Grafting of fibroblasts isolated from the synovial membrane of rheumatoid arthritis (RA) patients induces chronic arthritis in SCID mice-A novel model for studying the arthritogenic role of RA fibroblasts in vivo.

The objective of this study was to verify whether isolated rheumatoid arthritis (RA) synovial fibroblasts induce chronic arthritis in SCID mice, in analogy to whole tissue pieces. Fibroblasts were isolated from the synovial membrane of four RA patients (or controls) by out-growth and repeated-passage culture. Following flow-cytometry characterization, 2x10(6)cells were transferred into the left knee joint of SCID mice. The development of arthritis was assessed by joint swelling and histological changes. Human and murine cytokines were measured in vitro in co-cultures (or Transwelltrade mark systems) of human and murine cells. Purified RA synovial fibroblasts, but not healthy synovial or skin fibroblasts, induced hu/mu arthritis within 6 weeks. In-vitro secretion of murine and human interleukin(IL)-6, as well as murine tumour necrosis factor (TNF)-alpha, indicated cross-activation between murine macrophages and human RA fibroblasts. Soluble-factor mechanisms proved more effective than cell-contact mechanisms. Purified RA fibroblasts can, alone, induce hu/mu SCID arthritis. The cytokine profile suggests that xenogeneic interaction between human fibroblasts and murine macrophages may determine the sequence of events leading to hu/mu arthritis.

Systemic characteristics of chronic arthritis induced by transfer of human rheumatoid synovial membrane into SCID mice (human/murine SCID arthritis).

Erosive human/murine (hu/mu) SCID arthritis, caused by unilateral engrafting of human rheumatoid arthritis synovial membrane (RA-SM) in the knee joints of SCID mice, was monitored for up to 18 weeks by scintigraphic, radiological, morphological and immunohistochemical analyses.(99m)Tc-DPD scintigraphy and histology revealed secondary, oligoarticular spreading of arthritis to contralateral knees and hips, but not to forelimb joints. Also, there were no extraarticular manifestations. At 18 weeks, surviving human cells were found within the pannus, but not directly at the cartilage erosion front, where fibroblast-like cells and macrophages of murine origin predominated. The latter cells also predominated in secondarily affected joints, where no human cells were detectable. Preventive depletion of murine NK-cells by anti-asialo-GMI antibodies, to check the influence of NK cells independently of strain and MHC system, combined with application of autologous human PBMN cells, had virtually no effects on the disease process. The completeness of the SCID defect was not critical, i.e. T cells were completely absent in the organs examined, and the presence of a few B cells in the spleen did not correspond to particular disease features. The SCID defect itself had a clear impact, since, in the chronic phase, SCID.bg and RAG-2(-/-)knockout mice developed less consistent pathological/scintigraphic signs of disease than SCID mice. Thus, unilaterally-induced hu/mu SCID arthritis is an oligoarticular disorder of the hindlimbs. Murine macrophages and fibroblast-like cells appear responsible for tissue destruction in engrafted and non-engrafted arthritic joints.

Anti-inflammatory effects of systemic anti-tumour necrosis factor alpha treatment in human/murine SCID arthritis.

OBJECTIVES: To evaluate in vivo the contribution of tumour necrosis factor alpha (TNFalpha) to the chimeric transfer model of human rheumatoid arthritis synovial membrane into SCID mice (hu/mu SCID arthritis), systemic anti-TNFalpha treatment was performed and the clinical, serological, and histopathological effects of this treatment assessed. METHODS: Animals were treated with the rat-antimouse TNFalpha monoclonal antibody V1q, starting on day 1 after hu/mu engraftment, twice weekly for 12 weeks. Joint swelling, serum concentrations of human and murine interleukin 6 (IL6), and serum amyloid P (SAP) were measured. Histopathological and immunohistochemical analyses of the joints were also performed at the end of treatment. RESULTS: Neutralisation of murine TNFalpha induced the following effects: (a) reduction of extent and duration of the acute arthritis phase, with significant reduction of joint swelling at two weeks; (b) decrease of murine SAP concentrations after the first antibody administration; and (c) increase of murine IL6 in the serum. At the end of treatment, there was a significant reduction of the inflammatory infiltration in the engrafted joints. Because of the mild degree of joint erosion, no treatment effects could be demonstrated on the destructive process. CONCLUSION: In the lymphocyte independent hu/mu SCID arthritis, anti-TNFalpha treatment reduces local and systemic signs of inflammation.

Functional and structural changes in m. vastus lateralis and m. vastus medialis in cases of meniscopathy and chondropathia patellae.

The skeletal muscle undergoes selective cellular changes in the sense of the myopathic and neurogeneous tissue syndrome, in the case of degenerative joint diseases. The occurring FT-fibre atrophy is coupled with a decrease of the glycolytic activity and of the LDH isoenzyme pattern. A neurogeneous component is under discussion.

[Morphological and biochemical changes in the pars obliqua of the vastus medialis muscle in degenerative disorders of the knee joint]. / Morphologische und biochemische Veränderungen in der Pars obliqua m. vastus medialis bei degenerativen Erkrankungen des Kniegelenkes.

Using 34 muscle specimens from the pars obliqua of the vastus medialis muscle of patients with a clinically manifest patellar chondropathy and of those suffering from a gonarthrosis in various positions (cut biopsies under operation), we depicted the slow-twitch (ST) and the fast-twitch (FT) fibres histochemically and ascertained morphometrically the fibre distribution, the areas of the FT- and the ST-fibres as well as the relative fibre volume of the FT-fibres. Furthermore, we determined biochemically the total activity of the enzymes PGK and of the MDH, according to Bergmeyer (1970). By means of the electrophoresis, we determined the isoenzyme pattern of the LDH from simultaneously cut material (Agar-Agarose technique). The mathematical date processing was made by means of the cluster- und discriminance analysis. The results show that the "rule member" (pars obliqua m. vast. med.)--in order to maintain the orthograde gliding motion of the patella in the course of the development of degenerative joint illness--experiences extreme structural and biochemical changes caused by modifications within the neuromuscular motor control pattern. This becomes evident by a FT-hypertrophy at the beginning of the intraarticular disorders and by the increasing development of the "neurogeneous tissue syndrome" with partly fascicular FT-atrophy in cases of progressive degenerative joint processes.