Osteoprotegerin, RANK, and RANK Ligand: the Good, the Bad, and the Ugly in Rheumatoid Arthritis

Editorial Osteoprotegerin, RANK, and RANK Ligand: The Good, the Bad, and the Ugly in Rheumatoid Arthritis

Rheumatoid arthritis (RA) is the prototype of autoimmune in the orderly development and function of the immune disease that links the immune system with bone and carti- system, and may represent a molecular link between the lage metabolism1. The skeletal abnormalities in RA may immune system and bone metabolism. RANKL promotes include bone and cartilage erosions and progressive joint osteoclast formation and activation, and inhibits osteoclast destruction, as well as local and systemic osteoporosis1. It apoptosis3,4,11. The ensuing increased number and activity of has long been hypothesized that proinflammatory cytokines osteoclasts promoted by RANKL have been shown to cause excessively produced in areas of active inflammation may profound bone resorption and bone loss in vitro and in transfer signals from immune cells to osteoclasts, which vivo3,4,11. By contrast, RANKL deficiency is associated with constitute the specialized cells of bone resorption. However, generalized osteopetrosis due to impaired osteoclastic bone the cellular and molecular context of this process, and the resorption12. Osteoprotegerin (Latin: os, bone; protegere, to details of cross-talk between the immune system and bone protect) has been observed to completely antagonize the metabolism, remain elusive. Recent progress in the under- effects induced by RANKL both in vitro and in vivo. standing of osteoclast biology2, together with the recogni- Overexpression or exogenous administration of OPG tion that osteoclasts are important effector cells in the increased bone mass and prevented bone loss associated process of joint and bone damage in RA, has now shed light with estrogen deficiency9-11. on the pathogenesis of skeletal destruction in RA and offers RANKL produced by activated T lymphocytes is capable the chance of a powerful therapeutic intervention. of activating osteoclasts in vivo7 and increasing dendritic Receptor activator of NF-κB ligand (RANKL), a cell survival by blocking their apoptosis6, effects that are member of the tumor necrosis factor (TNF) ligand super- antagonized by OPG. The phenotype of RANKL deficient family, is the essential cytokine signal for various osteoclast mice is characterized by a lack of lymph nodes and functions3-7. RANKL is expressed on the membrane of cells hypoplasia of thymus and Peyer’s patches, indicating that of the osteoblastic lineage and activated T lymphocytes3-9. RANKL is essential for normal embryological development In addition to a cell-bound RANKL form, activated T of lymphoid tissue12. The parallel roles of RANKL and OPG lymphocytes produce a secreted RANKL form7. Soluble in regulating bone metabolism and the immune system, the RANKL can also be generated following cleavage of the expression of RANK by osteoclasts and dendritic cells, and cell-bound form by a protease. Both forms of RANKL act the cross-talk of T lymphocyte derived RANKL and osteo- through binding to and activating receptor activator of NF- clasts within the bone microenvironment have made κB (RANK), a cell-bound receptor of the TNF receptor RANKL an obvious candidate cytokine that promotes the (TNFR) superfamily that is located on osteoclast precursor skeletal complications of RA. cells, mature osteoclasts, and dendritic cells7. Similarly to Several in vivo studies using established animal models other cytokine systems [interleukin 1 (IL-1), TNF-α], the of RA provide support for this hypothesis7,13,14. Kong and potent stimulatory effects of RANK by RANKL are coun- associates7 have clearly demonstrated that RANKL mRNA terbalanced by an endogenous antagonist, osteoprotegerin is produced by synovial fibroblasts and activated T lympho- (OPG)9,10. OPG is secreted as a decoy receptor by many cytes in affected lesions of rats with adjuvant arthritis. These tissues and neutralizes all forms of RANKL through binding