Arthropod steroid hormone (20-Hydroxyecdysone) suppresses IL-1β- induced catabolic gene expression in cartilage

BMC Complementary and Alternative Medicine

Cherng-Jyh Ke³  Ching-Yun Chen²  Jui-Sheng Sun³  Shin-Rong Ho¹  Shiow-Yunn Sheu¹ 

[1] School of Pharmacy, College of Pharmacy, Taipei Medical University, Taipei, Taiwan;Institute of Biomedical Engineering, College of Engineering and College of Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan;Biomimetic Systems Research Center, National Chiao Tung University, Hsin-Chu City, Taiwan

关键词: HIF-2α;    Cartilage destruction;    Normoxia;    Hypoxia;    IL-1β;    20-Hydroxyecdysone;   

Others  :  1117837
DOI  :  10.1186/s12906-015-0520-z

 received in 2014-09-10, accepted in 2015-01-13,  发布年份 2015

【 摘 要 】

Background

In osteoarthritis (OA), the imbalance of chondrocytes’ anabolic and catabolic factors can induce cartilage destruction. Interleukin-1 beta (IL-1β) is a potent pro-inflammatory cytokine that is capable of inducing chondrocytes and synovial cells to synthesize MMPs. The hypoxia-inducible factor-2alpha (HIF-2alpha, encoded by Epas1) is the catabolic transcription factor in the osteoarthritic process. The purpose of this study is to validate the effects of ecdysteroids (Ecd) on IL-1β- induced cartilage catabolism and the possible role of Ecd in treatment or prevention of early OA.

Methods

Chondrocytes and articular cartilage was harvested from newborn ICR mice. Ecd effect on chondrocytes viability was tested and the optimal concentration was determined by MTT assay. The effect of HIF-2α (EPAS1) in cartilage catabolism simulated by IL-1β (5 ng/ml) was evaluated by articular cartilage explants culture. The effects of Ecd on IL-1β-induced inflammatory conditions and their related catabolic genes expression were analyzed.

Results

Interleukin-1β (IL-1β) treatment on primary mouse articular cartilage explants enhanced their Epas1, matrix metalloproteinases (MMP-3, MMP-13) and ADAMTS-5 genes expression and down-regulated collagen type II (Col2a1) gene expression. With the pre-treatment of 10⁻⁸M Ecd, the catabolic effects of IL-1β on articular cartilage were scavenged.

Conclusion

In conclusions, Ecd can reduce the IL-1β-induced inflammatory effect of the cartilage. Ecd may suppress IL-1β- induced cartilage catabolism via HIF-2α pathway.

