PREDICTION OF THE COURSE OF OSTEOARTHROSIS FROM mTOR (MAMMALIAN TARGET OF RAPAMYCIN) GENE EXPRESSION

Objective: To study whether the course of the disease can be predicted in patients with osteoarthrosis (OA), by monitoring mTOR (Mammalian Target Of Rapamycin) gene expression in their blood.
Material and methods. The investigation was conducted on the peripheral blood samples from 33 outpatients (58.4±7.4 years) with OA; 10 patients (56.5±8.9 years) before endoprosthetic knee joint replacement, и 27 healthy individuals (55.6+8.3 years) who formed a control group. Total RNA was isolated from the blood and used to estimate the gene expression of mTOR, autophagy-related protein 1 (ATG1), the cyclin-dependent kinase inhibitor p21, caspase
3, and tumor necrosis factor-а (TNF-а) by real-time polymerase chain reaction.
Results. Analysis of gene expression in the outpatients with OA identified two subgroups: in one subgroup (n = 13) mTOR expression was considerably much less than that in the control group; the expression of ATG1 and p21 did not differ greatly from the control and that of caspase 3 and TNF-α was significantly higher. The other outpatients (n = 20) and all the examined patients needing endoprosthetic replacement were ascertained to have a higher gene expression of mTOR, ATG1, p21, caspase 3, and TNF-α than in the control group. Before endoprosthetic replacement, severe joint destruction in patients with OA was associated with enhanced gene expression of mTOR, ATG1, p21, and caspase 3. Conclusion. In early-stage disease, increased mTOR gene expression may serve as a prognostic marker of the severity of the disease and articular cartilage destruction.