animals displayed severe bone loss due to enhanced osteo- to it3,11 (Figure 1). RANKL and OPG production is modu- clast formation and joint erosions within one week after lated by many osteotropic agents, including cytokines, subcutaneous administration of Mycobacterium tubercu- growth factors, peptide and steroid hormones, vitamins, and losis. In mice with collagen induced arthritis, another rodent drugs2. model of RA (induced by intradermal injection of type II Several lines of evidence indicate that RANKL and collagen), RANKL expression was detected in mononuclear RANK are essential for bone metabolism, play a critical role cells and chondrocytes within areas of inflammation, and

Personal non-commercial use only. The Journal of Rheumatology Copyright © 2001. All rights reserved. Hofbauer, et al: Editorial 685 Downloaded on September 28, 2021 from www.jrheum.org Figure 1. Mechanisms of bone resorption in RA. Activated T cells, stromal cells, and synovial fibroblasts express RANKL, which interacts with its specific receptor RANK to promote osteoclast differentiation and activation and to inhibit osteoclast apoptosis, resulting in bone and cartilage destruction. These effects are counteracted by the decoy receptor OPG, which binds RANKL and prevents its interaction with RANK. actively resorbing osteoclasts were located at sites where which was prevented by administration of OPG16. In addi- RANKL production was most abundant13. In addition, tion, IL-17 concentrations were elevated in synovial fluid in targeted overexpression of the antiresorptive cytokine IL-4 human RA, and were found to be among the most potent markedly suppressed RANKL production in collagen stimulators of RANKL production18. The sequential action induced arthritis, and protected these mice from developing of IL-17 and RANKL is supported by the finding that osteo- bone loss and cartilage damage14. clastogenesis induced by IL-17 was completely prevented There is mounting evidence supporting an essential role by administration of OPG17. of RANKL in human RA15-17. Both RANKL mRNA and Given the essential role of RANKL in RA as well as the protein are abundantly produced by activated T lymphocytes novel paradigm of RANKL and OPG as opposing factors in infiltrating the synovium, but are absent in synovial tissue osteoclast biology, OPG has been explored as a potential derived from patients with other forms of arthritis and in therapeutic agent. For instance, joint effusions of patients healthy subjects15,16. Expression of RANKL mRNA and with RA were found to contain lower OPG levels compared protein was confirmed in vitro with cultured fibroblasts and to patients with other joint diseases, indicating a relative T lymphocytes derived from synovial specimens of patients deficiency of local OPG production to compensate for the with RA15,16. Therefore, the systemic bone-sparing effects of increase of RANKL13,15,16,18. Furthermore, administration of immunosuppressants such as cyclosporin A in patients with OPG has been successfully used for the prevention and RA17 may be explained by an inhibition of T cell activation, treatment of several animal models of benign and malignant resulting in decreased RANKL production. Similar to acti- metabolic bone diseases, including bone loss associated vated T lymphocytes7, synovial fibroblasts from patients with estrogen deficiency, immobilization osteoporosis, oste- with active RA stimulated osteoclast formation in vitro, olytic bone metastasis, and humoral hypercalcemia of

