DOI QR코드

DOI QR Code

Nicotinamide as a therapeutic agent for bone diseases

  • Heein Yoon (Department of Molecular Genetics and Dental Pharmacology, Dental Multiomics Center, Dental Research Institute, School of Dentistry, Seoul National University) ;
  • Woo-Jin Kim (Department of Molecular Genetics and Dental Pharmacology, Dental Multiomics Center, Dental Research Institute, School of Dentistry, Seoul National University) ;
  • Young-Dan Cho (Department of Periodontology, Seoul National University Dental Hospital, Dental Research Institute, School of Dentistry, Seoul National University) ;
  • Hyun-Mo Ryoo (Department of Molecular Genetics and Dental Pharmacology, Dental Multiomics Center, Dental Research Institute, School of Dentistry, Seoul National University)
  • 투고 : 2024.08.28
  • 심사 : 2024.09.09
  • 발행 : 2024.09.30

초록

Nicotinamide (NAM), a water-soluble derivative of vitamin B3, has emerged as a potential therapeutic agent for bone-related disorders. In particular, it promotes bone metabolism and alleviates delayed tooth eruptions associated with cleidocranial dysplasia (CCD). NAM serves as a precursor for nicotinamide adenine dinucleotide, a key coenzyme involved in cellular metabolism that plays an essential role in oxidative phosphorylation and mitochondrial function. Recent research has highlighted the capacity of NAM to enhance osteogenic differentiation and regulate the interaction between osteoblasts and osteoclasts, which is critical for maintaining bone homeostasis. Moreover, the effect of NAM in preventing delayed tooth eruptions in CCD models underscores its potential as a noninvasive therapeutic option. Considering its safety profile and therapeutic potential, NAM is a promising candidate for long-term treatment of bone diseases and prevention of age-related bone disorders.

키워드

과제정보

This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT) (2020R1A4A1019423, RS-2023-00207971, RS-2024-00340752, RS-2024-00349549). This work also supported by the Bio & Medical Technology Development Program of the National Research Foundation (NRF) and funded by the Korean government (MSIT) (No. 2022M3A9F3082330).

