Investigation of ADAMTS9 and ADAMTS15 mRNA Expression Levels in Psoriasis and Psoriatic Arthritis Patients

Year 2023, , 94 - 99, 27.04.2023

Mehmet Ali Tekin , Sevgi İrtegün Kandemir

https://doi.org/10.35440/hutfd.1253551

Abstract

Background: In this study, we aimed to investigate the mRNA expression levels of ADAMTS9 and ADAMTS15 in peripheral blood mononuclear cells (PBMCs) of psoriasis (PsO) and psoriatic arthritis (PsA) patients and the effects of TNF-α/MAPK and IL-1β/NFkB signaling pathways on the regulation of the expression of these genes.
Materials and Methods: 15 PsO and 15 PsA patients and 15 healthy individuals (control) were included in the study. After PBMCs were isolated from venous blood, ADAMTS9 and ADAMTS15 mRNA expression levels were measured by Real-Time Quantitative PCR (RT-qPCR).
Results: It was found that ADAMTS9 mRNA expression in PBMCs did not change between groups, while the level of ADAMTS15 mRNA expression increased significantly in the PsA group compared to the control and PsO gro-ups. ADAMTS9 expression was observed not changed in the control and PsA groups in response to TNF-α stimula-tion, but decreased in the PsO group. However; TNF-α stimulation led to an increase in ADAMTS15 expression in the control group but did not change in the PsO and PsA groups. It has been revealed that the formation of TNF-α response and related changes in ADAMTS9 and ADAMTS15 expressions were regulated by MAP kinase genes (Erk1/2, p38 and JNK). ADAMTS9 expression was determined not affected by IL-1β stimulation, however; ADAMTS15 mRNA expression was decreased only in the PsA group. In addition, NFkB signaling molecule was involved in the formation of the IL-1β response and the regulation of ADAMTS15 expression.
Conclusions: ADAMTS15 expression increased in PBMCs of PsA patients is regulated by the IL-1β/NFkB signaling pathway. An increase in ADAMTS15 mRNA expressin level may play a role in PsA pathogenesis. Furthermore, the expression level of ADAMTS15 has a potential to be used as an important biomarker in monitoring the risk of PsA development for PsO patients.

Keywords

ADAMTS9, ADAMTS15, Psoriasis, Psoriatik Artrit

Project Number

(TÜBİTAK) 214S024 (DÜBAP) Tıp.16.024

Psoriasis ve Psoriatik Artrit Hastalarında ADAMTS9 ve ADAMTS15 mRNA Ekspresyon Düzeylerinin Araştırılması

Abstract

Amaç: Bu çalışmada, ADAMTS9 ve ADAMT15’ in psoriasis (PsO) ve psoriatik artrit (PsA) hastalarının periferik kan mononükleer hücrelerindeki (PBMC) mRNA ekspresyon düzeylerini ve bu genlerin ekspresyonlarının regülasyonunda TNF-α/MAPK ve IL-1β/NFkB sinyal yolaklarının etkilerini araştırmayı amaçladık.
Materyal ve metod: 15 PsO ve 15 PsA hastaları ile 15 sağlıklı birey (kontrol) çalışmaya dahil edildi. PBMC hücreleri venöz kandan izole edildikten sonra, ADAMTS9 ve ADAMTS15 mRNA ekspresyon düzeyleri Eş Zamanlı-Kantitatif qPCR (RT-qPCR) ile ölçüldü.
Bulgular: PBMC hücrelerinde ADAMTS9 mRNA ekspresyonunun gruplar arasında farklılık göstermediği, ADAMTS15 mRNA ekspresyon düzeyinin ise PsA grubunda kontrol ve PsO gruplarına oranla önemli bir artış gösterdiği bulunmştur. TNF-α stimülasyonu sonucu ADAMTS9 mRNA ekspresyonunun kontrol ve PsA gruplarında değişmediği, ancak PsO grubunda azalış gösterdiği gözlemlenmiştir. ADAMTS15 mRNA ekspresyonunun ise TNF-α stimülasyonu sonucu kontrol grubunda artış gösterdiği ancak PsO ve PsA gruplarında değişmediği saptanmıştır. TNF-α yanıtının oluşması ve buna bağlı ADAMTS9 ve ADAMTS15 mRNA ekpresyonundaki değişikliklerin MAP kinaz genleri (Erk1/2, p38 ve JNK) tarafından regüle edildiği ortaya konmuştur. IL-1β stimülasyonunun ADAMTS9 ekspresyonunda farklılık oluşturmadığı, ADAMTS15 mRNA ekspresyonunda ise sadece PsA grubunda azalmaya neden olduğu tespit edilmiştir. Ayrıca, IL-1β yanıtının oluşması ve ADAMTS15 ekspresyonun regülasyonunda NFkB sinyal molekünün etkili olduğu bulunmuştur.


