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Article

Tormentic acid inhibits IL-1β-induced chondrocyte apoptosis by activating the PI3K/Akt signaling pathway

  • Authors:
    • Yang Yang
    • Yawei Wang
    • Meng Zhao
    • Haobo Jia
    • Bing Li
    • Dan Xing
  • View Affiliations / Copyright

    Affiliations: Department of Orthopedics, Tianjin Hospital, Tianjin 300211, P.R. China, Department of Electromyography, Tianjin Hospital, Tianjin 300211, P.R. China, Clinical Laboratory, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin Medical University Cancer Institute and Hospital, Tianjin 300060, P.R. China
  • Pages: 4753-4758
    |
    Published online on: January 12, 2018
       https://doi.org/10.3892/mmr.2018.8425
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Abstract

Interleukin-1β (IL-1β) accelerates degradation of the cartilage matrix and induces apoptosis of chondrocytes. Tormentic acid (TA) is a triterpene isolated from the stem bark of the Vochysia divergens plant, which has been demonstrated to exert in vitro inhibitory activity against hepatocyte apoptosis. However, the effects of TA on IL‑1β‑induced apoptosis of human chondrocytes remain unclear. Therefore, the present study investigated the in vitro effects of TA on human osteoarthritic chondrocyte apoptosis cultivated in the presence of IL‑1β. Human chondrocytes were pretreated with or without various concentrations of TA and then co‑incubated in the absence or presence of IL‑1β for 24 h. Cell viability was determined using the MTT assay, and cell apoptosis was detected using a Nucleosome ELISA kit. Caspase‑3 activity was detected using a caspase‑3 colorimetric assay kit. The levels of B‑cell lymphoma 2 (Bcl‑2)‑associated X protein (Bax), Bcl‑2, phosphorylated (p)‑phosphoinositide 3‑kinase (PI3K), PI3K, p‑protein kinase B (Akt) and Akt were measured by western blotting. The results revealed that pretreatment with TA inhibited IL‑1β‑induced cytotoxicity and apoptosis in chondrocytes. In addition, TA pretreatment increased B‑cell lymphoma (Bcl)‑2 expression, and decreased caspase‑3 activity and Bax expressionin human chondrocytes. In addition, pretreatment with TA markedly increased the expression of p‑PI3K and p‑Akt in IL‑1β‑induced chondrocytes. Collectively, these results indicate that TA inhibits IL‑1β‑induced chondrocyte apoptosis by activating the PI3K/Akt signaling pathway. Therefore, TA may be considered a potential therapeutic target for the treatment of osteoarthritis.
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1 

Martel-Pelletier J: Pathophysiology of osteoarthritis. Osteoarthr Cartilage. 12 Suppl A:S31–S33. 2014. View Article : Google Scholar

2 

Johnson E, Charchandi A, Babis G and Soucacos P: Apoptosis in osteoarthritis: Morphology, mechanisms, and potential means for therapeutic intervention. J Surg Orthop Adv. 17:147–152. 2007.

3 

Grishko V, Xu M, Ho R, Mates A, Watson S, Kim JT, Wilson GL and Pearsall AW IV: Effects of hyaluronic acid on mitochondrial function and mitochondria-driven apoptosis following oxidative stress in human chondrocytes. J Biol Chem. 284:9132–9139. 2009. View Article : Google Scholar : PubMed/NCBI

4 

Dave M, Attur M, Palmer G, Al-Mussawir HE, Kennish L, Patel J and Abramson SB: The antioxidant resveratrol protects against chondrocyte apoptosis via effects on mitochondrial polarization and ATP production. Arthritis Rheum. 58:2786–2797. 2008. View Article : Google Scholar : PubMed/NCBI

5 

Blanco FJ, Rego I and Ruiz-Romero C: The role of mitochondria in osteoarthritis. Nat Rev Rheumatol. 7:161–169. 2011. View Article : Google Scholar : PubMed/NCBI

