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Clinical Immunity in Bone and Joints

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Journal of Bone and Mineral Metabolism (2019) 37:2–8 https://doi.org/10.1007/s00774-018-0965-5 INVITED REVIEW Clinical immunity in bone and joints Yoshiya Tanaka1 Received: 3 September 2018 / Accepted: 24 September 2018 / Published online: 15 October 2018 © The Japanese Society for Bone and Mineral Research and Springer Japan KK, part of Springer Nature 2018 Abstract The immune system and bone metabolism infuence each other. An imbalance in the immune system, resulting in infamma- tory stimuli may induce an imbalance in bone turnover via induction of osteoclast diferentiation and inhibition of osteoblast diferentiation, leading to various pathological conditions including osteoporosis. T-cell subsets, helper T (Th)1 and Th17, which activate the immune system, induce osteoclasts, whereas regulatory T (Treg) cells, responsible for immunosuppres- sion, inhibit osteoclastic diferentiation. In addition, infammatory cytokines, such as the tumor necrosis factor (TNF), also cause an imbalance in bone turnover, induction of osteoclasts and inhibition of osteoblasts. Treatments targeting the immune system may regulate abnormalities in bone metabolism, while also controlling immune abnormalities. In rheumatoid arthritis (RA), a representative autoimmune disease, immune abnormality and accompanying prolongation of synovial infammation cause bone and cartilage destruction, periarticular osteoporosis, and systemic osteoporosis. Joint damage and osteoporosis in RA occur through totally diferent mechanisms. Stimulation by infammatory cytokines induces the expression of the receptor activator for nuclear factor-κB ligand (RANKL) in T cells and synovial cells, thereby inducing bone destruction due to osteoblast-independent osteoclast maturation. However, biological products targeting TNF or interleukin-6 not only control disease activity, but also inhibit joint destruction. However, these biological products are not efective for osteopo- rosis. Conversely, anti-RANKL antibody inhibits osteoporosis and bone destruction, but exerts no infuence on RA disease activity. Such diferences in therapeutic efcacy may indicate the necessity for rethinking current theories on the mechanism of bone metabolism abnormality and joint destruction. Understanding the mechanisms underlying these pathologies via com- monalities existing between the immune system and the metabolic system may lead to the development of new treatments. Keywords Bone · Joint · Immunity · Rheumatoid arthritis · Osteoporosis Introduction immunity mechanisms which can process a variety of anti- gen information and memorize such information in prepa- The immune system is a biological defense mechanism ration for a second invasion in addition to self-tolerance. against foreign antigens established during several million Thymus-derived naive T cells diferentiate into memory years of evolution, starting from microorganisms. Natural T-cells that retain the memory of antigen information and immunity is a primitive mechanism originating in micro- homing information from dendritic cells in regional lymph organisms. This mechanism allows the macrophages, neu- nodes. Memory T-cells circulate into peripheral tissues, and trophils, and NK cells, among others, to recognize bacteria quickly take charge of the immune response, using memo- and viruses that invade the host, and eliminate them via rized antigen information. In contrast, T cells show immune processes such as phagocytosis, enzymatic treatment, and tolerance to autoantigens. However, if such self-tolerance is production of active oxygen among others. On the other broken by some factor, autologous reactive T cells will be hand, vertebrates evolved the immune system, and acquired activated to stimulate B cells to induce the production of autoantigens, causing autoimmunity. The immune system is involved in the maintenance of * Yoshiya Tanaka normality, prevention of various pathological conditions via [email protected]‑u.ac.jp initiation of biological defense and formation and resolution 1 The First Department of Internal Medicine, School of infammation. The immune system and the metabolic sys- of Medicine, University of Occupational and Environmental tem are both important biological regulatory mechanisms, Health, Japan, 1‑1 Iseigaoka, Kitakyushu 807‑8555, Japan Vol:.