Abstract
This study investigated the effects of the histone deacetylase (HDAC) inhibitor trichostatin A (TSA) on cartilage degradation in an experimental model of osteoarthritis (OA). Thirty-two male New Zealand rabbits underwent unilateral anterior cruciate ligament transection (ACLT) on left knee joints to induce OA and were randomly divided into two groups (n = 16), the TSA group was injected intra-articularly with 0.3 ml TSA [250 ng/ml in the dimethylsulphoxide (DMSO)], the OA group received DSMO since 4 weeks after operation once a week for 5 weeks. Rabbits were killed seven days after the last injection. Left knee cartilage was harvested for morphological, histological and genetic analysis. Another ten rabbits were used for normal control and received no injection. The TSA group showed less cartilage degradation as compared to the OA group assessed by morphological and histological evaluation. Gene expression of matrix metalloproteinase-1 (MMP-1), MMP-3, MMP-13, and interleukin-1 (IL-1) was increased significantly in the OA group compared to the normal group. The elevated expression was reduced by TSA. Our results suggest that TSA could be considered as a potential agent for treatment for OA.
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Thirunavukkarasu K, Pei Y, Wei T (2007) Characterization of the human ADAMTS-5 (aggrecanase-2) gene promoter. Mol Biol Rep 34:225–231
Mizui Y, Yamazaki K, Kuboi Y et al (2000) Characterization of 5′-flanking region of human aggrecanase-1 (ADAMTS4) gene. Mol Biol Rep 27:167–173
Huang K, Wu LD (2010) Suppression of aggrecanase: a novel protective mechanism of dehydroepiandrosterone in osteoarthritis? Mol Biol Rep 37:1241–1245
Caterina JJ, Shi J, Kozak CA, Engler JA, Birkedal-Hansen H (2000) Characterization, expression analysis and chromosomal mapping of mouse matrix metalloproteinase-19 (MMP-19). Mol Biol Rep 27:73–79
Burrage PS, Mix KS, Brinckerhoff CE (2006) Matrix metalloproteinases: role in arthritis. Front Biosci 11:529–543
Rengel Y, Ospelt C, Gay S (2007) Proteinases in the joint: clinical relevance of proteinases in joint destruction. Arthritis Res Ther 9:221
Martel-Pelletier J, Welsch DJ, Pelletier JP (2001) Metalloproteases and inhibitors in arthritic diseases. Best Pract Res Clin Rheumatol 15:805–829
Neuhold LA, Killar L, Zhao W et al (2001) Postnatal expression in hyaline cartilage of constitutively active human collagenase-3 (MMP-13) induces osteoarthritis in mice. J Clin Invest 107:35–44
Dahlberg L, Billinghurst RC, Manner P et al (2000) Selective enhancement of collagenase-mediated cleavage of resident type II collagen in cultured osteoarthritic cartilage and arrest with a synthetic inhibitor that spares collagenase 1 (matrix metalloproteinase 1). Arthritis Rheum 43:673–682
Tetlow LC, Adlam DJ, Woolley DE (2001) Matrix metalloproteinase and proinflammatory cytokine production by chondrocytes of human osteoarthritic cartilage: associations with degenerative changes. Arthritis Rheum 44:585–594
Goldring MB (2000) The role of the chondrocyte in osteoarthritis. Arthritis Rheum 43:1916–1926
Kobayashi M, Squires GR, Mousa A et al (2005) Role of interleukin-1 and tumor necrosis factor alpha in matrix degradation of human osteoarthritic cartilage. Arthritis Rheum 52:128–135
Bao JP, Chen WP, Wu LD (2010) Lubricin: a novel potential biotherapeutic approaches for the treatment of osteoarthritis. Mol Biol Rep. doi:10.1007/s11033-010-9949-9
Glauben R, Sonnenberg E, Zeitz M et al (2009) HDAC inhibitors in models of inflammation-relatedtumorigenesis. Cancer Lett 280:154–159
Glauben R, Batra A, Fedke I et al (2006) Histone hyperacetylation is associated with amelioration of experimental colitis in mice. J Immunol 176:5015–5022
Leoni F, Zaliani A, Bertolini G et al (2002) The antitumor histone deacetylase inhibitor suberoylanilide hydroxamic acid exhibits anti-inflammatory properties via suppression of cytokines. Proc Natl Acad Sci USA 99:2995–3000
Chabane N, Zayed N, Afif H et al (2008) Histone deacetylase inhibitors suppress interleukin-1beta-induced nitric oxide and prostaglandin E2 production in human chondrocytes. Osteoarthr Cartil 16:1267–1274
