Matrine induces the apoptosis of fibroblast-like synoviocytes derived from rats with collagen-induced arthritis by suppressing the activation of the JAK/STAT signaling pathway

Yang,Yongsheng; Dong,Qiumei; Li,Rongheng

doi:10.3892/ijmm.2016.2843

Matrine induces the apoptosis of fibroblast-like synoviocytes derived from rats with collagen-induced arthritis by suppressing the activation of the JAK/STAT signaling pathway

Authors:
- Yongsheng Yang
- Qiumei Dong
- Rongheng Li
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Affiliations: Department of the Combination of Chinese and Western Medicine, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, P.R. China, College of Traditional Chinese Medicine, Inner Mongolia Medical University, Hohhot, Inner Mongolia 010000, P.R. China
Published online on: December 29, 2016 https://doi.org/10.3892/ijmm.2016.2843
Pages: 307-316
Copyright: © Yang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

The induction of apoptosis-resistant rheumatoid synovial tissue cells has been related to constitutively active Janus kinase/signal transducers and activators of transcription (JAK/STAT) signaling in rheumatoid arthritis (RA). The excessive proliferation and inherent resistance to apoptosis of fibroblast-like synoviocytes (FLS) is an important mechanism by which RA originates. However, the effects of matrine on FLS in RA is unclear. The present study aimed to investigate the mechanism of action of matrine in a rat model of collagen‑induced arthritis (CIA). The CIA model was established using bovine type II collagen. FLS were isolated from control and CIA rats, cultured in vitro, and confirmed to harbor fibroblast‑like characteristics. After treatment of FLS with varying concentrations of matrine, the JAK2 inhibitor AG490, or a combination of both drugs, cell proliferation, apoptosis rate, expression of apoptotic markers and the activation of the JAK/STAT pathway were assessed. Additionally, CIA rats were administered either matrine or methotrexate by oral gavage to examine the effects of therapeutic intervention on arthritis pathogenesis. The arthritis index (AI) was measured and ankle joint structure was analyzed histologically to determine the severity of CIA. Furthermore, expression levels of apoptotic markers and members of the JAK/STAT family were also examined in vivo. Compared with the CIA group, matrine reduced AI and improved ankle pathology. Matrine also inhibited FLS proliferation, induced G0/G1 cell cycle arrest, and increased the rate of apoptosis in vitro. The effects of matrine on apoptosis induction were further confirmed by observations that Bcl-2 levels were decreased, whereas Bax and caspase-3 levels were increased in the matrine-treated synovial tissues and FLS. Finally, matrine treatment also diminished the phosphorylation, and hence activation of JAK2, STAT1 and STAT3. Our results suggest that matrine induces the apoptosis of FLS from rats with CIA by inhibiting activation of the JAK/STAT signaling pathway.

