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Journal of Orthopaedic Science
Published in: Journal of Orthopaedic Science 6/2011

01-11-2011 | Original Article

Geranylgeranylacetone suppresses hydrogen peroxide-induced apoptosis of osteoarthritic chondrocytes

Authors: Masaki Yoda, Tadahiro Sakai, Hirohito Mitsuyama, Hideki Hiraiwa, Naoki Ishiguro

Published in: Journal of Orthopaedic Science | Issue 6/2011

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Abstract

Background

Osteoarthritis (OA) is a common disease, afflicting many sufferers with both pain and functional disorders. Various therapies have been attempted for OA, but no fully effective treatment has been established yet. Apoptosis of chondrocytes caused by reactive oxygen species (ROS) has been considered important in the pathogenesis of OA. The progression of OA may be prevented by suppressing apoptosis of chondrocytes. Geranylgeranylacetone (GGA) has been used as an anti-ulcer drug in Japan for more than 20 years. Several recent studies have shown that GGA can induce heat shock protein (HSP) and exert cytoprotective actions on a large variety of cells and tissues. In this study, we investigated the effects of GGA on the apoptosis of OA chondrocytes induced by hydrogen peroxide (H2O2).

Methods

Human isolated OA chondrocytes were cultured in the absence or presence of GGA. Cell viability, caspase 3/7 and 9 activities, HSP70 mRNA and protein expressions were examined, and morphological analyses were conducted after exposure of cells to H2O2 to induce apoptosis.

Results

Geranylgeranylacetone dose-dependently reversed the H2O2-induced decrease in cell viability. It was recognized that GGA rendered OA chondrocytes resistant to H2O2-induced apoptosis from Hoechst 33342 staining and TUNEL staining. Caspases 3 and 9 were activated by addition of H2O2, and GGA suppressed this H2O2-induced activation of both caspases. H2O2-induced induction of HSP70 was enhanced in OA chondrocytes by pretreatment with GGA. The results showed that GGA can suppress apoptosis of chondrocytes and enhance production of HSP70.

