Investigation of the roles and molecular mechanisms of ADAMTS-8, ADAMTS-9, ADAMTS-15 genes in the pathogenesis of psoriatic arthritis

Aim of this study is to investigate the roles of ADAMTS8, -9 and- 15 aggrecanases, which are known to play roles in matrix destruction, in the pathogenesis of Psoriatic Arthritis (PsA), a chronic inflammatory disease, and which mediators involved in inflammatory signaling pathways regulate the expression level of these aggrecanases. 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 ADAMTS15 in PBMCs of PsA group was increased, but the expression levels of ADAMTS 8 and -9 did not change. The expression of ADAMTS8in in PBMCs of Ps group was increased. The expression of ADAMTS15 was increased by TNF-α stimulation, while the expression of ADAMTS8 and -9 were not changed in PBMCs of control group. Furthermore, it was determined that the mRNA expression levels of ADAMTS8, -9 and -15 mRNA were not changed by the IL-1β and IL-6 stimulations. The expression of ADAMTS8 and -9 in Ps group were decreased as a result of TNF-α, IL-1β and IL-6 stimulations; however, ADAMTS15 expression was not changed by these stimulations. It was found that there was no significant difference at the expression level of ADAMTS9 in PsA group after the TNF-α, IL-1β and IL-6 stimulations, whereas ADAMTS15 expression was decreased only by IL-1β stimulation. Moreover, it was observed that TNF-α and IL-1β simulations led to an increase in ADAMTS8 expression, while IL-6 stimulation did not alter the ADAMTS8 exipression. It was determined that the ADAMTS8, -9 and -15 mRNA expression levels were increased as a result of JNK, STAT3 and NFKB inhibitions in the control group. Furthermore, the expression levels of ADAMTS8 and -15 were decreased after ERK1/2 and p38 inhibitions, but there was no significant difference at the ADAMTS9 expression level. It was determined that the expression levels of ADAMTS8 and -9 in Ps group were decreased by ERK1/2, p38 and JNK inhibition, and ADAMTS15 expression was not changed by these inhibition. Additionaly, it was found that ADAMTS8 expression was increased by STAT3 inhibition, whereas the expression of ADAMTS9 was decreased and ADAMTS15 expression did not change. On the other hand, the expression of ADAMTS9 and -15 in Ps and PsA group were increased by NFKB inhibition, while ADAMTS8 expression was decreased. It was determined that the expression of ADAMTS9 in PsA group was increased by ERK1/2, p38 and JNK inhibitions, while ADAMTS8 expression was decreased and there was no significant difference at the ADAMTS15 expression level. STAT3 inhibition resulted in an increase in the expression of ADAMTS8 and -9, but ADAMTS15 expression was not changed by STAT3 inhibition. Conclusion: We found that the expression of ADAMTS8 and -9 were not changed in PBMCs of the patients with PsA, which is consistent with the literature findings about other arthritic derivatives. The increased expression of the ADAMTS15 gene suggests that this enzyme may be associated with the development of arthritis in PsA patients. Furthermore, we found that MAPK and NFkB signaling pathways may have regulatory effects on ADAMTS8 and -9 mRNA expression in the pathogenesis of PsA. We also showed that STAT3 signaling pathway could regulate the ADAMTS family aggrecaneses' activities with different regulatory mechanisms.