6 

Goldring MB: Osteoarthritis and cartilage: The role of cytokines. Curr Rheumatol Rep. 2:459–465. 2000. View Article : Google Scholar : PubMed/NCBI

7 

Bassleer CT, Combal JP, Bougaret S and Malaise M: Effects of chondroitin sulfate and interleukin-1 beta on human articular chondrocytes cultivated in clusters. Osteoarthr Cartilage. 6:196–204. 1998. View Article : Google Scholar

8 

Daheshia M and Yao JQ: The interleukin 1 beta pathway in the pathogenesis of osteoarthritis. J Rheumatol. 35:2306–2312. 2008. View Article : Google Scholar : PubMed/NCBI

9 

Yasuhara R, Miyamoto Y, Akaike T, Akuta T, Nakamura M, Takami M, Morimura N, Yasu K and Kamijo R: Interleukin-1beta induces death in chondrocyte-like ATDC5 cells through mitochondrial dysfunction and energy depletion in a reactive nitrogen and oxygen species-dependent manner. Biochem J. 389:315–323. 2005. View Article : Google Scholar : PubMed/NCBI

10 

Sanchez C, Deberg MA, Piccardi N, Msika P, Reginster JY and Henrotin YE: Osteoblasts from the sclerotic subchondral bone downregulate aggrecan but upregulate metalloproteinases expression by chondrocytes. This effect is mimicked by interleukin-6,-1beta and oncostatin M pre-treated non-sclerotic osteoblasts. Osteoarthr Cartilage. 13:979–987. 2005. View Article : Google Scholar

11 

Banno N, Akihisa T, Tokuda H, Yasukawa K, Higashihara H, Ukiya M, Watanabe K, Kimura Y, Hasegawa J and Nishino H: Triterpene acids from the leaves of Perilla frutescens and their anti-inflammatory and antitumor-promoting effects. Biosci Biotech Biochem. 68:85–90. 2004. View Article : Google Scholar

12 

Song YL, Zhang L, Gao JM, Du GH and Cheng YX: Speciosaperoxide, a new triterpene acid, and other terpenoids from Chaenomeles speciosa. J Asian Nat Prod Res. 10:217–222. 2008. View Article : Google Scholar : PubMed/NCBI

13 

Bortalanza LB, Ferreira J, Hess SC, Delle Monache F, Yunes RA and Calixto JB: Anti-allodynic action of the tormentic acid, a triterpene isolated from plant, against neuropathic and inflammatory persistent pain in mice. Eur J Pharmacol. 453:203–208. 2002. View Article : Google Scholar : PubMed/NCBI

14 

An HJ, Kim IT, Park HJ, Kim HM, Choi JH and Lee KT: Tormentic acid, a triterpenoid saponin, isolated from Rosa rugosa, inhibited LPS-induced iNOS, COX-2, and TNF-α expression through inactivation of the nuclear factor-κb pathway in RAW 264.7 macrophages. Int Immunopharmacol. 11:504–510. 2011. View Article : Google Scholar : PubMed/NCBI

15 

Lin X, Zhang S, Huang R, Tan S, Liang S, Wu X, Zhuo L and Huang Q: Protective effect of tormentic acid from Potentilla chinensis against lipopolysaccharide/D-galactosamine induced fulminant hepatic failure in mice. Int Immunopharmacol. 19:365–372. 2014. View Article : Google Scholar : PubMed/NCBI

16 

Shakibaei M and Merker HJ: beta1-Integrins in the cartilage matrix. Cell Tissue Res. 296:565–573. 1999. View Article : Google Scholar : PubMed/NCBI

17 

Aigner T and Kim HA: Apoptosis and cellular vitality: Issues in osteoarthritic cartilage degeneration. Arthritis Rheum. 46:1986–1996. 2002. View Article : Google Scholar : PubMed/NCBI

18 

Goldring MB: Update on the biology of the chondrocyte and new approaches to treating cartilage diseases. Best Pract Res Clin Rheumatol. 20:1003–1025. 2006. View Article : Google Scholar : PubMed/NCBI

