International Journal of Stem Cells

  • 제17권3호
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  • Pages.284-297
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  • 2024
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  • 2005-3606(pISSN)
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  • 2005-5447(eISSN)
한국줄기세포학회 (Korean Society for Stem Cell Research)
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Impaired Osteogenesis in Human Induced Pluripotent Stem Cells with Acetaldehyde Dehydrogenase 2 Mutations

  • Jooyoung Lim (Department of Biomedicine & Health Sciences, College of Medicine, The Catholic University of Korea) ;
  • Heeju Han (Department of Biomedicine & Health Sciences, College of Medicine, The Catholic University of Korea) ;
  • Se In Jung (Department of Biomedicine & Health Sciences, College of Medicine, The Catholic University of Korea) ;
  • Yeri Alice Rim (Catholic iPSC Research Center, CiSTEM Laboratory, College of Medicine, The Catholic University of Korea) ;
  • Ji Hyeon Ju (Catholic iPSC Research Center, CiSTEM Laboratory, College of Medicine, The Catholic University of Korea)
  • 투고 : 2023.09.14
  • 심사 : 2024.02.16
  • 발행 : 2024.08.30
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초록

Acetaldehyde dehydrogenase 2 (ALDH2) is the second enzyme involved in the breakdown of acetaldehyde into acetic acid during the process of alcohol metabolism. Roughly 40% of East Asians carry one or two ALDH2*2 alleles, and the presence of ALDH2 genetic mutations in individuals may affect the bone remodeling cycle owing to accumulation of acetaldehyde in the body. In this study, we investigated the effects of ALDH2 mutations on bone remodeling. In this study, we examined the effects of ALDH2 polymorphisms on in vitro osteogensis using human induced pluripotent stem cells (hiPSCs). We differentiated wild-type (ALDH2*1/*1-) and ALDH2*1/*2-genotyped hiPSCs into osteoblasts (OBs) and confirmed their OB characteristics. Acetaldehyde was administered to confirm the impact caused by the mutation during OB differentiation. Calcium deposits formed during osteogenesis were significantly decreased in ALDH2*1/*2 OBs. The expression of osteogenic markers were also decreased in acetaldehyde-treated OBs differentiated from the ALDH2*1/*2 hiPSCs. Furthermore, the impact of ALDH2 polymorphism and acetaldehyde-induced stress on inflammatory factors such as 4-hydroxynonenal and tumor necrosis factor α was confirmed. Our findings suggest that individuals with ALDH2 deficiency may face challenges in acetaldehyde breakdown, rendering them susceptible to disturbances in normal bone remodeling therefore, caution should be exercised regarding alcohol consumption. In this proof-of-concept study, we were able to suggest these findings as a result of a disease-in-a-dish concept using hiPSCs derived from individuals bearing a certain mutation. This study also shows the potential of patient-derived hiPSCs for disease modeling with a specific condition.

키워드

과제정보

This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (NRF-2020R1A2C3004123, NRF-2019R1A5A2027588, and NRF-2021R1C1C2004688). This research was also supported by the Catholic Institute of Cell Therapy in 2024 and by the Basic Medical Science Facilitation Program through the Catholic Medical Center of the Catholic University of Korea funded by the Catholic Education Foundation.

