Editorial The Osteoprotegerin/Osteoprotegerin Ligand Family: Role in Inflammation and Bone Loss There is much excitement surrounding osteoprotegerin upregulated by many soluble factors affecting bone resorp- (OPG), its osteoprotegerin ligand (OPGL), and their role in tion, including the proinflammatory cytokines, interleukin-1 bone metabolism. Bone growth and remodeling is a and TNF-α 11,12. T cells express a cell-surface membrane- dynamic process, balancing bone matrix synthesis by bound OPGL that is cleaved by metalloproteinases into a osteoblasts and resorption of bone by multinucleated osteo- soluble form13. There may be some functional differences clasts1,2. Osteoprotegerin ligand, a member of the tumor between membrane-bound and soluble OPGL, with cell- necrosis factor receptor family of molecules, is a key regu- bound OPGL being more effective mediators of osteoclasto- lator of bone remodeling through its key role in osteoclasto- genesis when measured by in vitro assays13. The presence of genesis3-6. both soluble and membrane-bound forms of OPGL and their OPGL was discovered by several groups, and was given functional differences may explain the conflicting data from different names depending on the reason behind its different groups. The method of quantitation of OPGL and discovery: TRANCE [tumor necrosis factor (TNF) related the specimen used may also help address these differences. activation induced cytokine]7, RANKL [receptor activator Investigators using ELISA assays on serum can only of nuclear factor-κB (RANK) ligand]8, osteoclast differenti- measure the soluble form, as in the report by Masi, et al. ation factor4, and OPGL ligand for OPG3. In addition to its Those researchers using flow cytometry on single cell essential role in the development and activation of osteo- suspensions will only measure cell-bound forms of OPGL, clasts, OPGL has been identified as an important costimula- and those using reverse transcription polymerase chain reac- tion molecule involved in T cell–dendritic cell communi- tion (RT-PCR) to quantitate messenger RNA production will cation and in dendritic cell survival8,9. RANK is the measure message precursors for both soluble and downstream signaling receptor for OPGL. OPG is a soluble membrane-bound variants. decoy receptor for OPGL, neutralizing its ability to bind In the article presented in this issue, Masi, et al report with RANK and induce a signal. Due to its expression on that serum levels of OPGL protein, as measured by ELISA, activated T cells and its role in inflammation and bone loss, in children with JIA are lower than those for healthy chil- OPGL has generated much interest in autoimmune disease dren. This would point to decreased osteoclastic activity in research, in particular in inflammatory arthritis. children with JIA compared to healthy children, a counter- In this issue of The Journal, Masi and colleagues inves- intuitive notion, given the body of literature demonstrating tigate the role of the OPG/OPGL system in modulating bone the increased risk and incidence of osteopenia in children injury in children with juvenile idiopathic arthritis (JIA)10. with JIA. Data from Varsani, et al14 and our own data15 They report an increased OPG/OPGL ratio in the peripheral differ from those reported by Masi, in finding an increased blood of children with JIA compared to controls, as well as level of OPGL in the peripheral circulation of children with the association of the TT polymorphism of the OPG gene in JIA compared to healthy children. The critical difference is children with JIA with lower bone mineral density. The the method of quantitation of OPGL. In Varsani’s case and authors suggest that increased OPG production in affected in ours, RT-PCR was used to measure OPGL mRNA, which children may reflect a compensatory mechanism for over- represents precursors of both soluble and membrane-bound production of OPGL. forms. The increase in OPGL in children with JIA is also seen when OPGL is assayed by flow cytometry, which THE OPG/OPGL PATHWAY measures cell-surface, membrane-bound forms of OPGL. OPGL is made by activated T cells and its expression is These differences serve to highlight the need to further See Osteoprotegerin/RANK-L System in JIA: Is there a potential modulating role for OPG/RANK-L in bone injury?, page 986 Personal, non-commercial use only. The Journal of Rheumatology Copyright © 2004. All rights reserved. Personal,844 non-commercial use only. The Journal of Rheumatology. CopyrightThe Journal © 2004. of Rheumatology All rights 2004; reserved. 