it has recently come to be appreciated that skeletal system homeostasis is greatly influenced by components of the immune system. For example, some pathological bone resorption observed under inflammatory conditions has been shown to be due, in part, to direct and indirect effects of activated T cells on osteoclasts. In this regard, we would like to review current progress and perspectives in "osteoimmunology", an interdisciplinary research principle governing the cross-talk between the bone and immune systems. Better understanding of how the osteoimmune system operates in normal and pathological situations is likely to lay the groundwork for future therapies for the variety of diseases that affect both bone and the immune system.

Earlier diagnosis and treatment, plus biological therapies, have transformed the outlook for many patients with rheumatoid arthritis. In the future, new biomarkers for diagnosis, prognosis and therapeutic response will further improve outcomes. Additionally, preclinical diagnosis and tolerogenic therapies could provide sustained remission for some individuals, although ethical and societal challenges must also be addressed before rheumatoid arthritis becomes 'yesterday's disease'.

Investigation into arthritis as well as the numerous bone phenotypes found in mice lacking immune-related genes has highlighted the importance of the dynamic interplay between the bone and immune systems. It has recently led to both the emergence and subsequent rapid evolution of the field of osteoimmunology. Receptor activator of nuclear factor-kappaB ligand (RANKL) stimulates osteoclastogenesis through the nuclear factor of activated T cells, cytoplasmic 1 (NFATc1), which is well known as a crucial regulator of immunity. Studies on RANKL signaling revealed various immune-related genes which are involved in the regulation of osteoclastogenesis. Bone destruction in rheumatoid arthritis is caused by the enhanced activity of osteoclasts resulting from the activation of T cells. Here we describe our efforts to address the challenging question as to how abnormal T-cell activation mechanistically induces bone destruction. The scope of osteoimmunology has been extended to encompass a wide range of molecular and cellular interactions, the elucidation of which will provide a scientific basis for future therapeutic approaches to diseases related to both the bone and immune systems.

Osteoimmunology is an interdisciplinary research field that investigates the interplay of the skeletal and immune systems at the molecular level. The interaction between immune cells and osteoclasts has been a major topic in this field. As osteoclasts are derived from the monocyte/macrophage lineage, the macrophage-osteoclast interaction has long been studied. The T cell-osteoclast interaction has also attracted much attention in the study of bone destruction in arthritis. In addition, recent reports have revealed new players linking osteoclasts and other immune cells, including B cells and dendritic cells. Thus, a large number of molecules are in fact shared by osteoclasts and immune cells. These findings will lead to a better understanding of the pathogenesis of diseases affecting both systems and will provide a molecular basis for novel therapeutic strategies.

Understanding the pathogenesis of joint inflammation and destruction in rheumatoid arthritis involves dissection of the cellular and molecular interactions that occur in synovial tissue. Development of effective targeted therapies has been based on progress in achieving such insights. Safer and more specific approaches to treatment could flow from discovery of cell-cell interaction pathways that are specific to inflammation of the joint and less important in the defense against systemic infection. This article highlights selected cell-cell interactions in rheumatoid arthritis synovium that may be worthy of evaluation as future therapeutic targets.

Recent data are presented which indicate a critical role for interleukin (IL)-18 in rheumatoid arthritis (RA). The T cells and macrophages invading the synovium or in the synovial fluid are the chief cellular targets of IL-18 in RA. Neutrophils, dendritic cells and endothelial cells may also be cellular mediators of IL-18. The direct effect of IL-18 on fibroblast-like synoviocytes or chondrocytes may not be essential or important. In RA, IL-18, which is mainly produced by macrophages, activates T cells and macrophages to produce proinflammatory cytokines, chemokines, adhesion molecules and RANKL which, in turn, perpetuate chronic inflammation and induce bone and cartilage destruction.

Recent studies have elucidated unanticipated connections between the immune and skeletal systems, and this relationship has led to the development of a new field known as osteoimmunology. The goal of research in this field is to: (1) further understand how the bone microenvironment influences immune cell ontogeny and subsequent effector functions, and (2) translate basic science findings in bone biology to clinical applications for autoimmune diseases that target the skeleton such as rheumatoid arthritis (RA). In this review, we will examine the recent findings of the interplay between the immune and skeletal systems. This discussion will focus on the cells and signaling pathways in osteoimmune interactions and how innate and adaptive immune effector cells as well as cytokines and chemokines play a role in the maintenance and dysregulation of skeletal-immune homeostasis. We will also discuss how immunomodulatory biologic drugs, which specifically target these cells and effector molecules, have transformed the treatment of autoimmune mediated inflammatory diseases (IMIDs) and metabolic bone diseases such as osteoporosis.

Chronic T cell responses, as they occur in rheumatoid arthritis, are complex and are likely to involve many mechanisms. There is a growing body of evidence that, in concert with the T cell antigen receptor signal, CD28 and cytotoxic T-lymphocyte antigen-4 (CTLA-4; CD152) are the primary regulators of T cell responses. Whereas CD28 primarily activates T cell processes, CTLA-4 inhibits them. The mechanism for this dichotomy is not fully understood, especially as CD28 and CTLA-4 recruit similar signalling molecules. In addition, recent studies demonstrate that CD28 and CTLA-4 have multiple functions during T cell responses. In particular, CTLA-4 exerts independent distinct effects during different phases of T cell responses that could be exploited for the treatment of rheumatoid arthritis.