The RANK/RANKL/osteoprotegerin system in rheumatoid arthritis: New insights from animal models

Neumann, Elena; Müller‐Ladner, Ulf

doi:10.1002/art.21361

Cited by 41 publications

(37 citation statements)

References 77 publications

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“…Several studies have demonstrated that human synovial fibroblasts express RANKL on the cell surface and secrete both RANKL and OPG into medium in response to the proinflammatory cytokines TNF␣, IL-1␤, and IL-17 (19,20,(30)(31)(32). However, the condition and source of fibroblasts or FLS were variable in different studies, which might have complicated the interpretation of results.…”

Section: Resultsmentioning

confidence: 99%

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

Tunyogi-Csapó¹,

Kis-Tóth²,

Radács³

et al. 2008

Arthritis & Rheumatism

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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.

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Section: Resultsmentioning

confidence: 99%

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

Tunyogi-Csapó¹,

Kis-Tóth²,

Radács³

et al. 2008

Arthritis & Rheumatism

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“…Denosumab, an investigational and fully human monoclonal antibody with a high affinity and specificity for RANKL, can inhibit structural damage in patients with RA when added to ongoing methotrexate treatment [36,37] . In contrast, OPG belongs to the TNF-receptor super family, and it negatively regulates the activation and development of osteoclasts by sequestering its ligand RANKL [38] . In this study, NOR was demonstrated to reduce serum levels of RANKL but not OPG in AIA rats, markedly decreasing the ratio of RANKL/OPG.…”

Section: Discussionmentioning

confidence: 99%

Norisoboldine alleviates joint destruction in rats with adjuvant-induced arthritis by reducing RANKL, IL-6, PGE2, and MMP-13 expression

et al. 2013

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Aim: To explore the effects of norisoboldine (NOR), a major isoquinoline alkaloid in Radix Linderae, on joint destruction in rats with adjuvant-induced arthritis (AIA) and its underlying mechanisms. Methods: AIA was induced in adult male SD rats by intradermal injection of Mycobacterium butyricum in Freund's complete adjuvant at the base of the right hind paw and tail. From d 14 after immunization, the rats were orally given NOR (7.5, 15, or 30 mg/kg) or dexamethasone (0.5 mg/kg) daily for 10 consecutive days. Joint destruction was evaluated with radiological scanning and H&E staining. Fibroblast-like synoviocytes (FLS) were prepared from fresh synovial tissues in the AIA rats. The expression of related proteins and mRNAs were detected by ELISA, Western blotting and RT-PCR. Results: In AIA rats, NOR (15 and 30 mg/kg) significantly decreased the swelling of paws and arthritis index scores, and elevated the mean body weight. NOR (30 mg/kg) prevented both the infiltration of inflammatory cells and destruction of bone and cartilage in joints. However, NOR (15 mg/kg) only suppressed the destruction of bone and cartilage, but did not obviously ameliorate synovial inflammation. NOR (15 and 30 mg/kg) significantly decreased the serum levels of receptor activator of nuclear factor κB ligand (RANKL), IL-6, PGE 2 , and MMP-13, but not the osteoprotegerin and MMP-1 levels. The mRNA levels of RANKL, IL-6, COX-2, and MMP-13 in synovium were also suppressed. Dexamethasone produced similar effects in AIA rats as NOR did, but without elevating the mean body weight. In the cultured FLS, treatment with NOR (10 and 30 mmol/L) significantly decreased the secretion of RANKL, IL-6, PGE 2 , and MMP-13 proteins. Furthermore, the treatment selectively prevented the activation of MAPKs, AKT and transcription factor AP-1 component c-Jun, but not the recruitment of TRAF6 or the activation of JAK2/STAT3. Treatment of the cultured FLS with the specific inhibitors of p38, ERK, AKT, and AP-1 significantly decreased the secretion of RANKL, IL-6, PGE 2 , and MMP-13 proteins. Conclusion: NOR can alleviate joint destruction in AIA rats by reducing RANKL, IL-6, PGE 2 , and MMP-13 expression via the p38/ERK/ AKT/AP-1 pathway.

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“…Dazu gehören der Tumornekrosefaktor-(TNF-) Rezeptor (TNFR), das Osteoprotegerin (OPG), der "receptor activator of nuclear factor"-κB (RANK-) und der RANK-Ligand (RANKL), welche aktiv an der Reifung und Funktion von Osteoklasten beteiligt sind [6,16,23]. Die Analyse dieser Zusammenhänge führte zum besseren Verständnis der Diversität der physiologischen und pathophysiologischen Effekte des zentralen RANK-Signalweges, die zur Osteoklastogenese, zum Knochenabbau und somit auch zur Regulation der Knochendichte beitragen.…”

Section: Osteoporoseunclassified

Neue pathophysiologische Stoffwechselwege in der Osteoporose

Neumann

2006

Z. Rheumatol.

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The RANK/RANKL/osteoprotegerin system in rheumatoid arthritis: New insights from animal models

Cited by 41 publications

References 77 publications

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

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

Norisoboldine alleviates joint destruction in rats with adjuvant-induced arthritis by reducing RANKL, IL-6, PGE2, and MMP-13 expression

Neue pathophysiologische Stoffwechselwege in der Osteoporose

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