참고문헌

  1. Rolfe HM. A review of nicotinamide: treatment of skin diseases and potential side effects. J Cosmet Dermatol 2014;13:324-8. doi: 10.1111/jocd.12119 
  2. Chen AC, Martin AJ, Choy B, Fernandez-Penas P, Dalziell RA, McKenzie CA, Scolyer RA, Dhillon HM, Vardy JL, Kricker A, St George G, Chinniah N, Halliday GM, Damian DL. A phase 3 randomized trial of nicotinamide for skin-cancer chemoprevention. N Engl J Med 2015;373:1618-26. doi: 10.1056/NEJMoa1506197 
  3. Iqbal T, Nakagawa T. The therapeutic perspective of NAD+ precursors in age-related diseases. Biochem Biophys Res Commun 2024;702:149590. doi: 10.1016/j.bbrc.2024.149590 
  4. Srivastava S. Emerging therapeutic roles for NAD+ metabolism in mitochondrial and age-related disorders. Clin Transl Med 2016;5:25. doi: 10.1186/s40169-016-0104-7 
  5. Mitchell SJ, Bernier M, Aon MA, Cortassa S, Kim EY, Fang EF, Palacios HH, Ali A, Navas-Enamorado I, Di Francesco A, Kaiser TA, Waltz TB, Zhang N, Ellis JL, Elliott PJ, Frederick DW, Bohr VA, Schmidt MS, Brenner C, Sinclair DA, Sauve AA, Baur JA, de Cabo R. Nicotinamide improves aspects of healthspan, but not lifespan, in mice. Cell Metab 2018;27:667-76.e4. doi: 10.1016/j.cmet.2018.02.001 
  6. Imai S, Armstrong CM, Kaeberlein M, Guarente L. Transcriptional silencing and longevity protein Sir2 is an NAD-dependent histone deacetylase. Nature 2000;403:795-800. doi: 10.1038/35001622 
  7. Avalos JL, Bever KM, Wolberger C. Mechanism of sirtuin inhibition by nicotinamide: altering the NAD+ cosubstrate specificity of a Sir2 enzyme. Mol Cell 2005;17:855-68. doi: 10.1016/j.molcel.2005.02.022 
  8. Hwang ES, Song SB. Nicotinamide is an inhibitor of SIRT1 in vitro, but can be a stimulator in cells. Cell Mol Life Sci 2017;74:3347-62. doi: 10.1007/s00018-017-2527-8 
  9. Meng Y, Ren Z, Xu F, Zhou X, Song C, Wang VY, Liu W, Lu L, Thomson JA, Chen G. Nicotinamide promotes cell survival and differentiation as kinase inhibitor in human pluripotent stem cells. Stem Cell Reports 2018;11:1347-56. doi: 10.1016/j.stemcr.2018.10.023 
  10. Ma L, Maruwge W, Strambi A, D'Arcy P, Pellegrini P, Kis L, de Milito A, Lain S, Brodin B. SIRT1 and SIRT2 inhibition impairs pediatric soft tissue sarcoma growth. Cell Death Dis 2014;5:e1483. doi: 10.1038/cddis.2014.385 
  11. Hill LJ, Williams AC. Meat intake and the dose of vitamin B3 - nicotinamide: cause of the causes of disease transitions, health divides, and health futures? Int J Tryptophan Res 2017;10:1178646917704662. doi: 10.1177/1178646917704662 
  12. Holubiec P, Leonczyk M, Staszewski F, Lazarczyk A, Jaworek AK, Wojas-Pelc A. Pathophysiology and clinical management of pellagra - a review. Folia Med Cracov 2021;61:125-37. doi: 10.24425/fmc.2021.138956 
  13. Kaymak Y, Onder M. An investigation of efficacy of topical niacinamide for the treatment of mild and moderate acne vulgaris. J Turk Acad Dermatol 2008;2:jtad82402a 
  14. Hakozaki T, Minwalla L, Zhuang J, Chhoa M, Matsubara A, Miyamoto K, Greatens A, Hillebrand GG, Bissett DL, Boissy RE. The effect of niacinamide on reducing cutaneous pigmentation and suppression of melanosome transfer. Br J Dermatol 2002;147:20-31. doi: 10.1046/j.1365-2133.2002.04834.x 
  15. Soma Y, Kashima M, Imaizumi A, Takahama H, Kawakami T, Mizoguchi M. Moisturizing effects of topical nicotinamide on atopic dry skin. Int J Dermatol 2005;44:197-202. doi: 10.1111/j.1365-4632.2004.02375.x 
  16. Elliott RB, Pilcher CC, Fergusson DM, Stewart AW. A population based strategy to prevent insulin-dependent diabetes using nicotinamide. J Pediatr Endocrinol Metab 1996;9:501-9. doi: 10.1515/jpem.1996.9.5.501 
  17. Yoon H, Kim HJ, Shin HR, Kim BS, Kim WJ, Cho YD, Ryoo HM. Nicotinamide improves delayed tooth eruption in Runx2+/- mice. J Dent Res 2021;100:423-31. doi: 10.1177/0022034520970471 
  18. Damian DL. Nicotinamide for skin cancer chemoprevention. Australas J Dermatol 2017;58:174-80. doi: 10.1111/ajd.12631 
  19. Wise GE, King GJ. Mechanisms of tooth eruption and orthodontic tooth movement. J Dent Res 2008;87:414-34. doi: 10.1177/154405910808700509 
  20. Heinrich J, Bsoul S, Barnes J, Woodruff K, Abboud S. CSF-1, RANKL and OPG regulate osteoclastogenesis during murine tooth eruption. Arch Oral Biol 2005;50:897-908. doi: 10.1016/j.archoralbio.2005.02.007 
  21. Ida-Yonemochi H, Noda T, Shimokawa H, Saku T. Disturbed tooth eruption in osteopetrotic (op/op) mice: histopathogenesis of tooth malformation and odontomas. J Oral Pathol Med 2002;31:361-73. doi: 10.1034/j.1600-0714.2002.00087.x 
  22. Sheng ZF, Ye W, Wang J, Li CH, Liu JH, Liang QC, Li S, Xu K, Liao EY. OPG knockout mouse teeth display reduced alveolar bone mass and hypermineralization in enamel and dentin. Arch Oral Biol 2010;55:288-93. doi: 10.1016/j.archoralbio.2010.02.007 
  23. Boyce BF, Xing L. Functions of RANKL/RANK/OPG in bone modeling and remodeling. Arch Biochem Biophys 2008;473:139-46. doi: 10.1016/j.abb.2008.03.018 