Conclusions

This study is the first, to our knowledge, to demonstrate that GGA protects OA chondrocytes from H2O2-induced apoptosis, at least in part by enhancing HSP70 production. These results indicate that GGA is a potentially useful drug for the treatment of OA.
Literature
1.
Zhang W, Moskowitz RW, Nuki G, Abramson S, Altman RD, Arden N, Bierma-Zeinstra S, Brandt KD, Croft P, Doherty M, Douqados M, Hochberq M, Hunter DJ, Kwoh K, Lohmander LS, Tuqwell P. OARSI recommendations for the management of hip and knee osteoarthritis, Part I: critical appraisal of existing treatment guidelines and systematic review of current research evidence. Osteoarthritis Cartilage. 2007;15(9):981–1000.PubMedCrossRef
2.
Zhang W, Moskowitz RW, Nuki G, Abramson S, Altman RD, Arden N, Bierma-Zeinstra S, Brandt KD, Croft P, Doherty M, Douqados M, Hochberq M, Hunter DJ, Kwoh K, Lohmander LS, Tuqwell P. OARSI recommendations for the management of hip and knee osteoarthritis, Part II: OARSI evidence-based, expert consensus guidelines. Osteoarthritis Cartilage. 2008;16(2):137–62.PubMedCrossRef
3.
Blanco FJ, Guitian R, Vázquez-Martul E, de Toro FJ, Galdo F. Osteoarthritis chondrocytes die by apoptosis. A possible pathway for osteoarthritis pathology. Arthritis Rheum. 1998;41(2):284–9.PubMedCrossRef
4.
Hashimoto S, Takahashi K, Amiel D, Coutts RD, Lotz M. Chondrocyte apoptosis and nitric oxide production during experimentally induced osteoarthritis. Arthritis Rheum. 1998;41(7):1226–74.CrossRef
5.
Asada S, Fukuda K, Oh M, Hamanishi C, Tanaka S. Effect of hydrogen peroxide on the metabolism of articular chondrocytes. Inflamm Res. 1999;48(7):399–403.PubMedCrossRef
6.
Aizawa T, Kon T, Einhorn TA, Gerstenfeld LC. Induction of apoptosis in chondrocytes by tumor necrosis factor-alpha. J Orthop Res. 2001;19(5):785–96.PubMedCrossRef
7.
Hashimoto S, Setareh M, Ochs RL, Lotz M. Fas/Fas ligand expression and induction of apoptosis in chondrocytes. Arthritis Rheum. 1997;40(10):1749–55.PubMedCrossRef
8.
Miwa M, Saura R, Hirata S, Hayashi Y, Mizuno K, Itoh H. Induction of apoptosis in bovine articular chondrocyte by prostaglandin E(2) through cAMP-dependent pathway. Osteoarthritis Cartilage. 2000;8(1):17–24.PubMedCrossRef
9.
Lee SW, Lee HJ, Chung WT, Choi SM, Rhyu SH, Kim DK, Kim KT, Kim JY, Kim JM, Yoo YH. TRAIL induces apoptosis of chondrocytes and influences the pathogenesis of experimentally induced rat osteoarthritis. Arthritis Rheum. 2004;50(2):534–42.PubMedCrossRef
10.
Schalkwijk J. van den Berg WB, van de Putte LB, Joosten LA. An experimental model for hydrogen peroxide-induced tissue damage. Effects of a single inflammatory mediator on (peri)articular tissues. Arthritis Rheum. 1986;29(4):532–8.PubMedCrossRef
11.
Sakamoto C, Ogoshi K, Saigenji K, Narisawa R, Nagura H, Mine T, Tada M, Umegaki E, Maekawa T, Maekawa R, Maeda K. Comparison of the effectiveness of geranylgeranylacetone with cimetidine in gastritis patients with dyspeptic symptoms and gastric lesions: a randomized, double-blind trial in Japan. Digestion. 2007;75:215–24.PubMedCrossRef
12.
Hirakawa T, Rokutan K, Nikawa T, Kishi K. Geranylgeranylacetone induces heat shock proteins in cultured guinea pig gastric mucosal cells and rat gastric mucosa. Gastroenterology. 1996;111(2):345–57.PubMedCrossRef
13.
Ooie T, Takahashi N, Saikawa T, Nawata T, Arikawa M, Yamanaka K, Hara M, Shimada T, Sakata T. Single oral dose of geranylgeranylacetone induces heat-shock protein 72 and renders protection against ischemia/reperfusion injury in rat heart. Circulation. 2001;104(15):1837–43.PubMedCrossRef
14.
Ikeyama S, Kusumoto K, Miyake H, Rokutan K, Tashiro S. A non-toxic heat shock protein 70 inducer, geranylgeranylacetone, suppresses apoptosis of cultured rat hepatocytes caused by hydrogen peroxide and ethanol. J Hepatol. 2001;35(1):53–61.PubMedCrossRef
15.
