Degenerative and inflammatory joint diseases lead to a destruction of the joint architecture. Whereas degenerative osteoarthritis results in the formation of new bone, rheumatoid arthritis leads to bone resorption. The molecular basis of these different patterns of joint disease is unknown. By inhibiting Dickkopf-1 (DKK-1), a regulatory molecule of the Wnt pathway, we were able to reverse the bone-destructive pattern of a mouse model of rheumatoid arthritis to the bone-forming pattern of osteoarthritis. In this way, no overall bone erosion resulted, although bony nodules, so-called osteophytes, did form. We identified tumor necrosis factor-alpha (TNF) as a key inducer of DKK-1 in the mouse inflammatory arthritis model and in human rheumatoid arthritis. These results suggest that the Wnt pathway is a key regulator of joint remodeling.

Active rheumatoid arthritis is characterized by originating from few but affecting subsequently the majority of joints. Thus far, the pathways of the progression of the disease are largely unknown. As rheumatoid arthritis synovial fibroblasts (RASFs) are key players in joint destruction and migrate in vitro, the current study evaluated the potential of RASFs to spread the disease in vivo. To simulate the primary joint of origin, healthy human cartilage was co-implanted subcutaneously into SCID mice together with RASFs. At the contralateral flank, healthy cartilage was implanted without cells. RASFs showed an active movement to the naïve cartilage via the vasculature independent of the site of application of RASFs into the SCID mouse, leading to a strong destruction of the target cartilage. These findings support the hypothesis that the characteristic clinical phenomenon of destructive arthritis spreading between joints is mediated, at least in part, by the transmigration of activated RASFs.

Apoptosis plays a pivotal role in tissue homoeostasis both under physiological and pathological conditions and several studies have shown that some characteristic changes in the composition and structure of the inflamed synovial membrane in rheumatoid arthritis (RA) are linked to an altered apoptotic response of synovial cells. As a result, a hyperplastic synovial tissue is generated that mediates the progressive destruction of articular cartilage and bone. In addition to inflammatory cells, these changes most prominently affect resident fibroblast-like cells that have been demonstrated to be of utmost importance for joint destruction. Once activated, these cells pass through prominent molecular changes resulting in an aggressive, invasive behaviour. Research of the past years has identified different mechanisms that prevent synovial cells in RA from apoptosis. They include changes in the mitochondrial pathway as well as altered expression of downstream modulators of death receptors and transcriptional regulators such as NFkappaB. This review summarises our recent progress in understanding aberrant apoptosis in the RA synovial membrane and points to possibilities of intervening specifically with this aspect of the pathogenesis of RA.

Objective. Activation of p38 MAPK is a key signaling step in chronic inflammation. Inhibition of p38 MAPK is considered to be a promising future strategy to control inflammatory diseases, but studies of compounds to inhibit this kinase have so far been limited to investigation of their side effects. We undertook the present study to investigate which specific molecule, among 4 different isoforms of p38 MAPK (␣, ␤, ␥, and ␦), is predominantly expressed and activated in inflammation. Such knowledge could allow more specific targeting of p38 MAPK in inflammatory disease.Methods. Studies were performed on inflamed tissue from patients with rheumatoid arthritis, as a prototype of inflammatory disease. The expression and activation of the ␣, ␤, ␥, and ␦ isoforms of p38 MAPK were examined by immunoblotting, immunoprecipitation, and immunohistochemistry.Results. Immunoblot analysis revealed that ␣ and ␥ were the predominantly expressed p38 MAPK isoforms, whereas the other 2 isoforms were less frequently present. By immunohistochemistry, the expression of all p38 MAPK isoforms was localized to the synovial lining layer as well as to blood vessels. Colabeling with cellspecific markers revealed that macrophages expressed the ␣ and ␥ isoforms, synovial fibroblasts the ␤ and ␥ isoforms, and granulocytes the ␦ isoform, whereas T lymphocytes were rarely positive for any p38 MAPK isoform. Double-labeling with isoform-specific antibody and pan-p38 antibody against the phosphorylated form of p38 MAPK showed activation of the ␣ and ␥ isoforms. Occasional activation of the ␤ isoform was also noted in the synovial lining and the endothelium, whereas the ␦ isoform, although expressed in pericytes around blood vessels, was not phosphorylated. This phosphorylation pattern was confirmed in immunoprecipitation studies in which activated p38 MAPK from synovial tissue extracts was identified as p38 MAPK␣ and -␥ but not p38 MAPK␤ or -␦.Conclusion. These data show that the ␣ and ␥ isoforms of p38 MAPK dominate in chronic inflammation. Effective strategies to inhibit p38 MAPK should therefore aim to specifically target either or both of these isoforms.The p38 MAPKs are members of a larger group of serine/threonine protein kinases, which allow the transduction of extracellular stress signals to the cell nucleus. MAPKs are reporters of changes in the extracellular milieu, which lead to cellular responses allowing adaptation to changed physiologic and pathologic circumstances. P38 MAPK is considered to be a common pathway of inflammatory stimuli such as tumor necrosis factor (TNF) and interleukin-1 (IL-1), as well as environmental stresses such as heat stress, osmotic shock, ultraviolet light, and cytotoxic chemicals (1,2). Thus, p38 MAPKs function as an "emergency switch" that allows a broad cellular response by turning on the target genes of transcription factors, cytokines, and their surface receptors. These proteins are therefore considered to be a

Conclusion. In addition to supporting the role of IFNs in SLE immunopathogenesis in general, the findings of the present study support a role of IFN␥ in this disease.Type I interferons (e.g., IFN␣) and type II IFN (IFN␥) have both been implicated in the immunopathogenesis of systemic lupus erythematosus (SLE). IFN␣ and IFN␥ serum levels are increased (1-5), and IFN messenger RNA (mRNA) signatures are expressed in the peripheral blood cells of SLE patients (6-8). IFN␣ and IFN␥ are known to induce SLE flares and druginduced lupus (9-11). In murine models of the disease, both IFN␣ and IFN␥ may be pathogenetically important (12-15), and, especially, a deficiency in either IFN␥ or the IFN␥ receptor (IFN␥R) totally abates the disease process (16)(17)(18)(19).IFNs act on a variety of cells, including lymphocytes and monocytes (20,21). The biologic effects of IFN␣ and IFN␥ are mediated via the phosphorylation, and thus the activation, of members of the STAT family