Anti-inflammatory and chondroprotective effects of atorvastatin in a cartilage explant model of osteoarthritis
This study aimed to assess the chondroprotective potential of atorvastatin in rat’s cartilage explant culture model of osteoarthritis, stimulated by interleukin-1β (IL-1β).
Materials and methods
The cartilage explants were treated with 20 ng/ml IL-1β alone or with 20 ng/ml IL-1β + various concentration of atorvastatin (1, 3, or 10 µM dissolved in DMSO) and incubated at 37 °C for 24 h. Also, control (0.25 % DMSO), stimulated (20 ng IL-1β) and treatment (atorvastatin 10 µM) cartilage explants were incubated without and with 1400W (10 µM). After 24 h of incubation, TNF-α, PGE2, MMP-13, TIMP-1, NO, and superoxide anion formation (O2 −) concomitant with glycosaminoglycans (GAGs) were estimated in the medium.
Atorvastatin inhibited IL-1β-induced GAGs release, TNF-α, MMP-13, and O2 − with no effect on TIMP-1 and NO. In addition, the source of NO in normal and atorvastatin-treated cartilage was eNOS, while for IL-1β-stimulated cartilage it was iNOS. The cartilage degradation was associated with the combined effects of increased NO and O2 − rather than only NO.
The present study suggests that atorvastatin has the ability to protect cartilage degradation following IL-1β-stimulated cartilage in in vitro OA model and supports additional therapeutic application of atorvastatin in OA.
KeywordsCartilage explants Proinflammatory cytokines MMP-13/TIMP-1 Reactive oxygen species 1400W Atorvastatin
Tissue inhibitors of matrix metalloproteinases
Tumor necrosis factor-α
1, 9-dimethylmethylene blue
Reactive oxygen species
Conflict of interest
All authors declare that they have no conflicts of interest concerning this article.
- 2.Baker CL, Ferguson CM. Future treatment of osteoarthritis. Orthopedics. 2005;28:227–34.Google Scholar
- 9.May SA, Lees P. Nonsteroidal anti-inflammatory drugs. In: McIlwraith CW, Trotter GW, editors. Joint disease in the horse. Philadelphia: Saunders WB; 1996. p. 223–37.Google Scholar
- 10.Burger D, Rezzonico R, Li JM, Modoux C, Pierce RA, Welgus HG, Dayer JM. Imbalance between interstitial collagenase and tissue inhibitor of metalloproteinases 1 in synoviocytes and fibroblasts upon direct contact with stimulated T lymphocytes: involvement of membrane-associated cytokines. Arthritis Rheum. 1998;41:1748–59.CrossRefPubMedGoogle Scholar
- 12.Mengshol JA, Vincenti MP, Coon CI, Barchowsky A, Brinckerhoff CE. Interleukin-1 induction of collagenase 3 (matrix metalloproteinase 13) gene expressions in chondrocytes require p38, c-Jun N-terminal kinase, and nuclear factor kappaB: differential regulation of collagenase 1 and collagenase 3. Arthritis Rheum. 2000;43:801–11.CrossRefPubMedGoogle Scholar
- 15.Roman-Blas JA, Contreras-Blasco MA, Largo R, Alvarez-Soria MA, Castañeda S, Herrero-Beaumont G. Differential effects of the antioxidant n-acetylcysteine on the production of catabolic mediators in IL-1beta-stimulated human osteoarthritic synoviocytes and chondrocytes. Eur J Pharmacol. 2009;623:125–31.CrossRefPubMedGoogle Scholar
- 18.Collins P, Ford I, Croal B, Ball D, Greaves M, Macaulay E, Brittenden J. Haemostasis, inflammation and renal function following exercise in patients with intermittent claudicating on statin and aspirin therapy. Thromb J. 2006;4–9.Google Scholar
- 31.Farkouh ME, Greenberg JD, Jeger RV, Ramanathan K, Verheugt FW, Chesebro JH, Kirshner H, Hochman JS, Lay CL, Ruland S, Mellein B, Matchaba PT, Fuster V, Abramson SB. Cardiovascular outcomes in high risk patients with osteoarthritis treated with ibuprofen, naproxen or lumiracoxib. Ann Rheum Dis. 2007;66:764–70.CrossRefPubMedCentralPubMedGoogle Scholar
- 34.Youssef S, Stuve O, Patarroyo JC, Rulz PJ, Radosevich JL, Hur EM, Bravo M, Mitchell DJ, Sobel RA, Steinman L, Zamvill SS. The HMG-CoA reductase inhibitors, atorvastatin, promote a Th2 bias and reverse paralysis in central nervous system autoimmune disease. Nature. 2002;420:78–84.CrossRefPubMedGoogle Scholar
- 54.Mandelbaum B, Waddell D. Etiology and pathophysiology of osteoarthritis. Orthopedics. 2005;28:207–14.Google Scholar
- 56.John DR, Orrenius S. Role of mitochondria in toxic cell death. Toxicology. 2002;491–496.Google Scholar
- 58.Bakogiannis C, Antoniades C, Tousoulis D, Demosthenous M, Antonopoulos AS, Psarros T, Ekonomopoulos G, Sfyras N, Channon KM. Atorvastatin directly reduces vascular superoxide generation in human vein grafts ex vivo, by improving eNOS coupling and reducing NADPH-oxidase activity. JACC. 2010;55:A51.E480–A51.E480.Google Scholar
- 60.Amin AR, Di Cesare PE, Vyas P, Attur M, Tzeng E, Billiar TR, Stuchin SA, Abramson SB. The expression and regulation of nitric oxide synthase in human osteoarthritis-affected chondrocytes: evidence for up-regulated neuronal nitric oxide synthase. J Exp Med. 1995;182:2097–102.CrossRefPubMedGoogle Scholar
- 61.Melchiorri C, Meliconi R, Frizziero L, Silvestri T, Pulsatelli L, Mazzetti I, Borzi RM, Uguccioni M, Facchini A. Enhanced and coordinated in vivo expression of inflammatory cytokines and nitric oxide synthase by chondrocytes from patients with osteoarthritis. Arthritis Rheum. 1998;41:2165–74.CrossRefPubMedGoogle Scholar