Molecular signatures and new candidates to target the pathogenesis of rheumatoid arthritis.

Rheumatoid arthritis (RA) is a chronic, inflammatory joint disease of unknown etiology and pronounced interpatient heterogeneity. To characterize RA at the molecular level and to uncover pathomechanisms, we performed genome-wide gene expression analysis. We identified a set of 1,054 genes significantly deregulated in pair-wise comparisons between RA and osteoarthritis (OA) patients, RA and normal donors (ND), or OA and ND. Correlation analysis revealed gene sets regulated identically in all three groups. As a prominent example secreted phosphoprotein 1 (SPP1) was identified to be significantly upregulated in RA compared with both OA and ND. SPP1 expression was found to correlate with genes expressed during an inflammatory response, T-cell activation and apoptosis, suggesting common underlying regulatory networks. A subclassification of RA patients was achieved on the basis of proteoglycan 4 (PRG4) expression, distinguishing PRG4 high and low expressors and reflecting the heterogeneity of the disease. In addition, we found that low PRG4 expression was associated with a more aggressive disease stage, which is in accordance with PRG4 loss-of-function mutations causing camptodactyly-arthropathy-coxa vara-pericarditis syndrome. Altogether we provide evidence for molecular signatures of RA and RA subclasses, sets of new candidate genes as well as for candidate gene networks, which extend our understanding of disease mechanisms and may lead to an improved diagnosis.

[Differential diagnosis of chronic synovitis]. / Differenzialdiagnostik der chronischen Synovialitis.

This review presents an algorithm for the standardised histopathological diagnostics of synovial biopsies and synovectomy specimens. In general, changes of the synovium can be inflammatory or non-inflammatory. To the latter group belong certain benign tumors such as the diffuse variant of the tenosynovial giant cell tumor, lipoma or synovial chondromatosis, additionally the rare group of storage diseases should be kept in mind. Inflammatory diseases can be discriminated into crystal-induced arthropathies such as gout and pseudogout, into granulomatous diseases such as tuberculosis, sarcoidosis and foreign-body inoculation, and into the large group of non-granulomatous synovitis. This group is by far the most common, and it often causes difficulties in assigning the histopathological findings to a concrete diagnosis. Therefore, the synovitis-score should be applied as a diagnostic device in these cases, leading to the diagnosis of a low-grade synovitis (which is associated with degenerative arthropathies) or of a high-grade synovitis (associated with rheumatic diseases), the sensitivity and specificity being 60.5% and 95.5%, respectively.

Emerging strategies of bone and joint repair.

The advances in biomedicine over the past decade have provided revolutionary insights into molecules that mediate cell proliferation and differentiation. Findings on the complex interplay of cells, growth factors, matrix molecules and cell adhesion molecules in the process of tissue patterning have vitalized the revolutionary approach of bioregenerative medicine and tissue engineering. Here we review the impact of recent work in this interdisciplinary field on the treatment of musculoskeletal disorders. This novel concept combines the transplantation of pluripotent stem cells, and the use of specifically tailored biomaterials, arrays of bioactive molecules and gene transfer technologies to direct the regeneration of pathologically altered musculoskeletal tissues.

[Role of cytokines and growth factors in joint destruction processes]. / Papel de las citocinas y factores de crecimiento en los procesos de destrucción articular.

Cytokines and growth factors are important mediators of inflammatory reactions and play a central role in the physiologic regulation of bone and cartilage cell activities and in joint destruction. The net effects of cytokines on target tissues depend on the relative pericellular concentrations of several cytokines and their inhibitors in the inflammatory tissue. It is possible to suppress the effects of cytokines with natural or synthetic inhibitory molecules. The measurement of cytokines and their inhibitors may be useful to understand the pathogenesis and to develop new therapies for inflammatory joint diseases. In this review the following cytokines will be reviewed: interleukin 1 and its inhibitor, tumor necrosis factor alpha and its inhibitor, interleukin 6, interferon gamma, transforming growth factor beta, colony-stimulating factors, fibroblast growth factors, platelet derived growth factor and prostaglandins.