31:5 Downloaded on September 25, 2021 from www.jrheum.org understand the biologic activity of membrane-bound versus In contrast, cytokines inhibiting osteoclastogenesis, such soluble forms of OPGL to accurately interpret data within as IL-13, interferon-γ, and transforming growth factor-ß1 the context of disease and normal physiologic states. suppress the expression of OPGL but enhance expression of Another important factor in the physiologic equation is its inhibitor OPG13. Interestingly, glucocorticoids, widely the interactions of OPGL with its natural decoy used to treat multisystem autoimmune disease and arthritis, receptor/neutralizer, OPG. Bone loss mediated by OPGL strongly induce OPGL expression and decrease expression can be blocked by administration of OPG16. OPG functions of its decoy receptor, OPG20,21. One of the well documented as a decoy receptor for OPGL, competing with RANK for morbidities of corticosteroid use is bone loss. binding with OPGL, effectively inhibiting osteoclastogen- In people with inflammatory arthritis, OPGL has also esis both in vitro and in vivo17. Thus evaluation of OPGL emerged as an important factor regulating bone loss. levels must go hand in hand with OPG levels, as the balance Synovial tissue from patients with rheumatoid arthritis and of the 2 will determine whether osteoclastic or osteoblastic osteoarthritis have been shown to express high levels of activity dominates. OPGL16. Similarly, patients with spondyloarthropathies However, this evaluation is not a simple one-to-one have also been found to express high levels of OPGL in calculation: OPG, although a member of the TNF receptor affected synovial tissue22. There remains debate whether super family, is secreted as a 110 kDa homodimer, not a cartilage destruction occurs independently or is dependent molecular trimer, as are others in this molecular family on subchondral bone loss23. In the adjuvant-induced rat including its ligand OPGL17. The report by Masi and arthritis model, both cartilage and bone are protected by colleagues shows that the ratio of OPG/OPGL is lower in administration of OPG16, but in collagen-induced arthritis in the peripheral blood of children with JIA compared with rats, the protective effects of OPG were less in cartilage than healthy controls, again opposite to what one would expect in in bone24. In patients with erosive psoriatic arthritis, an osteopenic scenario. increased numbers of osteoclast precursors (OCP) were The interaction of OPGL and OPG at the molecular level found in the peripheral blood. OCP numbers were decreased is not known. One way to assist in data interpretation is to by administration of OPG and anti-TNF25. link the determinations of OPGL and OPG with biologic Although administration of OPG in animal models of activity, in this case osteoclastogenesis leading to bone loss, arthritis is bone protective, inflammation and its systemic a biologically relevant measure of activity in the effects are not altered18,26. Many cell types, both immune OPG/OPGL pathway. To that end, investigators have quan- and non-immune, have now been found to express OPGL titated the presence of osteoclast precursors and their func- including lymphocytes, monocytes, macrophages, dendritic tional ability to resorb bone as a correlate to OPGL levels cells, synovial fibroblasts, and mammary gland epithelial and the balance of activities between OPGL and OPG. Proof cells of lactating females16,27,28. Additionally, the down- of principle would include neutralization of this OPGL- stream effects of inflammatory cytokines on the mediated biologic activity by exogenous OPG. OPG/OPGL pathway may be the temporal answer to the apparent “disconnect” between inflammation and bone loss OPGL, T CELLS, AND BONE LOSS in arthritis in some situations. This may in part explain the T cells appear to be the link between inflammation and bone lack of correlation between serum levels of members of the loss. Increasingly, the role of OPGL as a critical second OPG/OPGL family and classic markers of inflammation in signal involved in optimal T cell activation is recognized. T patients with arthritis. As reported by Masi, et al, there is no cell-derived OPGL can also regulate the development and correlation between OPG or OPGL and common laboratory activation of osteoclasts resulting in bone loss16. This mech- markers of inflammation such as erythrocyte sedimentation anism is true both for systemic and local activation of T rate or C-reactive protein, but genetic control of OPG cells. In Lewis rats, adjuvant arthritis is a T cell-dependent expression may be related to local bone loss and generalized disease leading to joint inflammation and bone erosions18. T osteopenia. cells from inflamed joints express OPGL16. Although T cells The OPG/OPGL pathway is a key regulator of bone appear to be important regulators of bone metabolism, metabolism through its effect on development and activa- mutant mice that lack T cells do not have abnormal bones or tion of osteoclasts. In addition to its role in osteoclastogen- dentition. But under conditions of chronic systemic activa- esis, OPGL is a critical factor in the immune system, from tion of T cells as in viral infections and multisystem autoim- regulating development of lymph nodes and Peyer’s patches mune disease, or chronic local inflammation involving bone to serving as an important costimulation molecule in and joints such as in arthritis, bone remodeling via produc- optimal T cell activation and mediating dendritic cell tion of OPGL by T cells plays a more prominent role19.