19 

Mistry D, Oue Y, Chambers MG, Kayser MV and Mason RM: Chondrocyte death during murine osteoarthritis. Osteoarthr Cartilage. 12:131–141. 2004. View Article : Google Scholar

20 

Caron JP, Fernandes JC, Martel-Pelletier J, Tardif G, Mineau F, Geng C and Pelletier JP: Chondroprotective effect of intraarticular injections of interleukin-1 receptor antagonist in experimental osteoarthritis. Suppression of collagenase-1 expression. Arthritis Rheum. 39:1535–1544. 1996. View Article : Google Scholar : PubMed/NCBI

21 

Joosten LA, Helsen MM, Saxne T, van De Loo FA, Heinegard D and van Den Berg WB: IL-1alpha beta blockade prevents cartilage and bone destruction in murine type II collagen-induced arthritis, whereas TNF-alpha blockade only ameliorates joint inflammation. J Immunol. 163:5049–5055. 1999.PubMed/NCBI

22 

Largo R, Alvarez-Soria M, Dıez-Ortego I, Calvo E, Sanchez-Pernaute O, Egido J and Herrero-Beaumont G: Glucosamine inhibits IL-1beta-induced NFkappaB activation in human osteoarthritic chondrocytes. Osteoarthritis Cartilage. 11:290–298. 2003. View Article : Google Scholar : PubMed/NCBI

23 

Mazzetti I, Grigolo B, Pulsatelli L, Dolzani P, Silvestri T, Roseti L, Meliconi R and Facchini A: Differential roles of nitric oxide and oxygen radicals in chondrocytes affected by osteoarthritis and rheumatoid arthritis. Clin Sci. 101:593–599. 2001. View Article : Google Scholar : PubMed/NCBI

24 

Venkatesan N, Barre L, Benani A, Netter P, Magdalou J, Fournel-Gigleux S and Ouzzine M: Stimulation of proteoglycan synthesis by glucuronosyltransferase-I gene delivery: A strategy to promote cartilage repair. Proc Natl Acad Sci USA. 101:pp. 18087–18092. 2004; View Article : Google Scholar : PubMed/NCBI

25 

Wang L, Gai P, Xu R, Zheng Y, Lv S, Li Y and Liu S: Shikonin protects chondrocytes from interleukin-1beta-induced apoptosis by regulating PI3K/Akt signaling pathway. Int J Clin Exp Pathol. 8:2982015.PubMed/NCBI

26 

Samali A, Zhivotovsky B, Jones D, Nagata S and Orrenius S: Apoptosis: Cell death defined by caspase activation. Cell Death Differ. 6:495–496. 1999. View Article : Google Scholar : PubMed/NCBI

27 

Shakibaei M, Schulze-Tanzil G, John T and Mobasheri A: Curcumin protects human chondrocytes from IL-1beta-induced inhibition of collagen type II and beta1-integrin expression and activation of caspase-3: An immunomorphological study. Anna Anat. 187:487–497. 2005. View Article : Google Scholar

28 

Chen J, Chu Y, Cao J, Yang Z, Guo X and Wang Z: T-2 toxin induces apoptosis, and selenium partly blocks, T-2 toxin induced apoptosis in chondrocytes through modulation of the Bax/Bcl-2 ratio. Food Chem Toxicol. 44:567–573. 2006. View Article : Google Scholar : PubMed/NCBI

29 

Malemud CJ and Gillespie HJ: The role of apoptosis in arthritis. Curr Rheumatol Rev. 1:131–142. 2005. View Article : Google Scholar

30 

Sugimori K, Matsui K, Motomura H, Tokoro T, Wang J, Higa S, Kimura T and Kitajima I: BMP-2 prevents apoptosis of the N1511 chondrocytic cell line through PI3K/Akt-mediated NF-kappaB activation. J Bone Miner Metab. 23:411–419. 2005. View Article : Google Scholar : PubMed/NCBI

