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http://dx.doi.org/10.15324/kjcls.2019.51.3.379

Cytological Study on the Cause of the Osteoporotic Side Effects of Adefovir Dipivoxil  

Park, Ho (Department of Clinical Laboratory Science, Wonkwang Health Science University)
Publication Information
Korean Journal of Clinical Laboratory Science / v.51, no.3, 2019 , pp. 379-385 More about this Journal
Abstract
Osteoporosis is a disease that increases the risk of fractures by inducing a decrease in bone strength by the changes in hormones and a decrease in minerals. Recent reports have indicated that the long-term administration of Adefovir dipivoxil (ADV), which is used as a treatment for the hepatitis virus and AIDS, may have osteoporotic side effects. On the other hand, there are few studies on the cytopathic correlation of these causes. In this study, the biological relevance of ADV was evaluated using osteoblast hFOB1.19 and vascular endothelial cell HUVEC. First, the cells were treated with ADV at different concentrations, and DAPI and crystal violet staining were performed for morphological analysis of each cell and nucleus. A CCK-8 assay, real-time PCR, alkaline phosphatase (ALP) staining, and activity was performed to evaluate the drug effects on cell proliferation, gene expression, and osteoblast differentiation. As a result, ADV induced cell hypertrophy in hFOB1.19 cells and HUVEC cells. Furthermore, ADV not only inhibited cell proliferation and TGF-${\beta}$ expression but was also involved in osteoblast differentiation. Overall, these results provide basic data to help better understand the mechanism of ADV-induced osteoporosis and its clinical implications.
Keywords
Adefovir dipivoxil; Hypertrophy; Osteogenic differentiation; Osteoporosis; TGF-${\beta}$;
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1 McKenna MJ, Frame B. Hormonal influences on osteoporosis. Am J Med. 1987;82:61-67.   DOI
2 Kurra S, Siris E. Diabetes and bone health: the relationship between diabetes and osteoporosis-associated fractures. Diabetes Metab Res Rev. 2011;27:430-435.   DOI
3 Schipper LG, Fleuren HW, van den Bergh JP, Meinardi JR, Veldman BA, Kramers C. Treatment of osteoporosis in renal insufficiency. Clin Rheumatol. 2015;34:1341-1345.   DOI
4 Drake MT. Osteoporosis and Cancer. Curr Osteoporos Rep. 2013;11:163-170.   DOI
5 Canalis E, Delany AM. Mechanisms of glucocorticoid action in bone. Ann N Y Acad Sci. 2002;966:73-81.   DOI
6 Kwon SY, Ahn SY, Ko SY, Jang YM, Choi YH, Kim BK, et al. A case of osteomalacia related to adefovir in a patient with chronic hepatitis B. Korean J Gastroenterol. 2010;56:117-120.   DOI
7 Jeong HY, Lee JM, Lee TH, Lee JY, Kim HB, Heo MH, et al. Two cases of hypophosphatemic osteomalacia after long-term low dose adefovir therapy in chronic hepatitis B and literature review. J Bone Metab. 2014;21:76-83.   DOI
8 Kramata P, Votruba I, Otova B, Holy A. Different inhibitory potencies of acyclic phosphonomethoxyalkyl nucleotide analogs toward DNA polymerases alpha, delta and epsilon. Mol Pharmacol. 1996;49:1005-1011.