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1	Zhang W, Zhu J, Du Z, Yu J, Xu Y and Wang F: Intraarticular gene transfer of SPRY2 suppresses adjuvant-induced arthritis in rats. Appl Microbiol Biotechnol. 99:6727–6735. 2015. View Article : Google Scholar : PubMed/NCBI
2	Liu H, Yang Y, Cai X, Gao Y, Du J and Chen S: The effects of arctigenin on human rheumatoid arthritis fibroblast-like synoviocytes. Pharm Biol. 53:1118–1123. 2015. View Article : Google Scholar : PubMed/NCBI
3	Tamai M, Kawakami A, Tanaka F, Miyashita T, Nakamura H, Iwanaga N, Izumi Y, Arima K, Aratake K, Huang M, et al: Significant inhibition of TRAIL-mediated fibroblast-like synovial cell apoptosis by IFN-gamma through JAK/STAT pathway by translational regulation. J Lab Clin Med. 147:182–190. 2006. View Article : Google Scholar : PubMed/NCBI
4	Zong M, Lu T, Fan S, Zhang H, Gong R, Sun L, Fu Z and Fan L: Glucose-6-phosphate isomerase promotes the proliferation and inhibits the apoptosis in fibroblast-like synoviocytes in rheumatoid arthritis. Arthritis Res Ther. 17:1002015. View Article : Google Scholar : PubMed/NCBI
5	Huang M, Zeng S, Qiu Q, Xiao Y, Shi M, Zou Y, Yang X, Xu H and Liang L: Niclosamide induces apoptosis in human rheumatoid arthritis fibroblast-like synoviocytes. Int Immunopharmacol. 31:45–49. 2016. View Article : Google Scholar
6	Coskun M, Salem M, Pedersen J and Nielsen OH: Involvement of JAK/STAT signaling in the pathogenesis of inflammatory bowel disease. Pharmacol Res. 76:1–8. 2013. View Article : Google Scholar : PubMed/NCBI
7	Seavey MM and Dobrzanski P: The many faces of Janus kinase. Biochem Pharmacol. 83:1136–1145. 2012. View Article : Google Scholar : PubMed/NCBI
8	Ghoreschi K, Laurence A and O'Shea JJ: Selectivity and therapeutic inhibition of kinases: to be or not to be? Nat Immunol. 10:356–360. 2009. View Article : Google Scholar : PubMed/NCBI
9	Kim SK, Park KY, Yoon WC, Park SH, Park KK, Yoo DH and Choe JY: Melittin enhances apoptosis through suppression of IL-6/sIL-6R complex-induced NF-κB and STAT3 activation and Bcl-2 expression for human fibroblast-like synoviocytes in rheumatoid arthritis. Joint Bone Spine. 78:471–477. 2011. View Article : Google Scholar : PubMed/NCBI
10	Kasperkovitz PV, Verbeet NL, Smeets TJ, van Rietschoten JG, Kraan MC, van der Pouw Kraan TC, Tak PP and Verweij CL: Activation of the STAT1 pathway in rheumatoid arthritis. Ann Rheum Dis. 63:233–239. 2004. View Article : Google Scholar : PubMed/NCBI
11	Krause A, Scaletta N, Ji JD and Ivashkiv LB: Rheumatoid arthritis synoviocyte survival is dependent on Stat3. J Immunol. 169:6610–6616. 2002. View Article : Google Scholar : PubMed/NCBI
12	Wang H, Fang Y, Wang Y, Wang Z, Zou Q, Shi Y, Chen J and Peng D: Inhibitory effect of curcumol on Jak2-STAT signal pathway molecules of fibroblast-like synoviocytes in patients with rheumatoid arthritis. Evid Based Complement Alternat Med. 2012:7464262012.PubMed/NCBI
13	Culshaw S, McInnes IB and Liew FY: What can the periodontal community learn from the pathophysiology of rheumatoid arthritis? J Clin Periodontol. 38(Suppl 11): 106–113. 2011. View Article : Google Scholar : PubMed/NCBI
14	Lee WS, Lim JH, Sung MS, Lee EG, Oh YJ and Yoo WH: Ethyl acetate fraction from Angelica sinensis inhibits IL-1β-induced rheumatoid synovial fibroblast proliferation and COX-2, PGE2, and MMPs production. Biol Res. 47:412014. View Article : Google Scholar
15	Xin W, Huang C, Zhang X, Xin S, Zhou Y, Ma X, Zhang D, Li Y, Zhou S, Zhang D, et al: Methyl salicylate lactoside inhibits inflammatory response of fibroblast-like synoviocytes and joint destruction in collagen-induced arthritis in mice. Br J Pharmacol. 171:3526–3538. 2014. View Article : Google Scholar : PubMed/NCBI