31 

Oh CD and Chun JS: Signaling mechanisms leading to the regulation of differentiation and apoptosis of articular chondrocytes by insulin-like growth factor-1. J Biol Chem. 278:36563–36571. 2003. View Article : Google Scholar : PubMed/NCBI

32 

Ikegami D, Akiyama H, Suzuki A, Nakamura T, Nakano T, Yoshikawa H and Tsumaki N: Sox9 sustains chondrocyte survival and hypertrophy in part through Pik3ca-Akt pathways. Development. 138:1507–1519. 2011. View Article : Google Scholar : PubMed/NCBI

33 

Stiles BL: PI-3-K and AKT: Onto the mitochondria. Adv Drug Deliver Rev. 61:1276–1282. 2009. View Article : Google Scholar

34 

Yin W, Park JI and Loeser RF: Oxidative stress inhibits insulin-like growth factor-I induction of chondrocyte proteoglycan synthesis through differential regulation of phosphatidylinositol 3-Kinase-Akt and MEK-ERK MAPK signaling pathways. J Biol Chem. 284:31972–31981. 2009. View Article : Google Scholar : PubMed/NCBI

35 

Starkman BG, Cravero JD, Delcarlo M and Loeser RF: IGF-I stimulation of proteoglycan synthesis by chondrocytes requires activation of the PI 3-kinase pathway but not ERK MAPK. Biochem J. 389:723–729. 2005. View Article : Google Scholar : PubMed/NCBI

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Copy and paste a formatted citation
Spandidos Publications style
Yang Y, Wang Y, Zhao M, Jia H, Li B and Xing D: Tormentic acid inhibits IL-1β-induced chondrocyte apoptosis by activating the PI3K/Akt signaling pathway. Mol Med Rep 17: 4753-4758, 2018.
APA
Yang, Y., Wang, Y., Zhao, M., Jia, H., Li, B., & Xing, D. (2018). Tormentic acid inhibits IL-1β-induced chondrocyte apoptosis by activating the PI3K/Akt signaling pathway. Molecular Medicine Reports, 17, 4753-4758. https://doi.org/10.3892/mmr.2018.8425
MLA
Yang, Y., Wang, Y., Zhao, M., Jia, H., Li, B., Xing, D."Tormentic acid inhibits IL-1β-induced chondrocyte apoptosis by activating the PI3K/Akt signaling pathway". Molecular Medicine Reports 17.3 (2018): 4753-4758.
Chicago
Yang, Y., Wang, Y., Zhao, M., Jia, H., Li, B., Xing, D."Tormentic acid inhibits IL-1β-induced chondrocyte apoptosis by activating the PI3K/Akt signaling pathway". Molecular Medicine Reports 17, no. 3 (2018): 4753-4758. https://doi.org/10.3892/mmr.2018.8425
Copy and paste a formatted citation
x
Spandidos Publications style
Yang Y, Wang Y, Zhao M, Jia H, Li B and Xing D: Tormentic acid inhibits IL-1β-induced chondrocyte apoptosis by activating the PI3K/Akt signaling pathway. Mol Med Rep 17: 4753-4758, 2018.
APA
Yang, Y., Wang, Y., Zhao, M., Jia, H., Li, B., & Xing, D. (2018). Tormentic acid inhibits IL-1β-induced chondrocyte apoptosis by activating the PI3K/Akt signaling pathway. Molecular Medicine Reports, 17, 4753-4758. https://doi.org/10.3892/mmr.2018.8425
MLA
Yang, Y., Wang, Y., Zhao, M., Jia, H., Li, B., Xing, D."Tormentic acid inhibits IL-1β-induced chondrocyte apoptosis by activating the PI3K/Akt signaling pathway". Molecular Medicine Reports 17.3 (2018): 4753-4758.
Chicago
Yang, Y., Wang, Y., Zhao, M., Jia, H., Li, B., Xing, D."Tormentic acid inhibits IL-1β-induced chondrocyte apoptosis by activating the PI3K/Akt signaling pathway". Molecular Medicine Reports 17, no. 3 (2018): 4753-4758. https://doi.org/10.3892/mmr.2018.8425
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