RANKL protein is expressed at the pannus–bone interface at sites of articular bone erosion in rheumatoid arthritis

Pettit, Allison R.; Walsh, Nicole C.; Manning, Catherine A.; Goldring, Steven R.; Gravallese, Ellen M.

doi:10.1093/rheumatology/kel045

Cited by 140 publications

(93 citation statements)

References 61 publications

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“…In contrast to MAB626, the polyclonal antibody to RANKL detected not only mononuclear cells in the sublining layer but also positive cells in the intimal lining layer ( Figures 1B and C). The specificity of this antibody was already suggested by the fact that immunostaining could be blocked by preincubating the antibody with the immunizing peptide (23). We further confirmed the specificity by Western blot analysis of synovial tissue: a single band was detected at the expected molecular weight of 37.5-kd ( Figure 1D).…”

Section: Resultssupporting

confidence: 74%

“…In our analysis, synovial immunostaining with MAB626 was restricted to mononuclear cells in the sublining layer ( Figure 1A). Therefore, we assessed the specificity and staining pattern of the polyclonal antibody to RANKL (PeproTech) used by Pettit et al (23). In contrast to MAB626, the polyclonal antibody to RANKL detected not only mononuclear cells in the sublining layer but also positive cells in the intimal lining layer ( Figures 1B and C).…”

Section: Resultsmentioning

confidence: 99%

“…Therefore, we used a different monoclonal anti-OPG antibody (clone IMG103A, mouse IgG1, final concentration 5 g/ml) (Imgenex, San Diego, CA), which has been extensively validated for immunohistochemistry and detects all forms of OPG (22). Finally, RANKL was detected by the polyclonal antibody recently validated by Pettit et al (23) (polyclonal rabbit IgG, 1 g/ml) (PeproTech, Rocky Hill, NJ). T lymphocytes were stained with anti-CD3 (clone UCHT1; Dako, Glostrup, Denmark), and B lymphocytes were stained with anti-CD20 (clone L26; Dako).…”

Section: Methodsmentioning

confidence: 99%

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The abundant synovial expression of the RANK/RANKL/Osteoprotegerin system in peripheral spondylarthritis is partially disconnected from inflammation

Vandooren

Cantaert

Noordenbos

et al. 2008

Arthritis & Rheumatism

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Objective. Spondylarthritis (SpA) and rheumatoid arthritis (RA) have different patterns of bone damage, with more pronounced bone erosions in RA. The RANK/RANKL/osteoprotegerin (OPG) system plays a central role in bone resorption by promoting the maturation and activation of osteoclasts. To assess the potential role of this system in the distinct bone phenotype, we studied the synovial expression of these mediators in SpA and RA peripheral synovitis.Methods. Synovial biopsy specimens were obtained from the actively inflamed peripheral joints of 35 patients with SpA and 19 patients with RA. Paired synovial biopsy samples were obtained from 24 patients with SpA after tumor necrosis factor ␣ (TNF␣) blockade. Synovial tissue sections were immunostained for RANKL, OPG, RANK, and TRAP and assessed by semiquantitative scoring and digital image analysis.Results. After extensive validation of the reactivity and specificity of the antibodies, we demonstrated the abundant expression of RANKL and OPG in SpA synovitis. RANKL was expressed by both fibroblast-like synoviocytes and sublining T lymphocytes. RANKpositive osteoclast precursors but no mature TRAPpositive osteoclasts were present in the inflamed tissue. The expression of these mediators was not different between patients with nonpsoriatic SpA, patients with psoriatic SpA, and patients with RA, was not related to the degree of systemic or local inflammation, and was not significantly modulated by highly effective treatment with TNF␣ blockers. Only the subset of patients with the best systemic response to TNF␣ blockade had decreased RANKL expression in the intimal lining layer.Conclusion. The relative protection against bone erosions in SpA cannot be explained by qualitative or quantitative differences in the synovial expression of RANKL, OPG, and RANK. The abundant expression of these factors in SpA peripheral synovitis is largely disconnected from systemic and local inflammation.

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Section: Resultssupporting

confidence: 74%

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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The abundant synovial expression of the RANK/RANKL/Osteoprotegerin system in peripheral spondylarthritis is partially disconnected from inflammation

Vandooren

Cantaert

Noordenbos

et al. 2008

Arthritis & Rheumatism

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“…Effects of NOR on levels of RANKL and OPG in the serum and synovial membranes of AIA rats The RANKL/OPG system plays an important role in joint destruction in RA by regulating the differentiation and function of osteoclasts [17,18] . To elucidate the mechanisms responsible for the joint-protective action of NOR in AIA rats, its effects on the levels of RANKL and OPG were assessed.…”

Section: Resultsmentioning

confidence: 99%

“…It is widely accepted that the RANKL/OPG system plays an important role in the destruction of joints in RA by regulating the differentiation, survival and function of osteoclasts [32,33] , which could create resorption pits and local bone destruction via the degradation of the bone matrix and calcium solubilization [17,18] . RANKL belongs to the tumor necrosis factor (TNF) family and may be detected as a secreted factor as a consequence of proteolytic cleavage.…”

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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Chapter 59. Inflammation‐Induced Bone Loss in the Rheumatic Diseases

Goldring¹

2008

Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism

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RANKL protein is expressed at the pannus–bone interface at sites of articular bone erosion in rheumatoid arthritis

Cited by 140 publications

References 61 publications

The abundant synovial expression of the RANK/RANKL/Osteoprotegerin system in peripheral spondylarthritis is partially disconnected from inflammation

The abundant synovial expression of the RANK/RANKL/Osteoprotegerin system in peripheral spondylarthritis is partially disconnected from inflammation

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

Chapter 59. Inflammation‐Induced Bone Loss in the Rheumatic Diseases

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