【 授权许可】

   
2015 Sheu et al.; licensee BioMed Central.

【 图 表 】

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【 参考文献 】

• [1]Fuerst M, Bertrand J, Lammers L, Dreier R, Echtermeyer F, Nitschke Y, et al.: Calcification of articular cartilage in human osteoarthritis. Arthritis Rheum 2009, 60(9):2694-703.
• [2]Kotlarz H, Gunnarsson CL, Fang H, Rizzo JA: Insurer and out-of-pocket costs of osteoarthritis in the US: evidence from national survey data. Arthritis Rheum 2009, 60(12):3546-53.
• [3]Saito T, Fukai A, Mabuchi A, Ikeda T, Yano F, Ohba S, et al.: Transcriptional regulation of endochondral ossification by HIF-2alpha during skeletal growth and osteoarthritis development. Nat Med 2010, 16(6):678-86.
• [4]Yang S, Kim J, Ryu JH, Oh H, Chun CH, Kim BJ, et al.: Hypoxia-inducible factor-2alpha is a catabolic regulator of osteoarthritic cartilage destruction. Nat Med 2010, 16(6):687-93.
• [5]Kamekura S, Kawasaki Y, Hoshi K, Shimoaka T, Chikuda H, Maruyama Z, et al.: Contribution of runt-related transcription factor 2 to the pathogenesis of osteoarthritis in mice after induction of knee joint instability. Arthritis Rheum 2006, 54(8):2462-70.
• [6]Husa M, Liu-Bryan R, Terkeltaub R: Shifting HIFs in osteoarthritis. Nat Med 2010, 16(6):641-4.
• [7]Ryu JH, Shin Y, Huh YH, Yang S, Chun CH, Chun JS: Hypoxia-inducible factor-2α regulates Fas-mediated chondrocyte apoptosis during osteoarthritic cartilage destruction. Cell Death Differ 2012, 19(3):440-50.
• [8]Dinan L, Savchenko T, Whiting P: On the distribution of phytoecdysteroids in plants. Cell Mol Life Sci 2001, 58(8):1121-32.
• [9]Nowickyj SM, Chithalen JV, Cameron D, Tyshenko MG, Petkovich M, Wyatt GR, et al.: Locust retinoid X receptors: 9-Cis-retinoic acid in embryos from a primitive insect. Proc Natl Acad Sci U S A 2008, 105(28):9540-5.
• [10]Kapur P, Jarry H, Wuttke W, Pereira BM, Seidlova-Wuttke D: Evaluation of the antiosteoporotic potential of Tinospora cordifolia in female rats. Maturitas 2008, 59(4):329-38.
• [11]Báthori M, Tóth N, Hunyadi A, Márki A, Zádor E: Phytoecdysteroids and anabolic-androgenic steroids–structure and effects on humans. Curr Med Chem 2008, 15(1):75-91.
• [12]Gorelick-Feldman J, Maclean D, Ilic N, Poulev A, Lila MA, Cheng D, et al.: Phytoecdysteroids increase protein synthesis in skeletal muscle cells. J Agric Food Chem 2008, 56(10):3532-7.
• [13]Kapur P, Wuttke W, Jarry H, Seidlova-Wuttke D: Beneficial effects of beta-Ecdysone on the joint, epiphyseal cartilage tissue and trabecular bone in ovariectomized rats. Phytomedicine 2010, 17(5):350-5.
• [14]Zhang X, Xu X, Xu T, Qin S: β-Ecdysterone suppresses interleukin-1β-induced apoptosis and inflammation in rat chondrocytes via inhibition of NF-κB signaling pathway. Drug Dev Res 2014, 75(3):195-201.
• [15]He CC, Hui RR, Tezuka Y, Kadota S, Li JX: Osteoprotective effect of extract from Achyranthes bidentata in ovariectomized rats. J Ethnopharmacol 2010, 127(2):229-34.
• [16]Dinan L, Lafont R: Effects and applications of arthropod steroid hormones (ecdysteroids) in mammals. J Endocrinol 2006, 191(1):1-8.
• [17]Salvat C, Pigenet A, Humbert L, Berenbaum F, Thirion S: Immature murine articular chondrocytes in primary culture: a new tool for investigating cartilage. Osteoarthritis Cartilage 2005, 13(3):243-9.
• [18]Elders MJ: The increasing impact of arthritis on public health. J Rheumatol Suppl 2000, 60:6-8.
• [19]Goldring MB, Goldring SR: Osteoarthritis. J Cell Physiol 2007, 213(3):626-34. Loeser RF. Molecular mechanisms of cartilage destruction: mechanics, inflammatory mediators, and aging collide. Arthritis Rheum. 2006; 54(5): 1357–1360
• [20]Daheshia M, Yao JQ: The interleukin 1beta pathway in the pathogenesis of osteoarthritis. J Rheumatol 2008, 35(12):2306-12.
• [21]Bertrand J, Cromme C, Umlauf D, Frank S, Pap T: Molecular mechanisms of cartilage remodelling in osteoarthritis. Int J Biochem Cell Biol 2010, 42(10):1594-601.
• [22]Aigner T, Söder S, Gebhard PM, McAlinden A, Haag J: Mechanisms of disease: role of chondrocytes in the pathogenesis of osteoarthritis–structure, chaos and senescence. Nat Clin Pract Rheumatol 2007, 3(7):391-9.
• [23]Martel-Pelletier J, Boileau C, Pelletier JP, Roughley PJ: Cartilage in normal and osteoarthritis conditions. Best Pract Res Clin Rheumatol 2008, 22(2):351-84.
• [24]Struglics A, Larsson S, Pratta MA, Kumar S, Lark MW, Lohmander LS: Human osteoarthritis synovial fluid and joint cartilage contain both aggrecanase- and matrix metalloproteinase-generated aggrecan fragments. Osteoarthritis Cartilage 2006, 14(2):101-13.
• [25]Brew CJ, Clegg PD, Boot-Handford RP, Andrew JG, Hardingham T: Gene expression in human chondrocytes in late osteoarthritis is changed in both fibrillated and intact cartilage without evidence of generalised chondrocyte hypertrophy. Ann Rheum Dis 2010, 69(1):234-40.
• [26]Little CB, Barai A, Burkhardt D, Smith SM, Fosang AJ, Werb Z, et al.: Matrix metalloproteinase 13-deficient mice are resistant to osteoarthritic cartilage erosion but not chondrocyte hypertrophy or osteophyte development. Arthritis Rheum 2009, 60(12):3723-33.
• [27]Brooks PM: The burden of musculoskeletal disease–a global perspective. Clin Rheumatol 2006, 25(6):778-81.
• [28]Poole AR, Nelson F, Dahlberg L, Tchetina E, Kobayashi M, Yasuda T, et al.: Proteolysis of the collagen fibril in osteoarthritis. Biochem Soc Symp 2003, 70:115-23.
• [29]Tortorella MD, Burn TC, Pratta MA, Abbaszade I, Hollis JM, Liu R, et al.: Purification and cloning of aggrecanase-1: a member of the ADAMTS family of proteins. Science 1999, 284(5420):1664-6.
• [30]Pattoli MA, MacMaster JF, Gregor KR, Burke JR: Collagen and aggrecan degradation is blocked in interleukin-1-treated cartilage explants by an inhibitor of IkappaB kinase through suppression of metalloproteinase expression. J Pharmacol Exp Ther 2005, 315(1):382-8.
• [31]Aigner T, Zien A, Hanisch D, Zimmer R: Gene expression in chondrocytes assessed with use of microarrays. J Bone Joint Surg Am 2003, 85-A(Suppl 2):117-23.
• [32]Rankin EB, Giaccia AJ, Schipani E: A central role for hypoxic signaling in cartilage, bone, and hematopoiesis. Curr Osteoporos Rep 2011, 9(2):46-52.
• [33]Murphy CL: HIF-2alpha–a mediator of osteoarthritis? Cell Res 2010, 20(9):977-9.