16	Wu Y, Wang Y, Zhang Y, Chen LP and Wang JY: Effect of matrine on NO and ADMA metabolism pathways in serum and tissues of mice with lipopolysaccharide-induced intestine tissue inflammation. Zhongguo Zhong Yao Za Zhi. 39:2318–2321. 2014.In Chinese. PubMed/NCBI
17	Yang N, Han F, Cui H, Huang J, Wang T, Zhou Y and Zhou J: Matrine suppresses proliferation and induces apoptosis in human cholangiocarcinoma cells through suppression of JAK2/STAT3 signaling. Pharmacol Rep. 67:388–393. 2015. View Article : Google Scholar : PubMed/NCBI
18	Sun N, Wang ZW, Wu CH, Li E, He JP, Wang SY, Hu YL, Lei HM and Li HQ: Antiviral activity and underlying molecular mechanisms of matrine against porcine reproductive and respiratory syndrome virus in vitro. Res Vet Sci. 96:323–327. 2014. View Article : Google Scholar : PubMed/NCBI
19	Yu JL, Li JH, Chengz RG, Ma YM, Wang XJ and Liu JC: Effect of matrine on transforming growth factor β1 and hepatocyte growth factor in rat liver fibrosis model. Asian Pac J Trop Med. 7:390–393. 2014. View Article : Google Scholar : PubMed/NCBI
20	Zhou Y, Wu Y, Deng L, Chen L, Zhao D, Lv L, Chen X, Man J, Wang Y, Shan H, et al: The alkaloid matrine of the root of Sophora flavescens prevents arrhythmogenic effect of ouabain. Phytomedicine. 21:931–935. 2014. View Article : Google Scholar : PubMed/NCBI
21	Fu Q, Wang J, Ma Z and Ma S: Anti-asthmatic effects of matrine in a mouse model of allergic asthma. Fitoterapia. 94:183–189. 2014. View Article : Google Scholar
22	Liu N, Kan QC, Zhang XJ, Xv YM, Zhang S, Zhang GX and Zhu L: Upregulation of immunomodulatory molecules by matrine treatment in experimental autoimmune encephalomyelitis. Exp Mol Pathol. 97:470–476. 2014. View Article : Google Scholar : PubMed/NCBI
23	Yuan X, Garrett-Sinha LA, Sarkar D and Yang S: Deletion of IFT20 in early stage T lymphocyte differentiation inhibits the development of collagen-induced arthritis. Bone Res. 2:140382014. View Article : Google Scholar : PubMed/NCBI
24	Caplazi P, Baca M, Barck K, Carano RA, DeVoss J, Lee WP, Bolon B and Diehl L: Mouse models of rheumatoid arthritis. Vet Pathol. 52:819–826. 2015. View Article : Google Scholar : PubMed/NCBI
25	Ota F, Maeshima A, Yamashita S, Ikeuchi H, Kaneko Y, Kuroiwa T, Hiromura K, Ueki K, Kojima I and Nojima Y: Activin A induces cell proliferation of fibroblast-like synoviocytes in rheumatoid arthritis. Arthritis Rheum. 48:2442–2449. 2003. View Article : Google Scholar : PubMed/NCBI
26	Zhang WD, Wang PM, Han RX and Zhang TS: Efficacy and safety evaluation of fire needling for rats with rheumatoid arthritis. Zhongguo Zhen Jiu. 33:334–338. 2013.In Chinese. PubMed/NCBI
27	Baharav E, Mor F, Halpern M and Weinberger A: Lactobacillus GG bacteria ameliorate arthritis in Lewis rats. J Nutr. 134:1964–1969. 2004.PubMed/NCBI
28	Yan C, Kong D, Ge D, Zhang Y, Zhang X, Su C and Cao X: Mitomycin C induces apoptosis in rheumatoid arthritis fibroblast-like synoviocytes via a mitochondrial-mediated pathway. Cell Physiol Biochem. 35:1125–1136. 2015. View Article : Google Scholar : PubMed/NCBI
29	Zheng CJ, Zhao XX, Ai HW, Lin B, Han T, Jiang YP, Xing X and Qin LP: Therapeutic effects of standardized Vitex negundo seeds extract on complete Freund's adjuvant induced arthritis in rats. Phytomedicine. 21:838–846. 2014. View Article : Google Scholar : PubMed/NCBI
30	Wang M, Li K, Nie Y, Wei Y and Li X: Antirheumatoid arthritis activities and chemical compositions of phenolic compounds-rich fraction from Urtica atrichocaulis, an endemic plant to China. Evid Based Complement Alternat Med. 2012:8182302012.
