Investigation of the roles and molecular mechanisms with adamts ( -1,-4,-5 ) genes in the pathogenesis of psoriatic arthritis

Aim: Our aim is to investigate the roles of ADAMTS proteases (ADAMTS-1, -4 and -5), which have important roles in articular destruction in the pathogenesis of Psoriatic Arthritis (PsA), which is a chronic inflamatuar disease and which mediators involved in inflammatory signaling pathways regulate these proteases. Method: Peripheral blood mononuclear cells (PBMCs) were isolated from total blood obtained from 15 PsA patients, 15 Psoriasis (Ps) patients and 15 healthy individuals and their primary culture have been done. The mRNA expression levels of ADAMTS8, -9 and -15 genes in PBMCs were measured by qPCR. After the stimulation of the cultured PBMC by TNF-α, IL-1β and IL-6, the mRNA expression levels of ADAMTS genes in the stimulated PBMC were determined by qPCR. Furthermore, PBMCs have been treated by mitogen-activated protein kinases (MAPK), transcription factor nuclear factor kappa B (NFkB) and signal transducer and activator of transcription 3 (STAT3) inhibitors before the stimulation with TNF-α, IL-1β and IL-6 and the expression of ADAMTS genes whether are regulated by MAPK (ERK1/2, p38, JNK), NFkB and STAT3 mediators in pro-inflammatory signaling pathways were examined by qPCR. Moreover, the effects of the inhibitors on the activities of MAPK (ERK1/2, p38, JNK), NFkB and STAT3 were determined by Western Blot. Results: It was found that the expression of ADAMTS1 and -4 in the PBMCs of PsA group were increased, but there was no any significant change in the expression levels of ADAMTS5. While stimulations by TNF-α and IL-6 caused a decreaase in the expression of ADAMTS1, -4 and -5, stimulation by IL-1β caused a reduction only in the expression of ADAMTS1 and -4. However, it was observed that the expression of ADAMTS5 was not changed by IL-1β stimulation. Morover, it was determined that inhibition of the p38, JNK and STAT3 resulted in a decline in the expression level of ADAMTS1. On the other hand, while the expression levels of ADAMTS5 was decreased by inhibition of NFκB, ERK1/2 and JNK, the expression of the ADAMTS5 was not influenced by inhibition of STAT3. Moreover, it was seen that STAT3 and NFkB inhibitors led to a reduction in the expression of ADAMTS4. xvi However, JNK inhibition in the control group, and ERK1/2, p38 and JNK inhibition in the Ps group led to a significant increase in the expression of ADAMTS1 expression. It was also observed that STAT3 and NF-κB inhibition resulted in an increase in the expression level of ADAMTS1 in both control and Ps groups. Conclusion: As observed in the literature of other arthritis types, the expression of ADAMTS1 and -4 in PBMC cells of PsA patients were increased compared to Ps and control groups, but ADAMTS5 expression did not change. These results suggest that ADAMTS1 and -4 genes may be effective aggrecanases in the degradation of extra cellular matrix (ECM) in PsA disease. It was determined that the expression of ADAMTS1 and -4 in PBMCs of the patients with PsA were decreased by TNF-α , IL-6 ve IL-1β stimulation. The expression of ADAMTS5 was also decreased by TNF-α ve IL-6 stimulation. These findings imply that TNF-α and IL-6 stimulations may have suppressive effects on the activity of ADAMTS1, -4 and -5 aggrecaneses. Furthermore, it was observed that MAPK and NFkB signaling pathways may have modulator effects on ADAMTS1, -4 ve -5 in the pathogenesis of PsA. Keywords : PsA, ADAMTS, PBMC, qPCR, biomarkers.