Association of systemic and intra-articular osteoclastogenic potential, pro-inflammatory mediators and disease activity with the form of inflammatory arthritis.

PURPOSE: We aimed to assess osteoclastogenic potential of peripheral blood mononuclear cells (PBMC) and synovial fluid-derived mononuclear cells (SFMC) in different forms of arthritis and to correlate it with inflammatory mediators within intra-articular and circulatory compartments. METHODS: Paired PBMC and SFMC samples of patients with rheumatoid arthritis (RA; n = 10) and psoriatic arthritis (PsA; n = 10), and PBMC of healthy controls were cultured to assess osteoclastogenic potential by the number of tartrate-resistant acid phosphatase (TRAP)-positive osteoclasts (OCs) and expression of OC-related genes (receptor activator of nuclear factor-κΒ (RANK), cFMS, and TRAP). Osteoclastogenesis was correlated with the arthritis-related inflammatory indicators in serum and synovial fluid (SF). RESULTS: Number of OCs differentiated from PBMC was significantly higher in RA and PsA compared with control, with RA having more OCs compared with PsA. There was no difference in SFMC OC number between arthritic patients, but RANK expression in OCs differentiated from SFMC was higher in PsA compared with RA. SF of PsA patients more potently induced OC differentiation from control CD3(-)CD19(-)CD56(-)CD11b(+)CD115(+) PBMC compared with RA, paralleled with higher RANK-ligand expression in PsA SFMC. Positive correlations of OC number with erythrocyte sedimentation rate, serum level of CCL2, and PBMC gene expression of interleukin-18 and Fas-ligand were observed. CONCLUSION: Osteoclastogenic potential is systemically enhanced in patients with RA, paralleled by disordered systemic and local expression of proinflammatory mediators, whereas PsA involves specific deregulation in RANKL/RANK axis. Our study reveals arthritis-specific mediators associated with the form of arthritis, indicating clinical relevance for diagnosis and treatment.

Bone morphogenetic proteins regulate differentiation of human promyelocytic leukemia cells.

We investigated the role of bone morphogenetic proteins (BMPs) in suppression of all-trans retinoic acid (ATRA)-mediated differentiation of leukemic promyelocytes. In NB4 and HL60 cell lines, BMPs reduced the percentage of differentiated cells, and suppressed PU.1 and C/EBPε gene expression induced by ATRA. BMP and ATRA synergized in the induction of ID genes, causing suppression of differentiation. In primary acute promyelocytic leukemia bone-marrow samples, positive correlation of PML/RARα and negative of RARα with the expression of BMP-4, BMP-6 and ID genes were found. We concluded that BMPs may have oncogenic properties and mediate ATRA resistance by a mechanism that involves ID genes.

Influence of UV radiation on immunological system and occurrence of autoimmune diseases.

During the last three decades scientists worldwide have investigated how ultraviolet radiation (UVR) influences the immune system. The vast majority of the researchers was primarily focused on the local immunomodulatory role of UVR. But today evidence is increasing in favor of plural immune activation and systemic reaction of the organism. Most of the attention is directed toward the regulatory T lymphocytes which are responsible for the local and systemic immunosuppressive response under the impact of sunlight. The role of regulatory T cells in autoimmune diseases is well studied on patients with systemic lupus erythematosus (SLE). Epidemiological research shows a proportional interdependence of latitude and prevalence of autoimmune diseases such as multiple sclerosis (MS), insulin-dependent diabetes mellitus (IDDM) and rheumatoid arthritis (RA). There is evidence that UVR has direct influence on the level of antibodies against the SNF2-superfamily helicase (Mi-2), distinctive for dermatomyositis (DM). On this basis a hypothesis is established that UVR is a risk factor for DM. A Croatian epidemiologic study o f systemic sclerosis (SSc) gave results consistent with the hypothesis that there is a higher prevalence of SSc in the Mediterranean regions of Croatia. Such discoveries encouraged further studies that found that not only regulatory T cells are responsible for a systemic immunosuppressive response, but that there is a complex interactive network of immune cells and mediators such as cytokines, neuropeptides, and chromophores like urocanic acid involved. Present findings require continued research on the importance of UVR on autoimmune disease prevalence and immunopathophysiology. Finally, it is necessary to distinguish whether UVR is a protective factor for some autoimmune diseases or a risk factor for their induction.