Autophagy in human articular chondrocytes is cytoprotective following glucocorticoid stimulation

Liu,Ning; Wang,Wenbo; Zhao,Zhe; Zhang,Tao; Song,Yuwen

doi:10.3892/mmr.2014.2102

Autophagy in human articular chondrocytes is cytoprotective following glucocorticoid stimulation

Authors:
- Ning Liu
- Wenbo Wang
- Zhe Zhao
- Tao Zhang
- Yuwen Song
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Affiliations: Department of Orthopaedic Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150001, P.R. China
Published online on: April 1, 2014 https://doi.org/10.3892/mmr.2014.2102
Pages: 2166-2172
Copyright: © Liu et al. This is an open access article distributed under the terms of Creative Commons Attribution License [CC BY_NC 3.0].

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Abstract

For the past 60 years, glucocorticosteroid (GC) drugs, including prednisone and dexamethasone (Dex), have been used for the treatment of early stage osteoarthritis (OA). However, multiple administration of GCs may destroy the articular cartilage. It has been previously reported that GC treatment may also lead to the initiation of autophagy, which is an essential mechanism for cell homeostasis and survival. Rapamycin (Rapa), an inhibitor of the mammalian target of Rapamycin, may cause a degeneration‑associated pathology in organs and induce autophagy in a variety of cell types, which has been applied in the treatment of experimental OA. A previous study by our group observed that GC apparently increases the apoptosis of chondrocytes, resulting in the inhibition of extracellular matrix synthesis. Therefore, the present study aimed to further examine the effects of autophagy in chondrocytes under GC treatment and to verify the molecular mechanisms involved in the cytoprotective role of Rapa. Short‑term GC treatment did not significantly inhibit chondrocyte viability, while cell autophagy was increased. In addition, upregulation of autophagy by Rapa prevented the expression of apoptosis‑associated genes and improved cell activity. In conclusion, the present study revealed that increased autophagy is an adaptive response to protect chondrocytes from short‑term GC exposure, whereas prolonged GC treatment decreases autophagy and increases apoptosis in vitro. Upregulation of autophagy by Rapa may protect chondrocytes against the adverse effect induced by GC.

