Joint Destruction In RA Patients Research Articles

Monocytic MDSCs skew Th17 cells toward a pro-osteoclastogenic phenotype and potentiate bone erosion in rheumatoid arthritis.

While myeloid-derived suppressor cells (MDSCs) were previously shown to promote a proinflammatory T helper (Th) 17 response in autoimmune conditions, a potential impact of the MDSC-Th17 immune axis on abnormal bone destruction in RA remains largely unknown. We investigated the correlation between the frequency of MDSCs or its subsets and joint destruction in RA patients. The reciprocal actions of patient-derived MDSCs and Th17 cells were studied using osteoclast (OC) differentiation and bone resorption assays in vitro, which were further validated using mouse models of RA. Contribution of MDSCs to osteoclastogenesis and bone erosion in vivo was determined by depletion or transfer of MDSCs. Human MDSCs, particularly monocytic MDSCs (M-MDSCs), exhibit inherent OC-differentiating capacity and positively correlate with clinical bone erosion in RA patients. Strikingly, patient-derived M-MDSCs can program Th17 cells towards a pro-osteoclastogenic phenotype, which in return potentiates OC differentiation via the receptor activator of nuclear factor κΒ ligand (RANK-L)-RANK signalling. This enhanced osteolysis driven by the reciprocal actions of M-MDSCs and Th17 cells is further confirmed using mouse models of RA. Selective depletion of M-MDSCs significantly ameliorates osteoclastogenesis and disease severity in arthritic mice, whereas transfer of M-MDSCs aggravates bone erosion associated with increased OCs in recipient mice. Our findings highlight the functional plasticity of MDSCs and identify a novel pro-osteoclastogenic pathway governed by interplay between myeloid cells and T lymphocytes in autoimmune RA.

Clinically relevant radiographic progression in joint destruction in RA patients with abnormal MMP-3 or high levels of CRP despite 1-year treatment with infliximab

Objective: Identify the independently related factors of joint destruction progression in RA patients despite of infliximab treatment.Methods: The subjects were cases who underwent infliximab treatment for one year or longer in our department (n = 244). Patients in which modified total sharp score (mTSS), joint erosion (JE), and joint space narrowing (JSN) had advanced to the standard value (3.0) or more for one year were defined as mTSS- Clinically-Relevant-Rapid Progression (CRRP) (n = 20), JE-CRRP (n = 20), and JSN-CRRP (n = 23), and the respective related factors at baseline and week 54 were defined by multiple logistic regression.Results: The median disease duration was 24 months and median mTSS 9.0 at baseline. The median DAS28, CRP, and yearly progression of mTSS improved from 5.8 to 2.6, 1.2 to 0.1 mg/dL, and 4.4 to 0.0 point/year, respectively. The related factor in each of mTSS-CRRP, JE-CRRP, and JSN-CRRP was high CRP levels at baseline. At week 54, the related factor of mTSS-CRRP and JSN-CRRP was high MMP-3 titer; however, the related factor of JE-CRRP was high CRP levels.Conclusion: High CRP levels at baseline were an independent predictive factor of joint destruction advancement during infliximab treatment. Moreover, it was believed that abnormal MMP-3 at week 54 was the index for mTSS and JSN advancement, while high CRP levels were the index for JE advancement.

Inhibitor of DNA binding/differentiation 2 induced by hypoxia promotes synovial fibroblast–dependent osteoclastogenesis

To map hypoxic areas in arthritic synovium and to establish the relevance of low oxygen levels to the phenotype of synovial fibroblasts, with special focus on bone degradation. To analyze the distribution of hypoxia in arthritic joints, the hypoxia marker EF5 was administered to mice with collagen-induced arthritis (CIA). To evaluate the effect of hypoxia on rheumatoid arthritis synovial fibroblasts (RASFs), reverse suppression subtractive hybridization and complementary DNA array were used. Real-time polymerase chain reaction, Western blotting, and immunohistochemistry were used to evaluate the expression of inhibitor of DNA binding/differentiation 2 (ID-2). To investigate the function of ID-2 in RASFs, cells were transfected either with ID-2 vector or with ID-2-specific small interfering RNA. EF5 staining showed the presence of hypoxia in arthritic joints, particularly at sites of synovial invasion into bone. Differential expression analysis revealed that ID-2 was strongly induced by hypoxia in RASFs. Immunohistochemical analysis of CIA mouse synovium and human RA synovium showed a strong expression of ID-2 by RASFs at sites of synovial invasion into bone. Overexpression of ID-2 in RASFs significantly induced the expression of several factors promoting osteoclastogenesis. The biologic relevance of the potent osteoclastogenesis-promoting effects was shown by coculture assays of ID-2-overexpressing RASFs with bone marrow cells, leading to an increased differentiation of osteoclasts from bone marrow precursors. The data show that hypoxic conditions are present at sites of inflammation and synovial invasion into bone in arthritic synovium. Hypoxia-induced ID-2 may contribute to joint destruction in RA patients by promoting synovial fibroblast-dependent osteoclastogenesis.

Reduction of cartilage destruction in a rapid progressive arthritis model in SCID mice

Fibroblasts are considered to be a crucial cell population for disease progression, as well as joint destruction in rheumatoid arthritis. Recent data underline the potency of rheumatoid synovial fibroblast-like cells to induce the destruction of cartilage and bone, e.g. following intra-articular injection into SCID mice. We have isolated a fibroblastoid cell line by co-cultivation of human rheumatoid fibroblasts with murine fibroblasts. The generated cell line exhibits characteristics of rheumatoid fibroblasts and genetic alterations indicating a transformed phenotype. These cells have been shown to induce a rapid destruction of articular cartilage following intra-articular instillation. Fibroblastoid cells (LS48) were examined for cytogenetic characteristics, morphology, surface molecules, cytokine secretion, and functional parameters. 500,000 cells were injected directly into SCID mouse knee joints to induce cartilage destruction. Mice were monitored for joint swelling, serological parameters and by radiological methods. Furthermore, the effects of immunosuppressive drugs such as cyclosporine A, methotrexate, and FK 506 were investigated in this model. In addition, transfection of LS48 was performed with IL-11 as well as IL-15 prior to arthritis induction to investigate influence on cartilage destruction. Finally, the histology of cartilage destruction was explored. LS48 shows characteristics of a fibroblast-like cell but is of murine origin. Secretion of matrix metalloproteinases 3,9 and 13 as well of inter-leukine-6 and tumor necrosis factor revealed similarities to human invasive rheumatoid synovial membrane fibroblasts. Rapid progressive cartilage destruction within 10 days was induced by instillation into SCID mouse knee joints. Morphology revealed invasion of fibroblast-like cells into the articular cartilage. Destruction could be reduced by methotrexate but not by cyclosporineA or FK506, indicating a fibroblast-directed action of methotrexate connected to reduction of joint destruction in RA patients. Transfection with cytokines did not act on cartilage destruction, but IL-11 reduced apoptosis of chondrocytes. Induction of cartilage destruction by intra-articular application of murine fibroblast-like cells, in particular LS48, is a rapid and highly reproducible model for investigating invasive arthritis and can be modulated by drugs or gene transfer. This provides the opportunity to check novel therapeutic strategies for the treatment of arthritis, especially focussing on the reduction of cartilage erosion.