참고문헌

  1. Hoshi H, Hao W, Fujita Y, et al. Aldehyde-stress resulting from Aldh2 mutation promotes osteoporosis due to impaired osteoblastogenesis. J Bone Miner Res 2012;27:2015-2023
  2. Chen CH, Ferreira JC, Gross ER, Mochly-Rosen D. Targeting aldehyde dehydrogenase 2: new therapeutic opportunities. Physiol Rev 2014;94:1-34
  3. Takeshima K, Nishiwaki Y, Suda Y, et al. A missense single nucleotide polymorphism in the ALDH2 gene, rs671, is associated with hip fracture. Sci Rep 2017;7:428
  4. Chen YC, Yang LF, Lai CL, Yin SJ. Acetaldehyde enhances alcohol sensitivity and protects against alcoholism: evidence from alcohol metabolism in subjects with variant ALDH2*2 gene allele. Biomolecules 2021;11:1183
  5. Chang JS, Hsiao JR, Chen CH. ALDH2 polymorphism and alcohol-related cancers in Asians: a public health perspective. J Biomed Sci 2017;24:19
  6. Zhang R, Wang J, Xue M, Xu F, Chen Y. ALDH2-the genetic polymorphism and enzymatic activity regulation: their epidemiologic and clinical implications. Curr Drug Targets 2017;18:1810-1816
  7. Brooks PJ, Enoch MA, Goldman D, Li TK, Yokoyama A. The alcohol flushing response: an unrecognized risk factor for esophageal cancer from alcohol consumption. PLoS Med 2009;6:e50
  8. Hoshi H, Monoe F, Ohsawa I, Ohta S, Miyamoto T. Astaxanthin improves osteopenia caused by aldehyde-stress resulting from Aldh2 mutation due to impaired osteoblastogenesis. Biochem Biophys Res Commun 2020;527:270-275
  9. Yamaguchi J, Hasegawa Y, Kawasaki M, et al. ALDH2 polymorphisms and bone mineral density in an elderly Japanese population. Osteoporos Int 2006;17:908-913
  10. Wakabayashi Y, Tamura Y, Kouzaki K, et al. Acetaldehyde dehydrogenase 2 deficiency increases mitochondrial reactive oxygen species emission and induces mitochondrial protease Omi/HtrA2 in skeletal muscle. Am J Physiol Regul Integr Comp Physiol 2020;318:R677-R690
  11. Gao J, Hao Y, Piao X, Gu X. Aldehyde dehydrogenase 2 as a therapeutic target in oxidative stress-related diseases: post-translational modifications deserve more attention. Int J Mol Sci 2022;23:2682
  12. Kim Y, Rim YA, Yi H, Park N, Park SH, Ju JH. The generation of human induced pluripotent stem cells from blood cells: an efficient protocol using serial plating of reprogrammed cells by centrifugation. Stem Cells Int 2016;2016:1329459
  13. Han H, Kim Y, Mo H, et al. Preferential stimulation of melanocytes by M2 macrophages to produce melanin through vascular endothelial growth factor. Sci Rep 2022;12:6416
  14. Jung H, Rim YA, Park N, Nam Y, Ju JH. Restoration of osteogenesis by CRISPR/Cas9 genome editing of the mutated COL1A1 gene in osteogenesis imperfecta. J Clin Med 2021;10:3141
  15. Li K, Guo W, Li Z, et al. ALDH2 repression promotes lung tumor progression via accumulated acetaldehyde and DNA damage. Neoplasia 2019;21:602-614
  16. Marcadet L, Bouredji Z, Argaw A, Frenette J. The roles of RANK/RANKL/OPG in cardiac, skeletal, and smooth muscles in health and disease. Front Cell Dev Biol 2022;10:903657
  17. Joenje H. Alcohol, DNA and disease. Nature 2011;475:45-46
  18. Hsu LA, Tsai FC, Yeh YH, et al. Aldehyde dehydrogenase 2 ameliorates chronic alcohol consumption-induced atrial fibrillation through detoxification of 4-HNE. Int J Mol Sci 2020;21:6678
  19. Sreenathan RN, Padmanabhan R, Singh S. Teratogenic effects of acetaldehyde in the rat. Drug Alcohol Depend 1982;9:339-350
  20. Moser SC, van der Eerden BCJ. Osteocalcin-a versatile bone-derived hormone. Front Endocrinol (Lausanne) 2019;9:794