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1	Felson DT and Zhang Y: An update on the epidemiology of knee and hip osteoarthritis with a view to prevention. Arthritis Rheum. 41:1343–1355. 1998. View Article : Google Scholar : PubMed/NCBI
2	Larsson E, Erlandsson Harris H, Larsson A, Månsson B, Saxne T and Klareskog L: Corticosteroid treatment of experimental arthritis retards cartilage destruction as determined by histology and serum COMP. Rheumatology (Oxford). 43:428–434. 2004. View Article : Google Scholar : PubMed/NCBI
3	Hollander JL: Intra-articular hydrocortisone in arthritis and allied conditions; a summary of two years’ clinical experience. J Bone Joint Surg Am. 35-A:983–990. 1953.PubMed/NCBI
4	Flanagan J, Casale FF, Thomas TL and Desai KB: Intra-articular injection for pain relief in patients awaiting hip replacement. Ann R Coll Surg Engl. 70:156–157. 1988.PubMed/NCBI
5	Friedman DM and Moore ME: The efficacy of intraarticular steroids in osteoarthritis: a double-blind study. J Rheumatol. 7:850–856. 1980.PubMed/NCBI
6	Lambert RG, Hutchings EJ, Grace MG, Jhangri GS, Conner-Spady B and Maksymowych WP: Steroid injection for osteoarthritis of the hip: a randomized, double-blind, placebo-controlled trial. Arthritis Rheum. 56:2278–2287. 2007. View Article : Google Scholar : PubMed/NCBI
7	Hainque B, Dominice J, Jaffray P, Ronot X and Adolphe M: Effects of dexamethasone on the growth of cultured rabbit articular chondrocytes: relation with the nuclear glucocorticoid- recepter complex. Ann Rheum Dis. 46:146–152. 1987. View Article : Google Scholar : PubMed/NCBI
8	Héraud F, Héraud A and Harmand MF: Apoptosis in normal and osteoarthritic human articular cartilage. Ann Rheum Dis. 59:959–965. 2000.
9	Mizushima N, Levine B, Cuervo AM and Klionsky DJ: Autophagy fights disease through cellular self-digestion. Nature. 451:1069–1075. 2008. View Article : Google Scholar : PubMed/NCBI
10	Levine B and Kroemer G: Autophagy in the pathogenesis of disease. Cell. 132:27–42. 2008. View Article : Google Scholar : PubMed/NCBI
11	Martinet W, Agostinis P, Vanhoecke B, Dewaele M and De Meyer GR: Autophagy in disease: a double-edged sword with therapeutic potential. Clin Sci (Lond). 116:697–712. 2009. View Article : Google Scholar : PubMed/NCBI
12	Caramés B, Taniguchi N, Otsuki S, Blanco FJ and Lotz M: Autophagy is a protective mechanism in normal cartilage, and its aging-related loss is linked with cell death and osteoarthritis. Arthritis Rheum. 62:791–801. 2010.PubMed/NCBI
13	Caramés B, Kiosses WB, Akasaki Y, Brinson DC, Eap W, Koziol J and Lotz M: Glucosamine activates autophagy in vitro and in vivo. Arthritis Rheum. 65:1843–1852. 2013.
14	Shigemitsu K, Tsujishita Y, Hara K, Nanahoshi M, Avruch J and Yonezawa K: Regulation of translational effectors by amino acid and mammalian target of rapamycin signaling pathways. Possible involvement of autophagy in cultured hepatoma cells. J Biol Chem. 274:1058–1065. 1999. View Article : Google Scholar
15	Cardenas ME, Cutler NS, Lorenz MC, Di Como CJ and Heitman J: The TOR signaling cascade regulates gene expression in response to nutrients. Genes Dev. 13:3271–3279. 1999. View Article : Google Scholar : PubMed/NCBI
16	Dann SG, Selvaraj A and Thomas G: mTOR Complex1-S6K1 signaling: at the crossroads of obesity, diabetes and cancer. Trends Mol Med. 13:252–259. 2007. View Article : Google Scholar : PubMed/NCBI
17	Harrison DE, Strong R, Sharp ZD, Nelson JF, Astle CM, Flurkey K, Nadon NL, Wilkinson JE, Frenkel K, Carter CS, Pahor M, Javors MA, Fernandez E and Miller RA: Rapamycin fed late in life extends lifespan in genetically heterogeneous mice. Nature. 460:392–395. 2009.PubMed/NCBI
18	Pan T, Rawal P, Wu Y, Xie W, Jankovic J and Le W: Rapamycin protects against rotenone-induced apoptosis through autophagy induction. Neuroscience. 164:541–551. 2009. View Article : Google Scholar : PubMed/NCBI
19	Spilman P, Podlutskaya N, Hart MJ, Debnath J, Gorostiza O, Bredesen D, Richardson A, Strong R and Galvan V: Inhibition of mTOR by rapamycin abolishes cognitive deficits and reduces amyloid-beta levels in a mouse model of Alzheimer’s disease. PLoS One. 5:e99792010.PubMed/NCBI
20	Song YW, Zhang T and Wang WB: Gluococorticoid could influence extracellular matrix synthesis through Sox9 via p38 MAPK pathway. Rheumatol Int. 32:3669–3673. 2012. View Article : Google Scholar : PubMed/NCBI
21	Buss LW, Anderson C, Westerman E, Kritzberger C, Poudyal M, Moreno MA and Lakkis FG: Allorecognition triggers autophagy and subsequent necrosis in the cnidarian Hydractinia symbiolongicarpus. PLoS One. 7:e489142012. View Article : Google Scholar : PubMed/NCBI
22	Dobson F, Hinman RS, Roos EM, Abbott JH, Stratford P, Davis AM, Buchbinder R, Snyder-Mackler L, Henrotin Y, Thumboo J, Hansen P and Bennell KL: OARSI recommended performance-based tests to assess physical function in people diagnosed with hip or knee osteoarthritis. Osteoarthritis Cartilage. 21:1042–1052. 2013. View Article : Google Scholar : PubMed/NCBI