Altman R, Asch E, Bloch D, Bole G, Borenstein D, Brandt K, Christy W, Cooke TD, Greenwald R, Hochberg M, Howell D, Kaplain D, Koopman W, Longley S, Mankin H, Mcshane DJ, Medsger T, Meenan R, Mikkelsen W, Moskowitz R, Murphy W, Rothschild B, Segal M, Sokoloff L, Wolfe F. Development of criteria for the classification and reporting of osteoarthritis. Classification of osteoarthritis of the knee. Arthritis Rheum. 1986;29(8):1039–49.PubMedCrossRef
16.
Tonomura H, Takahashi KA, Mazda O, Arai Y, Inoue A, Terauchi R, Shin-YA M, Kishida T, Imanishi J, Kubo T. Glutamine protects articular chondrocytes from heat stress and NO-induced apoptosis with HSP70 expression. Osteoarthritis Cartilage. 2006;14(6):545–53.PubMedCrossRef
17.
Thompson CB. Apoptosis in the pathogenesis and treatment of disease. Science. 1995;267(5203):1456–62.PubMedCrossRef
18.
Aigner T, Hemmel M, Neureiter D, Gebhard PM, Zeiler G, Kirchner T, Mckenna L. Apoptotic death is not a widespread phenomenon in normal ageing and osteoarthritic human articular knee cartilage. Arthritis Rheum. 2001;44(6):1304–12.PubMedCrossRef
19.
Kerr JF, Wyllie AH, Currie AR. Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics. Br J Cancer. 1972;26(4):239–57.PubMedCrossRef
20.
Earnshaw WC, Martins LM, Kaufmann SH. Mammalian caspases: structure, activation, substrates, and functions during apoptosis. Annu Rev Biochem. 1999;68:383–424.PubMedCrossRef
21.
22.
Mosser DD, Caron AW, Bourget L, Meriin AB, Sherman MY, Morimoto RI, Massie B. The chaperone function of hsp70 is required for protection against stress-induced apoptosis. Mol Cell Biol. 2000;20(19):7146–59.PubMedCrossRef
23.
Li CY, Lee JS, Ko YG, Kim JI, Seo JS. Heat shock protein 70 inhibits apoptosis downstream of cytochrome c release and upstream of caspase-3 activation. J Biol Chem. 2000;275(33):25665–71.PubMedCrossRef
24.
Mosser DD, Caron AW, Bourget L, Denis-Larose C, Massie B. Role of human heat shock protein hsp70 in protection against stress-induced apoptosis. Mol Cell Biol. 1997;17(9):5317–27.PubMed
25.
Terauchi R, Takahashi KA, Arai Y, Ikeda T, Ohashi S, Imanishi J, Mazda O, Kubo T. Hsp70 prevents nitric oxide-induced apoptosis in articular chondrocytes. Arthritis Rheum. 2003;48(6):1562–8.PubMedCrossRef
26.
Tanaka K, Tsutsumi S, Arai Y, Hoshino T, Suzuki K, Takai E, Ito T, Takeuchi K, Nakai A, Mizushima T. Genetic evidence for a protective role of heat shock factor 1 against irritant-induced gastric lesions. Mol Pharmacol. 2007;71(4):985–93.PubMedCrossRef
27.
Almonte-Becerril M, Navarro-Garcia F, Gonzalez-Robles A, Vega-Lopez MA, Lavalle C, Kouri JB. Cell death of chondrocytes is a combination between apoptosis and autophagy during the pathogenesis of osteoarthritis within an experimental model. Apoptosis. 2010;15(5):631–8.PubMedCrossRef
28.
Boileau C, Martel-Pelletier J, Jouzeau JY, Netter P, Moldovan F, Laufer S, Tries S, Pelletier JP. Licofelone (ML-3000), a dual inhibitor of 5-lipoxygenase and cyclooxygenase, reduces the level of cartilage chondrocyte death in vivo in experimental dog osteoarthritis: inhibition of pro-apoptotic factors. J Rheumatol. 2002;29(7):1446–53.PubMed
29.
Lin HD, He CQ, Luo QL, Zhang JL, Zeng DX. The effect of low-level laser to apoptosis of chondrocyte and caspases expression, including caspase-8 and caspase-3 in rabbit surgery-induced model of knee osteoarthritis. Rheumatol Int. 2010, Epub ahead of print.
30.
Hasegawa J, Morishita N, Seki T, Hashida N, Kanazawa T, Sato A. Effect of meales in healthy adult administered Selbex®. Shoukakika. 1987;7(6):740–52 (in Japanese).
Metadata
Title
Geranylgeranylacetone suppresses hydrogen peroxide-induced apoptosis of osteoarthritic chondrocytes
Authors
Masaki Yoda
Tadahiro Sakai
Hirohito Mitsuyama
Hideki Hiraiwa
Naoki Ishiguro
Publication date
01-11-2011
Publisher
Springer Japan
Published in
Journal of Orthopaedic Science / Issue 6/2011
Print ISSN: 0949-2658
Electronic ISSN: 1436-2023
DOI
https://doi.org/10.1007/s00776-011-0138-z

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