Sonuç: PsA hastalarının PBMC hücrelerinde artış gösteren ADAMTS15 mRNA ekresyonu IL-1β/NFkB sinyal yolağı tarafından regüle edilmektedir. ADAMTS15 mRNA ekspresyon düzeyindeki artış PsA patogenezinde rol oynayabilir. Ayrıca, ADAMS15 mRNA ekspresyon düzeyinin PsO hastaları için PsA gelişim riskinin takibinde önemli bir biyobelirteç olarak kullanılabilme potansiyeli vardır.

Keywords

ADAMTS9, ADAMTS15, Psoriasis, Psoriatik Artrit

Supporting Institution

TÜBİTAK ve DÜBAP

Project Number

(TÜBİTAK) 214S024 (DÜBAP) Tıp.16.024

Thanks

Prof. Dr Kemal Nas, Prof Dr Remzi Çevik ve Prof. Dr. Bilal Sula’ ya hasta örneklerini sağlamadaki katkılarından dolayı teşekkür ederiz.

References

• 1. Boehncke WH, Schon M.P. Psoriasis. Lancet. 2015; 386: 983-94.
• 2. Gudjonsson JE, Elder JT. Psoriasis: epidemiology. Clin Derma-tol. 2007; 25(6): 535-46
• 3. Haberman R, Perez-Chada LM, Merola JF, Scher J, Ogdie A, Reddy SM. Bridging the Gaps in the Care of Psoriasis and Pso-riatic Arthritis: the Role of Combined Clinics. Curr Rheumatol Rep. 2018; 20(12): 76
• 4. Butt AQ, McArdle A, Gibson DS, FitzGerald O. Pennington SR. Psoriatic arthritis under a proteomic spotlight: application of novel technologies to advance diagnosis and management. Curr Rheumatol Rep. 2015; 17(5): 35
• 5. Veale DJ, Fearon U. The pathogenesis of psoriatic arthritis. Lancet. 2018; 391(10136): 2273-84.
• 6. Rose KWJ, Taye N, Karoulias SZ, Hubmacher D. Regulation of ADAMTS Proteases. Front. Mol. Biosci. 2021; 8: 701959. doi: 10.3389/fmolb.2021.701959
• 7. Apte SS. ADAMTS Proteins: Concepts, Challenges, and Pros-pects. Methods Mol. Biol. 2020; 2043: 1-12.
• 8. Mead TJ, Apte SS. ADAMTS proteins in human disorders. Matrix Biol. 2018; 71-72: 225–239.
• 9. Dancevic CM, McCulloch DR. Current and emerging therape-utic strategies for preventing inflammation and aggrecanase-mediated cartilage destruction in arthritis. Arthritis Res Ther. 2014; 16(5): 429
• 10. Zhong Y, Lu YT, Sun Y, Shi ZH, Li NG, Tang YP et al. Recent opportunities in matrix metalloproteinase inhibitor drug de-sign for cancer. Expert Opin Drug Discov. 2018; 13(1) 75–87. 11.
• 11. Mateen S, Zafar A, Moin S, Khan AQ, Zubair S. Understanding the role of cytokines in the pathogenesis of rheumatoid arth-ritis. Clin Chim Acta. 2016; 455: 161-171.
• 12. Tian Ye, Yuan W, Fujita N, Wang J, Wang H, Shapiro IM and Risbud MV. Inflammatory Cytokines Associated with Dege-nerative Disc Disease Control Aggrecanase-1 (ADAMTS-4) Expression in Nucleus Pulposus Cells through MAPK and NF-kB. Am J Pathol. 2013; 182(6): 2310-21
• 13. Ding X, Xiang W, Meng D, Chao W, Fei H, Wang W. Osteob-lasts Regulate the Expression of ADAMTS and MMPs in Chondrocytes through ERK Signaling Pathway. Z Orthop Un-fall. 2021; doi: 10.1055/a-1527-7900. Online ahead of print.
• 14. Chen L, Tang J, Feng Y, Li S, Xiang Q, He X et al. ADAMTS9 is Silenced by Epigenetic Disruption in Colorectal Cancer and Inhibits Cell Growth and Metastasis by Regulating Akt/p53 Signaling. Cell Physiol Biochem. 2017; 44(4):1370-80.
