Introduction: Matrix metalloproteinases (MMPs) are important in tissue remodelling. Here we investigate the role of collagenase-3 (MMP-13) in antibody-induced arthritis.
Methods: For this study we employed the K/BxN serum-induced arthritis model. Arthritis was induced in C57BL/6 wild type (WT) and MMP-13-deficient (MMP-13–/–) mice by intraperitoneal injection of 200 μl of K/BxN serum. Arthritis was assessed by measuring the ankle swelling. During the course of the experiments, mice were sacrificed every second day for histological examination of the ankle joints. Ankle sections were evaluated histologically for infiltration of inflammatory cells, pannus tissue formation and bone/cartilage destruction. Semi-quantitative PCR was used to determine MMP-13 expression levels in ankle joints of untreated and K/BxN serum-injected mice.
Results: This study shows that MMP-13 is a regulator of inflammation. We observed increased expression of MMP-13 in ankle joints of WT mice during K/BxN serum-induced arthritis and both K/BxN serum-treated WT and MMP-13–/– mice developed progressive arthritis with a similar onset. However, MMP-13–/– mice showed significantly reduced disease over the whole arthritic period. Ankle joints of WT mice showed severe joint destruction with extensive inflammation and erosion of cartilage and bone. In contrast, MMP-13–/– mice displayed significantly decreased severity of arthritis (50% to 60%) as analyzed by clinical and histological scoring methods.
Conclusions: MMP-13 deficiency acts to suppress the local inflammatory responses. Therefore, MMP-13 has a role in the pathogenesis of arthritis, suggesting MMP-13 is a potential therapeutic target.
Complement receptor type II/CD21 is the functional receptor for complement fragments such as C3d, iC3b and the Epstein Barr Virus. A soluble form of CD21 (sCD21) is shed from lymphocytes surface and is able to bind to its ligands found in the plasma. The amount of sCD21 in serum may modulate immunity as the plasma levels are correlated with autoimmune conditions, such as Systemic Lupus Erythematosus, Rheumatoid Arthritis and Sjoegren’s Syndrome. Because of the fact that pregnancy may lead to remission of autoimmune diseases we determined the serum levels of sCD21 during pregnancy and postpartum. The serum sCD21 levels during pregnancy are significantly lower as compared to that of the healthy controls. There were no significant differences in sCD21 levels between the mother and the cord blood also immediately after parturition. Restoration of sCD21 levels to normal values takes between 6 weeks and 1 year after childbirth. Our study indicates that CD21-shedding is affected during pregnancy comparable to that of autoimmunity.
A soluble form of the complement receptor CD21 (sCD21) is shed from the lymphocyte surface. The sCD21 is able to bind all known ligands such as CD23, sCD23, Epstein–Barr virus and C3d in immune complexes. Here, we show the serum levels of sCD21 in sera the of antiphospholipid syndrome (APS) patients. Antiphospholipid syndrome is an autoimmune disorder in which autoantibodies cause heart attack, stroke and miscarriage. Antiphospholipid syndrome may appear as primary or in association with systemic lupus erythromatosus (SLE) and other autoimmune diseases. Here, we ask whether APS patients have different sCD21 titers compared to healthy persons and whether sCD21 levels correlate with the presence of anti-β2-GPI autoantibodies. We show that autoimmune APS patients have significantly reduced amounts of sCD21 in their sera, irrespective of the presence of anti-β2-GPI autoantibodies. In our APS patients cohort additional SLE, vasculities, DVT (deep vein thrombosis), fetal loss or thrombosis did not correlate to the reduced level of sCD21.
A soluble form of CD21 (sCD21) and CD23 (sCD23) is released from the surface of human white blood cells upon shedding of the extracellular domain. sCD21 circulates in a complex with cleavage fragments of C3 and sCD23, which were previously identified as ligands of membrane and soluble CD21. sCD21 seems to be a marker of chronic inflammatory disease. To assess the sCD21 and sCD23 status in patients with subsets of juvenile arthritis (JA), we determined plasma levels sCD21 and sCD23. Plasma sCD21 levels were significantly decreased in all JA subtypes (O-JA P < 0.0068; P- and S-JA P < 0.0001) compared to healthy controls. Plasma sCD23 levels were significantly decreased in P-JA and S-JA (both P < 0.0001), but not in O-JA (P < 0.3843) in comparison with healthy controls, and data statistically analyzed. Our results suggest that pathological mechanisms relevant to autoimmune disorders interfere with the regulation of both CD21 and CD23 shedding.
A soluble form of the complement receptor CD21 (sCD21) is shed from the lymphocyte surface. The sCD21 is able to bind all known ligands such as CD23, sCD23, Epstein-Barr virus and C3d in immune complexes. Here, we show the serum levels of sCD21 in sera the of antiphospholipid syndrome (APS) patients. Antiphospholipid syndrome is an autoimmune disorder in which autoantibodies cause heart attack, stroke and miscarriage. Antiphospholipid syndrome may appear as primary or in association with systemic lupus erythromatosus (SLE) and other autoimmune diseases. Here, we ask whether APS patients have different sCD21 titers compared to healthy persons and whether sCD21 levels correlate with the presence of anti-β2-GPI autoantibodies. We show that autoimmune APS patients have significantly reduced amounts of sCD21 in their sera, irrespective of the presence of anti-β2-GPI autoantibodies. In our APS patients cohort additional SLE, vasculities, DVT (deep vein thrombosis), fetal loss or thrombosis did not correlate to the reduced level of sCD21.
Rheumatoid arthritis (RA) is characterized by the interaction of multiple mediators, among the most important of which are cytokines. In recent years, extensive studies demonstrate a pivotal role for one cytokine, macrophage migration inhibitory factor (MIF), in fundamental events in innate and adaptive immunity. MIF has now been demonstrated to be involved in the pathogenesis of many diseases, but in the case of RA the evidence for a role of MIF is very strong. MIF is abundantly expressed in the sera of RA patients and in RA synovial tissue correlating with disease activity. MIF-deficient mice were used to induce arthritis by serum transfer from K/BxN mice. K/BxN serum transfer arthritis was markedly attenuated in MIF(-) mice, with reduction in clinical index and histological severity as well as decrease in synovial cytokines. Macrophage transfers were done to investigate the specific role of macrophage-derived MIF. We show that adoptive transfer of wild-type macrophages into MIF(-) mice restores the sensitivity of MIF(-) mice to arthritis development, and this affect was associated with a restoration in serum IL-1? and IL-6 production. These results indicate that MIF plays a critical role in inflammation and joint destruction in K/BxN serum-induced arthritis and that the systemic expression of MIF by a subpopulation of macrophages is necessary and sufficient for the full development of arthritis.
