Mechanisms and therapeutic targets for bone damage in rheumatoid arthritis, in particular the RANK-RANKL system

Tanaka, Yoshiya; Ohira, Takeshi

doi:10.1016/j.coph.2018.03.006

Cited by 68 publications

(48 citation statements)

References 64 publications

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“…Recent studies have provided insights into the enrichment of memory B cell subsets distinguished by the expression of Fc-like receptor 4 (FcRL4) in the joints and mucosa-associated lymphoid tissues of RA patients. Interestingly, antibodies produced from FcRL4 + B cells have high binding capacity to citrullinated autoantigens [19].…”

Section: B Cells and Autoantibodiesmentioning

confidence: 99%

Molecular and Cellular Pathways Contributing to Joint Damage in Rheumatoid Arthritis

Fang

Zhou

Nandakumar

2020

Mediators of Inflammation

143

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Rheumatoid arthritis is a chronic autoimmune syndrome associated with several genetic, epigenetic, and environmental factors affecting the articular joints contributing to cartilage and bone damage. Although etiology of this disease is not clear, several immune pathways, involving immune (T cells, B cells, dendritic cells, macrophages, and neutrophils) and nonimmune (fibroblasts and chondrocytes) cells, participate in the secretion of many proinflammatory cytokines, chemokines, proteases (MMPs, ADAMTS), and other matrix lysing enzymes that could disturb the immune balance leading to cartilage and bone damage. The presence of autoantibodies preceding the clinical onset of arthritis and the induction of bone erosion early in the disease course clearly suggest that initiation events damaging the cartilage and bone start very early during the autoimmune phase of the arthritis development. During this process, several signaling molecules (RANKL-RANK, NF-κB, MAPK, NFATc1, and Src kinase) are activated in the osteoclasts, cells responsible for bone resorption. Hence, comprehensive knowledge on pathogenesis is a prerequisite for prevention and development of targeted clinical treatment for RA patients that can restore the immune balance improving clinical therapy.

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Section: B Cells and Autoantibodiesmentioning

confidence: 99%

Molecular and Cellular Pathways Contributing to Joint Damage in Rheumatoid Arthritis

Fang

Zhou

Nandakumar

2020

Mediators of Inflammation

143

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“…Rheumatoid arthritis (RA) is a chronic and systemic inflammatory disease characterized by autoimmune inflammation and progressive joint destruction [1,2]. Persistent synovitis results in progressive joint destruction, characterized by the destruction of bone and cartilage [3][4][5], leading to joint deformity and dysfunction, and eventually resulting in difficulties engaging in activities of daily living and the deterioration of quality of life [3,[6][7][8]. Because joint destruction is largely irreversible, complete suppression of joint destruction is a critical goal for RA treatment.…”

Section: Introductionmentioning

confidence: 99%

Predictors of new bone erosion in rheumatoid arthritis patients receiving conventional synthetic disease-modifying antirheumatic drugs: Analysis of data from the DRIVE and DESIRABLE studies

Takeuchi

Soen

Ishiguro

et al. 2020

Modern Rheumatology

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Objective: To investigate new bone erosion and cartilage destruction predictors in rheumatoid arthritis (RA) patients treated with conventional synthetic disease-modifying antirheumatic drugs (csDMARDs). Methods: Placebo-treated patient data from two 12-month, randomized, double-blind, phase 2 (DRIVE) and 3 (DESIRABLE) trials that evaluated denosumab efficacy in csDMARD-treated RA patients were used. Change from baseline in erosion score (ES) of 1.0 at 12 months was considered new bone erosion; predictors were identified using a multivariate model. Results: Among 306 patients, mean ± standard deviation disease activity score 28-C-reactive protein (CRP) at baseline was 3.58 ± 1.03. New bone erosion was observed in 90 patients (29.4%). Univariate analysis identified female sex, anti-cyclic citrullinated peptide (CCP) antibody positivity, rheumatoid factor (RF) positivity, tender joint count 6, CRP 0.3 mg/dL, erythrocyte sedimentation rate (ESR) 28 mm/h, and baseline ES 3 as significant predictors for new bone erosion. In multivariate analysis, predictors were anti-CCP antibody positivity, CRP 0.3 mg/dL, and baseline ES 3; RF and ESR were excluded as they strongly correlated with anti-CCP antibody and CRP, respectively. Conclusion: In RA patients treated with csDMARDs, new bone erosion predictors were seropositivity, elevated inflammatory markers, and baseline ES 3.

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“…RA is an autoimmune disease characterized by systemic synovitis, followed by articular cartilage destruction and bone erosion, which results from increased osteoclast differentiation [2][3][4][5]. Furthermore, treatment with anti-RANKL antibodies (denosumab) strongly suppresses bone erosion in patients with RA [16].…”

Section: Introductionmentioning

confidence: 99%

TGFβ1 Regulates Human RANKL-Induced Osteoclastogenesis via Suppression of NFATc1 Expression

Tokunaga

Mokuda

Kohno

et al. 2020

IJMS

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Osteoclasts are multinucleated giant cells responsible for bone resorption. Various mediators involved in osteoclast differentiation have been investigated as possible therapeutic targets for osteoporosis and rheumatoid arthritis (RA). Although transforming growth factor beta1 (TGFβ1) has been described as one such multifunctional cytokine essential for bone remodeling, its effect on osteoclastogenesis remains controversial. Therefore, we sought to examine the effect of TGFβ1 on osteoclast generation induced by receptor activator of nuclear factor (NF)-κB ligand (RANKL) in humans. Peripheral blood monocytes, isolated using magnetic bead sorting, were cultured with macrophage-colony stimulating factor (M-CSF) or RANKL with or without TGFβ1. Tartrate-resistant acid phosphatase (TRAP) staining, as well as bone resorption assays, revealed that TGFβ1 suppressed RANKL-mediated human osteoclast development. Real-time reverse transcription PCR and Western blotting revealed that TGFβ1 reduced the gene and protein expression of nuclear factor of activated T cells, cytoplasmic 1 (NFATc1), the master regulator of osteoclast differentiation, respectively. Luciferase assays indicated that TGFβ1 inhibited the NF-κB p65-stimulated promoter activity of NFATc1. Immunofluorescence analysis demonstrated that TGFβ1 abrogated RANKL-induced nuclear translocation of p65. Thus, TGFβ1 regulates human RANKL-induced osteoclastogenesis via downregulation of NFATc1 by blocking nuclear translocation of NF-κB, suggesting that TGFβ1 may be a potential therapeutic target for RA.

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Mechanisms and therapeutic targets for bone damage in rheumatoid arthritis, in particular the RANK-RANKL system

Cited by 68 publications

References 64 publications

Molecular and Cellular Pathways Contributing to Joint Damage in Rheumatoid Arthritis

Molecular and Cellular Pathways Contributing to Joint Damage in Rheumatoid Arthritis

Predictors of new bone erosion in rheumatoid arthritis patients receiving conventional synthetic disease-modifying antirheumatic drugs: Analysis of data from the DRIVE and DESIRABLE studies

TGFβ1 Regulates Human RANKL-Induced Osteoclastogenesis via Suppression of NFATc1 Expression

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