mTOR, osteoarthrosis, gene expression, mTOR, blood

1. <div><p>Четина Е.В. Механизмы эмбриогенеза при остеоартрозе: роль дифференцировки хондроцитов в резорбции суставного хряща. Науч-практич ревматол 2010;3:65-77.</p><p>Buckwalter J.A., Saltzman C., Brown T. et al. The impact of osteoarthritis: implications for research. Clin Orthop 2004;427:S6-S15.</p><p>Dean D.D., Azzo W., Martel-Pelletier J. et al. Evidence for metalloproteinase and metalloproteinase inhibitor imbalance in human osteoarthritic cartilage. J Clin Invest 1989;84:678-85.</p><p>Muller B. Cytokine imbalance in non-immunological chronic disease. Cytokine 2002;18:334-9.</p><p>Aigner T., Rose J., Martin J. et al. Aging theories of primary osteoarthritis: from epidemiology to molecular biology. Rejuvenation Res 2004;7:134-45.</p><p>Lorenzo P., Bayliss M.T., Heinegard D. Altered patterns and synthesis of extracellular matrix macromolecules in early osteoarthritis. Matrix Biol 2004;23:381-91.</p><p>Sharif M., Whitehouse A., Sharman P. et al. Increased apoptosis in human osteoarthritic cartilage corresponds to reduced cell density and expression of caspase 3. Arthr Rheum 2004;50:507-15.</p><p>Четина Е.В., Пул А.Р. Способность фрагмента коллагена 2 типа индуцировать расщепление коллагена и гипертрофию суставных хондроцитов. Bестн. РАМН 2008;9:40-5.</p><p>Tchetina E.V., Webb G., Poole A.R. Increased type II collagen degradation and very early focal cartilage degeneration is associated with upregulation of chondrocyte differentiation related genes in early human articular cartilage lesions. J Rheumatol 2005;32:876-86.</p><p>Четина Е.В., Пул А.Р. Роль ростовых факторов в подавлении разрушения коллагена и дифференциации хондроцитов при остеоартрозе. Bестн РАМН 2008;5:15-21.</p><p>Четина Е.В., ДиБатиста Д., Пул А.Р. Роль простагландина E2 в ингибировании разрушения коллагена суставного хряща больных остеоартрозом. Науч-практич ревматол 2009;3:18-23.</p><p>Mahr S., Burmester G.-R., Hilke D. et al. Cis and Trans-acting gene regulation is associated with osteoarthritis. Am J Hum Genet 2006;78:793-803.</p><p>Grcevic D., Jajic Z., Kovacic N. et al. Peripheral blood expression profiles of bone morphogenetic proteins, tumor necrosis factor-superfamily molecules, and transcription factor Runx2 could be used as markers of the form of arthritis, disease activity, and therapeutic responsiveness. J Rheumatol 2010;37:246-56.</p><p>Sesselmann S., Söder S., Voigt R. et al. DNA methylation is not responsible for p21WAF1/CIP1 down-regulation in osteoarthritic chondrocytes. Osteoarthr Cartilage 2009;17:507-12.</p><p>Fukuda K. Progress of research for osteoarthritis. Involvement of reactive oxygen species in the pathogenesis of osteoarthritis. Clin Calcium 2009;19:1602-6.</p><p>Dai S.M., Shan Z.Z., Nakamura H. et al. Catabolic stress induces features of chondrocyte senescence through overexpression of caveolin 1: possible involvement of caveolin 1-induced down-regulation of articular chondrocytes in the pathogenesis of osteoarthritis. Arthr Rheum 2006;54:818-31.</p><p>Zhou H.W., Lou S.Q., Zhang K. Recovery of function in osteoarthritic chondrocytes induced by p16INK4a-specific siRNA in vitro. Rheumatology (Oxford) 2004;43:555-68.</p><p>Hay N., Sonnenberg N. Upstream and downstream of mTOR. Genes Dev 2004;18:1926-45.</p><p>Raught B., Gingras A.C., Sonenberg N. The target of rapamycin (TOR) proteins. Proc Natl Аcad Sci USA 2005;98:7037-44.</p><p>Lum J.J., DeBerardinis R.J., Thompson C.B. Autophagy in metazoans: cell survival in the land of plenty. Nat Rev Mol Cell Biol 2005;6:439-48.</p><p>Roach H.I., Aigner T., Kouri J.B. Chondroptosis: a variant of apoptotic cell death in chondrocytes? Apoptosis 2004;9:265-77.</p><p>Lu B., Capan E., Li C. Autophagy induction and autophagic cell death in effector T cells. Autophagy 2007;3:158-9.</p><p>Wei Y., Sinha S., Levine B. Dual role of JNK1-mediated phosphorylation of Bcl-2 in autophagy and apoptosis regulation. Autophagy 2008;4:949-51.</p><p>Patel V.A., Lee D.J., Longacre-Antoni A. et al. Apoptotic and necrotic cells as sentinels of local tissue stress and inflammation: Response pathways initiated in nearby viable cells. Autoimmunity 2009;42:317-21</p><p>Zhu M., Chen M., Zuscik M. et al. Inhibition of beta-catenin signaling in articular chondrocytes results in articular cartilage destruction. Arthr Rheum 2008;58:2053-64.</p><p>Aigner T., Hemmel M., Neureiter D. et al. Apoptotic cell death is not a widespread phenomenon in normal aging and osteoarthritis human articular knee cartilage: a study of proliferation, programmed cell death (apoptosis), and viability of chondrocytes in normal and osteoarthritic human knee cartilage. Arthr Rheum 2001;44:1304-12.</p><p>Goldring S.R., Goldring M.B. The role of cytokines in cartilage matrix degeneration in osteoarthritis. Clin Orthopaed 2004;427(Suppl.):S27-S36.</p><p>Goldring S.R., Berenbaum F. The regulation of chondrocyte function by proinflammatory mediators: prostaglandins and nitric oxide. Clin Orthopaed 2004;427(Suppl.):S37-S46.</p><p>Benito M.J., Veale D.J., FitzGerald O. et al. Synovial tissue inflammation in early and late osteoarthritis. Annals Rheum Dis 2005;64:1263-7.</p><p>Fernandes J.C., Martel-Pelletier J., Pelletier J.P. The role of cytokines in osteoarthritis pathophysiology. Biorheology 2002;39:237-46.</p><p>Лимфоциты - методы. Под. ред. Д. Клауса М., 1990.</p><p>Batliwalla F.M., Baechler E.C., Xiao X. et al. Peripheral blood gene expression profiling in rheumatoid arthritis. Genes Immun 2005;6:388-97.</p><p>Bonnet C.S., Walsh D.A. Osteoarthritis, angiogenesis and inflammation. Rheumatology 2005;44:7-16.</p><p>Poole A.R. Cartilage in health and disease. In: Arthritis and allied conditions: A textbook of rheumatology. Ed. 15. Ed. by</p><p>W. Koopman. Philadelphia: Lippincott, Williams, and Wilkins, 2005;223-69.</p><p>Abou-Shousha S.A., Salah E., Wagby E. Study of P53 in peripheral blood and synovial mononuclear cells of rheumatoid arthritis and osteoarthritis patients and its relation to the degree of disease activity. Egypt J Immunol 2005;12:61-70.</p><p>Sigal L.H., Johnston S.L., Phillips P.E. Cellular immune responses to cartilage components in rheumatoid arthritis and osteoarthritis: a review and report of a study. Clin Exp Rheumatol 1988;6:59-66.</p><p>Бененсон Е.В., Тсай Е.Г., Табушалиева А.С. Иммунорегуляторные нарушения и пролиферативная активность Т- и В-лимфоцитов при остеоартрозе. Ревматология 1989;2:45-9.</p><p>Conrozier T., Chappuis-Cellier C., Richard M. et al. Increased serum C-reactive protein levels by immunonephelometry in patients with rapidly destructive hip osteoarthritis. Rev Rhum Engl Ed 1998;65:759-65.</p><p>Spector T.D., Hart D.J., Nandra D. et al. Low-level increases in serum C-reactive protein are present in early osteoarthritis of the knee and predict progressive disease. Arthr Rheum 1997;40:723-7.</p></div><br />