23	Van Manen MD, Nace J and Mont MA: Management of primary knee osteoarthritis and indications for total knee arthroplasty for general practitioners. J Am Osteopath Assoc. 112:709–715. 2012.PubMed/NCBI
24	Schumacher HR and Chen LX: Injectable corticosteroids in treatment of arthritis of the knee. Am J Med. 118:1208–1214. 2005. View Article : Google Scholar : PubMed/NCBI
25	Bjordal JM, Klovning A, Ljunggren AE and Slørdal L: Short-term efficacy of pharmacotherapeutic interventions in osteoarthritic knee pain: A meta-analysis of randomised placebo-controlled trials. Eur J Pain. 11:125–138. 2007. View Article : Google Scholar : PubMed/NCBI
26	Olney RC: Mechanisms of impaired growth: effect of steroids on bone and cartilage. Horm Res. 72(Suppl 1): 30–35. 2009. View Article : Google Scholar : PubMed/NCBI
27	Fubini SL, Todhunter RJ, Burton-Wurster N, Vernier-Singer M and MacLeod JN: Corticosteroids alter the differentiated phenotype of articular chondrocytes. J Orthop Res. 19:688–695. 2001. View Article : Google Scholar : PubMed/NCBI
28	Farkas B, Kvell K, Czömpöly T, Illés T and Bárdos T: Increased chondrocyte death after steroid and local anesthetic combination. Clin Orthop Relat Res. 468:3112–3120. 2010. View Article : Google Scholar : PubMed/NCBI
29	Gozuacik D and Kimchi A: Autophagy as a cell death and tumor suppressor mechanism. Oncogene. 23:2891–2906. 2004. View Article : Google Scholar : PubMed/NCBI
30	He C and Klionsky DJ: Regulation mechanisms and signaling pathways of autophagy. Annu Rev Genet. 43:67–93. 2009. View Article : Google Scholar : PubMed/NCBI
31	Lires-Deán M, Caramés B, Cillero-Pastor B, Galdo F, López-Armada MJ and Blanco FJ: Anti-apoptotic effect of transforming growth factor-beta1 on human articular chondrocytes: role of protein phosphatase 2A. Osteoarthritis Cartilage. 16:1370–1378. 2008.PubMed/NCBI
32	Blanco FJ, López-Armada MJ and Maneiro E: Mitochondrial dysfunction in osteoarthritis. Mitochondrion. 4:715–728. 2004. View Article : Google Scholar : PubMed/NCBI
33	Mobasheri A: Role of chondrocyte death and hypocellularity in ageing human articular cartilage and the pathogenesis of osteoarthritis. Med Hypotheses. 58:193–197. 2002. View Article : Google Scholar : PubMed/NCBI
34	Roach HI, Aigner T and Kouri JB: Chondroptosis: a variant of apoptotic cell death in chondrocytes? Apoptosis. 9:265–277. 2004. View Article : Google Scholar : PubMed/NCBI
35	Caramés B, Hasegawa A, Taniguchi N, Miyaki S, Blanco FJ and Lotz M: Autophagy activation by rapamycin reduces severity of experimental osteoarthritis. Ann Rheum Dis. 71:575–581. 2012.PubMed/NCBI
36	Sasaki H, Takayama K, Matsushita T, Ishida K, Kubo S, Matsumoto T, Fujita N, Oka S, Kurosaka M and Kuroda R: Autophagy modulates osteoarthritis-related gene expression in human chondrocytes. Arthritis Rheum. 64:1920–1928. 2012. View Article : Google Scholar : PubMed/NCBI
37	Almonte-Becerril M, Navarro-Garcia F, Gonzalez-Robles A, Vega-Lopez MA, Lavalle C and Kouri JB: Cell death of chondrocytes is a combination between apoptosis and autophagy during the pathogenesis of Osteoarthritis within an experimental model. Apoptosis. 15:631–638. 2010. View Article : Google Scholar : PubMed/NCBI
38	Kimball SR and Jefferson LS: Molecular mechanisms through which amino acids mediate signaling through the mammalian target of rapamycin. Curr Opin Clin Nutr Metab Care. 7:39–44. 2004. View Article : Google Scholar : PubMed/NCBI
39	Kim MS, Wu KY, Auyeung V, Chen Q, Gruppuso PA and Phornphutkul C: Leucine restriction inhibits chondrocyte proliferation and differentiation through mechanisms both dependent and independent of mTOR signaling. Am J Physiol Endocrinol Metab. 296:E1374–E1382. 2009. View Article : Google Scholar : PubMed/NCBI
40	Chen J, Crawford R and Xiao Y: Vertical inhibition of the PI3K/Akt/mTOR pathway for the treatment of osteoarthritis. J Cell Biochem. 114:245–249. 2013. View Article : Google Scholar : PubMed/NCBI
41	Bohensky J, Terkhorn SP, Freeman TA, Adams CS, Garcia JA, Shapiro IM and Srinivas V: Regulation of autophagy in human and murine cartilage: hypoxia-inducible factor 2 suppresses chondrocyte autophagy. Arthritis Rheum. 60:1406–1415. 2009. View Article : Google Scholar : PubMed/NCBI
42	Lo YY, Conquer JA, Grinstein S and Cruz TF: Interleukin-1 beta induction of c-fos and collagenase expression in articular chondrocytes: involvement of reactive oxygen species. J Cell Biochem. 69:19–29. 1998. View Article : Google Scholar : PubMed/NCBI
43	Henrotin YE, Bruckner P and Pujol JP: The role of reactive oxygen species in homeostasis and degradation of cartilage. Osteoarthritis Cartilage. 11:747–755. 2003. View Article : Google Scholar : PubMed/NCBI