(1234567890)1 3 Journal of Bone and Mineral Metabolism (2019) 37:2–8 3 and an abnormality in the immune system may infuence through blood fow, mature to become polynuclear osteo- the metabolic system. In autoimmune infammatory con- clasts, in response to stimulation by the receptor activator for ditions, caused by immune abnormalities such as rheuma- nuclear factor-κB ligand (RANKL) expressed in osteoblasts toid arthritis (RA), bone metabolism abnormalities may be and osteocytes, and when activated, induce bone resorption induced via immunocompetent cells and cytokines, resulting (Fig. 1). in consequent bone and joint destruction [1–5]. However, Homeostasis of bone tissue is maintained bone remod- current understanding of the pathology of RA and advances eling cycle (bone turnover) of bone resorption by osteoclasts in treatment indicate that bone and cartilage destruction and and bone formation by osteoblasts, via regulatory mecha- osteoporosis are caused by totally diferent mechanisms, nisms that include the endocrine system [6–12] (Fig. 2). requiring diferent therapeutic strategies. This paper presents Various factors produced by osteocytes such as TGF-β an outline of the infuence of the immune system on bone and BMP also induce the diferentiation of mesenchymal metabolism as well as the related therapeutic processes, stem cells into osteoblasts and osteocytes, bone modeling. while focusing on the pathology of RA. In addition, sclerostin and Dickkopf (DKK)-1 produced by osteocytes inhibit Wnt-mediated signals expressed in osteo- Mechanism of bone metabolism blast precursors to control the diferentiation and activation of osteoblasts. Osteocytes, which account for about 95% of The skeleton is the structure that supports the body. It is all cell components in bone, possess many dendrites which also the organ in which bone and mineral metabolism take support the three-dimensional structure of bone, thus play- place. Bone and hard tissues impart structural rigidity and ing a central role in both modeling and remodeling of bone. form to vertebrates, and enable bone and mineral metabo- Abnormalities in modeling and remodeling may lead to lism which is vital for life. Bone tissue is composed of the abnormal bone metabolism, resulting in conditions such as bone matrix consisting of type I collagen with hydroxyapa- osteoporosis. tite crystal deposits and cell groups such as osteoblasts and osteocytes. Osteoblasts, which diferentiate from mesen- Infuence of rheumatoid arthritis on bone chymal stem cells to produce the bone matrix, diferentiate metabolism further into osteocytes which play a key role in maintaining bone structure. Osteoclasts are derived from hematopoietic Rheumatoid arthritis is a systemic autoimmune disease stem cells. Precursor monocytes, which migrate into bone with synovitis in multiple joints as its principal pathological M-CSF, IL-6, IL-17, TNF, Activated PGE2 Hematopoietic Osteoclast precursor osteoclast stem cell (monocyte) RANK RANKL TGF, BMP Anti-RANKL Wnt Mesenchymal osteoblast osteocyte Stem cell Bone matrix Bone matrix TNF, DKK-1, sclerostin IL-1, IL-6, IL-7, IL-17, TNF, PGE2 Anti-TNF Anti-TNF, anti-IL-6R Fig. 1 Diferentiation of osteocyte and osteoclast and its regulation. targeting TNF and IL-6 inhibit bone destruction, but they do not exert Osteoblasts and osteocytes diferentiate from mesenchymal stem cells any infuence on systemic osteoporosis. The anti-RANKL antibody, to produce the bone matrix and osteoclasts derived from hematopoi- denosumab, also inhibits the process of osteoclast maturation by etic stem cells are involved in bone resorption. Biological DMARDs RANKL expressed in synovial cells and T cells 1 3 4 Journal of Bone and Mineral Metabolism (2019) 37:2–8 PTH Anti-SOST resting osteoblast TNFα, IL-6 Anti-TNF Anti-IL-6(R) Bone formation Activation of osteoclast Activated osteoclast Activated osteoclast bisphosphonate Anti-RANKL osteoporosis (osteoblast-dependent, TNF-independent) Anti-RANKL Bone damage in RA (osteoblast-independent, TNF-dependent) Fig. 2 Mechanisms and treatment strategies of osteoporosis and joint ated with RA represents the maturation of osteoclasts enhanced in an damage in RA. Homeostasis of bone is maintained bone remodeling osteoblast-independent manner, demonstrating deviation from bone cycle of bone resorption by osteoclasts and bone formation by osteo- turnover due to stimulation by TNF and IL-6 blasts via regulatory mechanisms. However, bone destruction associ- feature. This disease occurs frequently in women in their Helper T (Th)1 and Th17 cells induce osteoclasts via the 30s and 50s, where the total number of patients is estimated production of TNF and IL-17, and Th1 cells inhibit the to be about 7–800,000 in Japan. Clinical symptoms of RA expression of osteoprotegerin (OPG) via the production of such as pain, swelling, and stifness of multiple joints and interferon (IFN)-γ (Fig. 3). In contrast, regulatory T (Treg) joint deformity markedly impair the daily-life activities of cells inhibit the diferentiation of osteoclasts by express- patients. Joint destruction begins to progress from early ing cytotoxic T-lymphocyte antigen-4. In addition, trans- stages of RA-onset, and resulting joint deformities may forming
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