  21. Delmas PD, Eastell R, Garnero P, Seibel MJ, Stepan J; Committee of Scientific Advisors of the International Osteoporosis Foundation. The use of biochemical markers of bone turnover in osteoporosis. Osteoporos Int 2000;11 Suppl 6:S2-S17
  22. Ducy P, Desbois C, Boyce B, et al. Increased bone formation in osteocalcin-deficient mice. Nature 1996;382:448-452
  23. Gupte AA, Sabek OM, Fraga D, et al. Osteocalcin protects against nonalcoholic steatohepatitis in a mouse model of metabolic syndrome. Endocrinology 2014;155:4697-4705
  24. Zhang M, Tu WJ, Zhang Q, Wu XL, Zou XY, Jiang S. Osteocalcin reduces fat accumulation and inflammatory reaction by inhibiting ROS-JNK signal pathway in chicken embryonic hepatocytes. Poult Sci 2022;101:102026
  25. Zarkovic N. 4-hydroxynonenal as a bioactive marker of pathophysiological processes. Mol Aspects Med 2003;24:281-291
  26. Tsuneyama K, Harada K, Kono N, et al. Damaged interlobular bile ducts in primary biliary cirrhosis show reduced expression of glutathione-S-transferase-pi and aberrant expression of 4-hydroxynonenal. J Hepatol 2002;37:176-183
  27. Xiao F, Wei T, Xiao H, He W, Wei Q. Decreased serum 4-Hydroxynonenal level as a biomarker for the progression of steroid-induced osteonecrosis of the femoral head. J Orthop Surg Res 2023;18:732
  28. Huang RL, Yuan Y, Tu J, Zou GM, Li Q. Opposing TNF-α/IL-1β- and BMP-2-activated MAPK signaling pathways converge on Runx2 to regulate BMP-2-induced osteoblastic differentiation. Cell Death Dis 2014;5:e1187
  29. Yang S, Wang J, Brand DD, Zheng SG. Role of TNF-TNF receptor 2 signal in regulatory T cells and its therapeutic implications. Front Immunol 2018;9:784
  30. Fischer R, Marsal J, Gutta C, et al. Novel strategies to mimic transmembrane tumor necrosis factor-dependent activation of tumor necrosis factor receptor 2. Sci Rep 2017;7:6607
  31. Schett G. Effects of inflammatory and anti-inflammatory cytokines on the bone. Eur J Clin Invest 2011;41:1361-1366
  32. Vandooren B, Noordenbos T, Ambarus C, et al. Absence of a classically activated macrophage cytokine signature in peripheral spondylarthritis, including psoriatic arthritis. Arthritis Rheum 2009;60:966-975
  33. Chen JR, Shankar K, Nagarajan S, Badger TM, Ronis MJ. Protective effects of estradiol on ethanol-induced bone loss involve inhibition of reactive oxygen species generation in osteoblasts and downstream activation of the extracellular signal-regulated kinase/signal transducer and activator of transcription 3/receptor activator of nuclear factor-kappaB ligand signaling cascade. J Pharmacol Exp Ther 2008;324:50-59
  34. Kobayashi H, Nakamura S, Sato Y, et al. ALDH2 mutation promotes skeletal muscle atrophy in mice via accumulation of oxidative stress. Bone 2021;142:115739
  35. Ishii H, Afify SM, Hassan G, Salomon DS, Seno M. Cripto1 as a potential target of cancer stem cells for immunotherapy. Cancers (Basel) 2021;13:2491
  36. Sakharkar MK, Dhillon SK, Rajamanickam K, et al. Alteration in gene pair correlations in tryptophan metabolism as a hallmark in cancer diagnosis. Int J Tryptophan Res 2020;13:1178646920977013
  37. Tokunaga A, Oya T, Ishii Y, et al. PDGF receptor beta is a potent regulator of mesenchymal stromal cell function. J Bone Miner Res 2008;23:1519-1528
  38. Liu Y, Kou X, Chen C, et al. Chronic high dose alcohol induces osteopenia via activation of mTOR signaling in bone marrow mesenchymal stem cells. Stem Cells 2016;34:2157-2168
  39. Nanes MS. Tumor necrosis factor-alpha: molecular and cellular mechanisms in skeletal pathology. Gene 2003;321:1-15
  40. Dai J, Lin D, Zhang J, et al. Chronic alcohol ingestion induces osteoclastogenesis and bone loss through IL-6 in mice. J Clin Invest 2000;106:887-895