9 Romaniuk PJ, Eckstein F. A study of the mechanism of T4 DNA polymerase with diastereomeric phosphorothioate analogues of deoxyadenosine triphosphate. J Biol Chem. 1982;257:7684-7688.   DOI
10 Nakashima K, Nakashima H, Shimoyama M. Deoxyadenosine triphosphate acting as an energy-transferring molecule in adenosine deaminase inhibited human erythrocytes. Biochim Biophys Acta. 1991;1094:257-262.   DOI
11 Kahn J, Lagakos S, Wulfsohn M, Cherng D, Miller M, Cherrington J, et al. Efficacy and safety of adefovir dipivoxil with antiretroviral therapy: a randomized controlled trial. JAMA. 1999;282:2305-2312.   DOI
12 Marcellin P, Chang TT, Lim SG, Tong MJ, Sievert W, Shiffman ML, et al. Adefovir dipivoxil for the treatment of hepatitis B e antigen-positive chronic hepatitis B. N Engl J Med. 2003;348:808-816.   DOI
13 ADHOC International Steering Committee. A randomized placebo-controlled trial of adefovir dipivoxil in advanced HIV infection: the ADHOC trial. HIV Med. 2002;3:229-238.   DOI
14 Fisher EJ, Chaloner K, Cohn DL, Grant LB, Alston B, Brosgart CL, et al. The safety and efficacy of adefovir dipivoxil in patients with advanced HIV disease: a randomized, placebo-controlled trial. AIDS. 2001;15:1695-1700.   DOI
15 Eguchi H, Tsuruta M, Tani J, Kuwahara R, Hiromatsu Y. Hypophosphatemic osteomalacia due to drug-induced Fanconi's syndrome associated with adefovir dipivoxil treatment for hepatitis B. Intern Med. 2014;53:233-237.   DOI
16 Girgis CM, Wong T, Ngu MC, Emmett L, Archer KA, Chen RC, et al. Hypophosphataemic osteomalacia in patients on adefovir dipivoxil. J Clin Gastroenterol. 2011;45:468-473.   DOI
17 Yang X, Chen L, Xu X, Li C, Huang C, Deng CX. TGF-${\beta}$/Smad3 signals repress chondrocyte hypertrophic differentiation and are required for maintaining articular cartilage. J Cell Biol. 2001;153:35-46.   DOI
18 Owens GK, Geisterfer AA, Yang YW, Komoriya A. Transforming growth factor-beta-induced growth inhibition and cellular hypertrophy in cultured vascular smooth muscle cells. J Cell Biol. 1988;107:771-780.   DOI
19 Liu Z, Li C, Kang N, Malhi H, Shah VH, Maiers JL. Transforming growth factor ${\beta}$ ($TGF{\beta}$) cross-talk with the unfolded protein response is critical for hepatic stellate cell activation. J Biol Chem. 2019;294:3137-3151.   DOI
20 Zhuang H, Wang W, Tahernia AD, Levitz CL, Luchetti WT, Brighton CT. Mechanical strain-induced proliferation of osteoblastic cells parallels increased TGF-${\beta}$ 1 mRNA. Biochem Biophys Res Commun. 1996;229:449-453.   DOI
21 Bostrom P, Mann N, Wu J, Quintero PA, Plovie ER, Panakova D, Gupta RK, et al. $C/EBP{\beta}$ controls exercise-induced cardiac growth and protects against pathological cardiac remodeling. Cell. 2010;143:1072-1083.   DOI
22 Hirata M, Kugimiya F, Fukai A, Ohba S, Kawamura N, Ogasawara T, et al. $C/EBP{\beta}$ promotes transition from Proliferation to hypertrophic differentiation of chondrocytes through transactivation of $p57^{Kip2}$. PLoS One. 2009;4:E4543.   DOI
23 Zou J, Li H, Chen X, Zeng S, Ye J, Zhou C, et al. $C/EBP{\beta}$ knockdown protects cardiomyocytes from hypertrophy via inhibition of $p65-NF{\kappa}B$. Mol Cell Endocrinol. 2014;390:18-25.   DOI
24 Wu L, Derynck R. Essential role of TGF-${\beta}$ signaling in glucose-induced cell hypertrophy. Dev Cell. 2009;17:35-48.   DOI
25 Izzedine H, Launay-Vacher V, Deray G. Antiviral durg-induced nephrotoxicity, Am J Kidney Dis. 2005;45:804-817.   DOI
26 Xu P, Wang Y, Qin Z, Qiu L, Zhang M, Huang Y, et al. Combined medication of antiretroviral drugs tenofovir disoproxil fumarate, emtricitabine, and raltegravir reduces neural progenitor cell proliferation in vivo and in vitro. J Neuroimmune Pharmacol. 2017;12:682-692.   DOI
27 Zhang X, Wang R, Piotrowski M, Zhang H, Leach KL. Intracellular concentrations determine the cytotoxicity of adefovir, cidofovir and tenofovir. Toxicol In Vitro. 2015;29:251-258.   DOI
28 Balogh E, Paragh G, Jeney V. Influence of iron on bone homeostasis. Pharmaceuticals. 2018;11:E107.   DOI
29 Wu M, Chen G, Li YP. TGF-${\beta}$ and BMP signaling in osteoblast, skeletal development, and bone formation, homeostasis and disease. Bone Res. 2016;4:16009.   DOI
30 Jones E, Mazirka P, McNurlan MA, Darras F, Gelato MC, Caso G. Highly active antiretroviral therapy dysregulates proliferation and differentiation of human pre-adipocytes. World J Virol. 2017;6:53-58.   DOI