Personal non-commercial use only. The Journal of Rheumatology Copyright © 2001. All rights reserved. 686 The Journal of Rheumatology 2001; 28:4 Downloaded on September 28, 2021 from www.jrheum.org malignancy2. In rat adjuvant arthritis, treatment with recom- 4. Yasuda H, Shima N, Nakagawa N, et al. Osteoclast differentiation binant OPG protected against the development of bone and factor is a ligand for osteoprotegerin/osteoclastogenesis inhibitory 19 factor and is identical to TRANCE/RANKL. Proc Natl Acad Sci cartilage destruction . Interestingly, OPG treatment of rats USA 1998;95:3597-602. with adjuvant arthritis revealed a bone-sparing effect, even 5. Wong BR, Rho J, Arron J, et al. TRANCE is a novel ligand of the though the coexisting inflammation was not ameliorated7. A tumor necrosis factor receptor family that activates c-jun N-terminal followup study in this animal model then provided evidence kinase in T cells. J Biol Chem 1997;272:25190-4. that combined anticytokine therapy with OPG and soluble 6. Anderson MA, Maraskovsky E, Billingsley WL, et al. A homologue α of the TNF receptor and its ligand enhance T-cell growth and TNFR I (which neutralizes TNF- ) or IL-1 receptor antago- dendritic-cell function. Nature 1997;390:175-9. nist (which neutralizes IL-1α and IL-1ß) may not only 7. Kong Y-Y, Feige U, Sarosi I, et al. Activated T cells regulate bone prevent bone and cartilage loss, but also inhibit the inflam- loss and joint destruction in adjuvant arthritis through matory process. These studies have shown that RANKL osteoprotegerin ligand. Nature 1999;402:304-9. antagonists such as OPG mitigate the clinical course of 8. Horwood NJ, Kartsogiannis V, Quinn JMW, Romas E, Martin TJ, Gillespie MT. Activated T cells support osteoclast formation in arthritis in animal models of RA, and may potentiate the vitro. Biochem Biophys Res Commun 1999;265:144-50. effects of TNF-α blockade, which is currently used to treat 9. Simonet WS, Lacey DL, Dunstan CR, et al. Osteoprotegerin: a patients with severe juvenile and adult RA as well as refrac- novel secreted protein involved in the regulation of bone density. tory Crohn’s disease. Administration of recombinant human Cell 1997;89:309-19. OPG has already been assessed in postmenopausal women, 10. Yasuda H, Shima N, Nakagawa N, et al. Identity of osteoclastogenesis inhibitory factor (OCIF) and osteoprotegerin where it was found to substantially reduce biochemical (OPG): a mechanism by which OPG/OCIF inhibits 20 markers of bone turnover without significant side effects . osteoclastogenesis in vitro. Endocrinology 1998;139:1329-37. Moreover, several randomized controlled studies have 11. Fuller K, Wong B, Fox S, Choi Y, Chambers TJ. TRANCE is reported that bisphosphonates, by inhibiting osteoclast necessary and sufficient for osteoblast-mediated activation of bone activity, act to prevent generalized bone loss and may reduce resorption in osteoclasts. J Exp Med 1998;188:997-1001. 12. Kong Y-Y, Yoshida H, Sarosi I, et al. OPGL is a key regulator of local disease activity in patients with RA. Thus, patients osteoclastogenesis, lymphocyte development and lymph-node with severe RA may benefit locally and systemically from organogenesis. Nature 1999;397:315-23. antiresorptive agents such as bisphosphonates or RANKL 13. Romas E, Bakharevski O, Hards DK, et al. Expression of osteoclast inhibitors. differentiation factor at sites of bone erosion in collagen-induced arthritis. Arthritis Rheum 2000;43:821-6. 14. Lubberts E, Joosten LAB, Chabaud M, et al. IL-4 gene therapy for LORENZ C. HOFBAUER, MD, collagen arthritis suppresses synovial IL-17 and osteoprotegerin Endocrine Fellow; ligand and prevents bone erosions. J Clin Invest 2000; ARMIN E. HEUFELDER, MD, 105:1697-710. Professor of Medicine, Endocrinology and Rheumatology, 15. Gravallese EM, Manning C, Tsay A, et al. Synovial tissue in Division of Gastroenterology, Endocrinology, rheumatoid arthritis is a source of osteoclast differentiation factor. and Metabolism, Zentrum für Innere Medizin, Arthritis Rheum 2000;43:250-8. Philipps University, Baldingerstrasse, D-35033 Marburg; 16. Takayanagi H, Iizuka H, Juji T, et al. Involvement of receptor REINHOLD G. ERBEN, MD, DVM, activator of nuclear factor κB ligand osteoclast differentiation factor Associate Professor, in osteoclastogenesis from synoviocytes in rheumatoid arthritis. Institute of Physiology, Physiological Chemistry Arthritis Rheum 2000;43:259-69. and Animal Nutrition, Ludwig Maximilians University, 17. Ferraccioli G, Casatta L, Bartoli E. 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