• 15. Julia A, Pinto JA, Gratacos J et al. A deletion at ADAMTS9-MAGI1 locus is associated with psoriatic arthritis risk. Ann. Rheu Dis. 2015; 74(10): 1875-81.
• 16. Molokwu CN, Adeniji OO, Chandrasekharan S, Hamdy FC, Buttle DJ. Androgen Regulates ADAMTS15 Gene Expression in Prostate Cancer Cells. Cancer Invest. 2010; 28(7): 698-710.
• 17. Binder MJ, McCoombe S, Williams ED, McCulloch DR, Ward AC. ADAMTS-15 Has a Tumor Suppressor Role in Prostate Cancer. Biomolecules. 2020; 10(5): 682.
• 18. Porter S, Span PN, Sweep FC, Tjan-Heijnen VC, Pennington CJ et al. ADAMTS8 and ADAMTS15 expression predicts survi-val in human breast carcinoma. Int J Cancer. 2006; 118(5): 1241-47.
• 19. Viloria CG, Obaya AJ, Moncada-Pazos A, Llamazares M, Astu-dillo A, Capella G. Genetic inactivation of ADAMTS15 metal-loprotease in human colorectal cancer. Cancer Res. 2009; 69(11): 4926-34.
• 20. Kelwick R, Wagsta L, Decock J, Roghi C, Cooley LS, Robinson SD et al. Metalloproteinase-dependent and -independent processes contribute to inhibition of breast cancer cell migra-tion, angiogenesis and liver metastasis by a disintegrin and metalloproteinase with thrombospondin motifs-15. Int J Cancer. 2015; 136: E14–E26.
• 21. Irtegun S, Pektanc G, Akkurt ZM, Bozkurt M, Turkcu FM and Kalkanli-Tas. Pharmacological Inactivation of Src Family Kina-ses Inhibits LPS-Induced TNF-𝛼 Production in PBMC of Pati-ents with Behçet’s Disease. Mediators of Inflamm. 2016; 2016: 5414369.
• 22. Kevorkian L, Young DA, Darrah C, Donell ST, Shepstone L et al. Expression Profiling of Metalloproteinases and Their Inhi-bitors in Cartilage. Arthritis Rheum. 2004; 50(1): 131-41.
• 23. Özler K. The utility of synovial fluid levels of ADAMTS9 and ADAMTS4 in predicting treatment responses to intraarticular steroid injections in patients with knee osteoarthritis. Turk J Med Sci. 2020; 50: 1330-36
• 24. Talpin A, Costantino F, Bonilla N, Leboime A, Letourneur F, Jacques S et al. Monocyte-derived dendritic cells from HLA-B27+ axial spondyloarthritis (SpA) patients display altered functional capacity and deregulated gene expression. Arthri-tis Res. Ther. 2014; 16:417.
• 25. Yamamoto K, Okano H, Miyagawa W, Visse R, Shitomi Y, Santamaria S et al. MMP-13 is constitutively produced in hu-man chondrocytes and co-endocytosed with ADAMTS-5 and TIMP-3 by the endocytic receptor LRP1. Matrix Biol. 2016; 56: 57-73.
• 26. Ohtsuki T, Asano K, Inagaki J, Shinaoka A, Kumagishi-Shinaoka K, Cilek ZM. High molecular weight hyaluronan pro-tects cartilage from degradation by inhibiting aggrecanase expression. J. Orthop. Res. 2018; 36: 3247-55.
• 27. Demircan K, Hirohata S, Nishida K, Hatipoğlu OF, Oohashi T, Yonezawa T et al. ADAMTS-9 is synergistically induced by in-terleukin-1β and tumor necrosis factor α in OUMS-27 chond-rosarcoma cells and in human chondrocytes. Arthritis Rheu-matol. 2005; 52: 1451-60.
• 28. He L, Pan Y, Yu J, Wang B, Dai G, Ying X. Decursin alleviates the aggravation of osteoarthritis via inhibiting PI3K-Akt and NF-kB signal pathway. Int. Immunopharmacol. 2021; 97: 107657.