Young DA, Lakey RL, Pennington CJ et al (2005) Histone deacetylase inhibitors modulate metalloproteinase gene expression in chondrocytes and block cartilage resorption. Arthritis Res Ther 7:R503–R512
Wang X, Song Y, Jacobi JL et al (2009) Inhibition of histone deacetylases antagonized FGF2 and IL-1beta effects on MMP expression in human articular chondrocytes. Growth Factors 27:40–49
Nishida K, Komiyama T, Miyazawa S et al (2004) Histone deacetylase inhibitor suppression of autoantibody-mediated arthritis in mice via regulation of p16INK4a and p21(WAF1/Cip1) expression. Arthritis Rheum 50:3365–3376
Lin HS, Hu CY, Chan HY et al (2007) Anti-rheumatic activities of histone deacetylase (HDAC) inhibitors in vivo in collagen-induced arthritis in rodents. Br J Pharmacol 150:862–872
Nasu Y, Nishida K, Miyazawa S et al (2008) Trichostatin A, a histone deacetylase inhibitor, suppresses synovial inflammation and subsequent cartilage destruction in a collagen antibody-induced arthritis mouse model. Osteoarthr Cartil 16:723–732
Wu LD, Yu HC, Xiong Y et al (2006) Effect of dehydroepiandrosterone on cartilage and synovium of knee joints with osteoarthritis in rabbits. Rheumatol Int 27:79–85
Shikhman AR, Amiel D, D’Lima D et al (2005) Chondroprotective activity of N-acetylglucosamine in rabbits with experimental osteoarthritis. Ann Rheum Dis 64:89–94
Mankin HJ, Dorfman H, Lippiello L et al (1971) Biochemical and metabolic abnormalities in articular cartilage from osteoarthritic human hips. II. Correlation of morphology with biochemical and metabolic data. J Bone Joint Surg Am 53:523–537
Bau B, Gebhard PM, Haag J et al (2002) Relative messenger RNA expression profiling of collagenases and aggrecanases in human articular chondrocytes in vivo and in vitro. Arthritis Rheum 46(10):2648–2657
Ailenberg M, Silverman M (2003) Differential effects of trichostatin A on gelatinase A expression in 3T3 fibroblasts and HT-1080 fibrosarcoma cells: implications for use of TSA in cancer therapy. Biochem Biophys Res Commun 302:181–185
Daheshia M, Yao JQ (2008) The interleukin 1beta pathway in the pathogenesis of osteoarthritis. J Rheumatol 35:2306–2312
Fernandes JC, Martel-Pelletier J, Pelletier JP (2002) The role of cytokines in osteoarthritis pathophysiology. Biorheology 39:237–246
Leoni F, Zaliani A, Bertolini G et al (2002) The an-titumor histone deacetylase inhibitor suberoylanilide hydroxamic acidexhibits anti-inflammatory properties via suppression of cytokines. Proc Natl Acad Sci USA 99:2995–3000
Leoni F, Fossati G, Lewis EC et al (2005) The histone deacetylase inhibitor ITF2357 reduces production of pro-inflammatory cytokines in vitro and systemic inflammation in vivo. Mol Med 11:11–15
Yan C, Boyd DD (2007) Regulation of matrix metalloproteinase gene expression. J Cell Physiol 211:19–26
Ahn KS, Aggarwal BB (2005) Transcription factor NF-kappaB: a sensor for smoke and stress signals. Ann N Y Acad Sci 1056:218–233
Imre G, Gekeler V, Leja A et al (2006) Histone deacetylase inhibitors suppress the inducibility of nuclear factor-kappa B by tumor necrosis factor-alpha receptor-1 down-regulation. Cancer Res 66:5409–5418
Yin L, Laevsky G, Giardina C (2001) Butyrate suppression of colonocyte NF-kappa B activation and cellular proteasome activity. J Biol Chem 276:44641–44646
Davie JR (1997) Nuclear matrix, dynamic histone acetylation and transcriptionally active chromatin. Mol Biol Rep 24:197–207
Marks P, Rifkind RA, Richon VM et al (2001) Histone deacetylases and cancer: causes and therapies, Nat. Rev Cancer 3:194–202
Johnstone RW (2002) Histone-deacetylase inhibitors: novel drugs for the treatment of cancer. Nat Rev Drug Discov 1:287–299
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This study was supported by grants from Health Bureau of Zhejiang Province (2006A055).
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Chen, WP., Bao, JP., Hu, PF. et al. Alleviation of osteoarthritis by Trichostatin A, a histone deacetylase inhibitor, in experimental osteoarthritis. Mol Biol Rep 37, 3967–3972 (2010). https://doi.org/10.1007/s11033-010-0055-9
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DOI: https://doi.org/10.1007/s11033-010-0055-9