31	Shao Q, Zhao X and Yao L: Matrine inhibits the growth of retinoblastoma cells (SO-Rb50) by decreasing proliferation and inducing apoptosis in a mitochondrial pathway. Mol Biol Rep. 41:3475–3480. 2014. View Article : Google Scholar : PubMed/NCBI
32	Shi M, Cui F, Liu AJ, Ma HJ, Cheng M, Song SX, Yuan F, Li DP and Zhang Y: The protective effects of chronic intermittent hypobaric hypoxia pretreatment against collagen-induced arthritis in rats. J Inflamm (Lond). 12:232015. View Article : Google Scholar
33	Luo Y, Wei Z, Chou G, Wang Z, Xia Y and Dai Y: Noriso-boldine induces apoptosis of fibroblast-like synoviocytes from adjuvant-induced arthritis rats. Int Immunopharmacol. 20:110–116. 2014. View Article : Google Scholar : PubMed/NCBI
34	Correia C, Lee SH, Meng XW, Vincelette ND, Knorr KL, Ding H, Nowakowski GS, Dai H and Kaufmann SH: Emerging understanding of Bcl-2 biology: implications for neoplastic progression and treatment. Biochim Biophys Acta. 1853:1658–1671. 2015. View Article : Google Scholar : PubMed/NCBI
35	Bartok B and Firestein GS: Fibroblast-like synoviocytes: key effector cells in rheumatoid arthritis. Immunol Rev. 233:233–255. 2010. View Article : Google Scholar : PubMed/NCBI
36	Lee SY, Kwok SK, Son HJ, Ryu JG, Kim EK, Oh HJ, Cho ML, Ju JH, Park SH and Kim HY: IL-17-mediated Bcl-2 expression regulates survival of fibroblast-like synoviocytes in rheumatoid arthritis through STAT3 activation. Arthritis Res Ther. 15:R312013. View Article : Google Scholar : PubMed/NCBI
37	Jie L, Du H, Huang Q, Wei S, Huang R and Sun W: Tanshinone IIA induces apoptosis in fibroblast-like synoviocytes in rheumatoid arthritis via blockade of the cell cycle in the G2/M phase and a mitochondrial pathway. Biol Pharm Bull. 37:1366–1372. 2014. View Article : Google Scholar : PubMed/NCBI
38	Yeh CT, Huang WC, Rao YK, Ye M, Lee WH, Wang LS, Tzeng DT, Wu CH, Shieh YS, Huang CY, et al: A sesquiterpene lactone antrocin from Antrodia camphorata negatively modulates JAK2/STAT3 signaling via microRNA let-7c and induces apoptosis in lung cancer cells. Carcinogenesis. 34:2918–2928. 2013. View Article : Google Scholar : PubMed/NCBI
39	Shouda T, Yoshida T, Hanada T, Wakioka T, Oishi M, Miyoshi K, Komiya S, Kosai K, Hanakawa Y, Hashimoto K, et al: Induction of the cytokine signal regulator SOCS3/CIS3 as a therapeutic strategy for treating inflammatory arthritis. J Clin Invest. 108:1781–1788. 2001. View Article : Google Scholar : PubMed/NCBI
40	Liu H and Pope RM: The role of apoptosis in rheumatoid arthritis. Curr Opin Pharmacol. 3:317–322. 2003. View Article : Google Scholar : PubMed/NCBI
41	Li GF, Qin YH and Du PQ: Andrographolide inhibits the migration, invasion and matrix metalloproteinase expression of rheumatoid arthritis fibroblast-like synoviocytes via inhibition of HIF-1α signaling. Life Sci. 136:67–72. 2015. View Article : Google Scholar : PubMed/NCBI