Cytokine‐controlled RANKL and osteoprotegerin expression by human and mouse synovial fibroblasts: Fibroblast‐mediated pathologic bone resorption

Abstract

Objective. To determine whether proinflammatory cytokine treatment or the complete absence of select cytokines modulates the expression of RANKL and osteoprotegerin (OPG) in synovial fibroblasts.Methods. Fibroblasts were isolated from normal and rheumatoid human synovium and from normal or arthritic joints of wild-type and cytokine gene-deficient Conclusion. Proinflammatory cytokines induce the expression of RANKL and OPG in both human and murine synovial fibroblasts. The RANKL:OPG ratios are shifted in favor of bone protection by IL-4 treatment, and, to a lesser extent, by IFN␥ treatment. Unexpectedly, an IL-17 deficiency alone does not induce reduced inflammatory bone destruction. Our results suggest that synovial fibroblasts may significantly contribute to bone resorption through modulation of RANKL and OPG production in a cytokine-rich milieu of inflamed joints.

Combination therapy with dexamethasone and osteoprotegerin protects against arthritis-induced bone alterations in antigen-induced arthritis of the rat

“…In the case of inflammation, as is present in AIA, glucocorticoids may indirectly inhibit RANKL expression by suppressing proinflammatory cytokines that induce RANKL, such as TNF-a, IL-1 and IL-6 [39], resulting in a protective effect on inflammationinduced bone alterations. However, the proinflammatory°* cytokines that are suppressed by glucocorticoids induce not only RANKL but also OPG [40][41][42][43][44][45]. Thus, glucocorticoid inhibition of these cytokines in the inflammatory setting may also result in a decrease of OPG.…”

Dysfunctional Immune-Mediated Inflammation in Rheumatoid Arthritis Dictates that Development of Anti-Rheumatic Disease Drugs Target Multiple Intracellular Signaling Pathways

“…Thus, it will be crucial to determine the effect of IL-32 on intracellular protein kinase signaling under these conditions even though IL-17 has previously been shown to activate the JAK/STAT pathway in RA FLS [5,9]. RANKL/RANK-driven bone resorption mediated by activated FLS in vitro has also been reported [44]. Thus, the synthesis of RANKL by activated FLS may increase the synovial fluid concentration of RANKL and represent an alternative pathway to osteoclastic-mediated bone destruction in RA.…”

Bone Regulatory Mechanisms Destruction in Experimental Chronic Kidney Disease

“…Імовірно, що і його вплив на експре-сію RANKL та остеопротегерину неістотний. Таке припущення знаходить підтвердження в літературних даних, де дефіцит ІЛ-17 не знижує кісткову резорбцію [16]. Водночас у групі тварин із ХХН була виявлена позитив-на кореляція між RANKL та ІЛ-17, це може поясню ватися тим, що останній індукує екс-пресію RANKL у цій групі.…”