  24. Sai Charan KV, Sangeetha R, Santana N, Priya GH, Kumari M, Murali P, Gayathri VS. The tooth eruption and its abnormalities - a narrative review. SRM J Res Dent Sci 2022;13:109-14. doi: 10.4103/srmjrds.srmjrds_83_22 
  25. Suri L, Gagari E, Vastardis H. Delayed tooth eruption: pathogenesis, diagnosis, and treatment. A literature review. Am J Orthod Dentofacial Orthop 2004;126:432-45. doi: 10.1016/j.ajodo.2003.10.031 
  26. Ray JG, Dutta S, Sarangi S, Yadav P. Noneruption of teeth in amelogenesis imperfecta: a report of two cases and review. J Oral Maxillofac Pathol 2022;26:254-8. doi: 10.4103/jomfp.JOMFP_471_20 
  27. Kaloust S, Ishii K, Vargervik K. Dental development in Apert syndrome. Cleft Palate Craniofac J 1997;34:117-21. doi: 10.1597/1545-1569_1997_034_0117_ddias_2.3.co_2 
  28. Kreiborg S, Jensen BL. Tooth formation and eruption - lessons learnt from cleidocranial dysplasia. Eur J Oral Sci 2018;126(Suppl 1):72-80. doi: 10.1111/eos.12418 
  29. Canger EM, Celenk P, Yenisey M, Odyakmaz SZ. Amelogenesis imperfecta, hypoplastic type associated with some dental abnormalities: a case report. Braz Dent J 2010;21:170-4. doi: 10.1590/s0103-64402010000200014 
  30. Hohoff A, Joos U, Meyer U, Ehmer U, Stamm T. The spectrum of Apert syndrome: phenotype, particularities in orthodontic treatment, and characteristics of orthognathic surgery. Head Face Med 2007;3:10. doi: 10.1186/1746-160X-3-10 
  31. Kim HJ, Kim WJ, Ryoo HM. Post-translational regulations of transcriptional activity of RUNX2. Mol Cells 2020;43:160-7. doi: 10.14348/molcells.2019.0247 
  32. Ryoo HM, Kang HY, Lee SK, Lee KE, Kim JW. RUNX2 mutations in cleidocranial dysplasia patients. Oral Dis 2010;16:55-60. doi: 10.1111/j.1601-0825.2009.01623.x 
  33. Kim WJ, Shin HL, Kim BS, Kim HJ, Ryoo HM. RUNX2-modifying enzymes: therapeutic targets for bone diseases. Exp Mol Med 2020;52:1178-84. doi: 10.1038/s12276-020-0471-4 
  34. Barth FA, Menuci Neto A, Almeida-Pedrin RR, Ladewig VM, Conti ACCF. Therapeutic protocol for orthosurgical management of class III malocclusion in patients with cleidocranial dysostosis. J Craniofac Surg 2018;29:1642-7. doi: 10.1097/SCS.0000000000004656 
  35. Roberts T, Stephen L, Beighton P. Cleidocranial dysplasia: a review of the dental, historical, and practical implications with an overview of the South African experience. Oral Surg Oral Med Oral Pathol Oral Radiol 2013;115:46-55. doi: 10.1016/j.oooo.2012.07.435 
  36. Yoda S, Suda N, Kitahara Y, Komori T, Ohyama K. Delayed tooth eruption and suppressed osteoclast number in the eruption pathway of heterozygous Runx2/Cbfa1 knockout mice. Arch Oral Biol 2004;49:435-42. doi: 10.1016/j.archoralbio.2004.01.010 
  37. Martinez-Reyes I, Chandel NS. Mitochondrial TCA cycle metabolites control physiology and disease. Nat Commun 2020;11:102. doi: 10.1038/s41467-019-13668-3 
  38. Suh J, Kim NK, Shim W, Lee SH, Kim HJ, Moon E, Sesaki H, Jang JH, Kim JE, Lee YS. Mitochondrial fragmentation and donut formation enhance mitochondrial secretion to promote osteogenesis. Cell Metab 2023;35:345-60.e7. doi: 10.1016/j.cmet.2023.01.003 
  39. Yoon H, Park SG, Kim HJ, Shin HR, Kim KT, Cho YD, Moon JI, Park MS, Kim WJ, Ryoo HM. Nicotinamide enhances osteoblast differentiation through activation of the mitochondrial antioxidant defense system. Exp Mol Med 2023;55:1531-43. doi: 10.1038/s12276-023-01041-w 
  40. Kim HJ, Kim WJ, Shin HR, Yoon HI, Moon JI, Lee E, Lim JM, Cho YD, Lee MH, Kim HG, Ryoo HM. ROS-induced PADI2 downregulation accelerates cellular senescence via the stimulation of SASP production and NFκB activation. Cell Mol Life Sci 2022;79:155. doi: 10.1007/s00018-022-04186-5 
  41. Verdin E. NAD+ in aging, metabolism, and neurodegeneration. Science 2015;350:1208-13. doi: 10.1126/science.aac4854 
  42. Covarrubias AJ, Perrone R, Grozio A, Verdin E. NAD+ metabolism and its roles in cellular processes during ageing. Nat Rev Mol Cell Biol 2021;22:119-41. doi: 10.1038/s41580-020-00313-x 
  43. Song J, Li J, Yang F, Ning G, Zhen L, Wu L, Zheng Y, Zhang Q, Lin D, Xie C, Peng L. Nicotinamide mononucleotide promotes osteogenesis and reduces adipogenesis by regulating mesenchymal stromal cells via the SIRT1 pathway in aged bone marrow. Cell Death Dis 2019;10:336. doi: 10.1038/s41419-019-1569-2 
  44. Liang H, Gao J, Zhang C, Li C, Wang Q, Fan J, Wu Z, Wang Q. Nicotinamide mononucleotide alleviates Aluminum induced bone loss by inhibiting the TXNIP-NLRP3 inflammasome. Toxicol Appl Pharmacol 2019;362:20-7. doi: 10.1016/j.taap.2018.10.006 
  45. Huang RX, Tao J. Nicotinamide mononucleotide attenuates glucocorticoid‑induced osteogenic inhibition by regulating the SIRT1/PGC‑1α signaling pathway. Mol Med Rep 2020;22:145-54. doi: 10.3892/mmr.2020.11116 
  46. Kim HN, Ponte F, Warren A, Ring R, Iyer S, Han L, Almeida M. A decrease in NAD+ contributes to the loss of osteoprogenitors and bone mass with aging. NPJ Aging Mech Dis 2021;7:8. doi: 10.1038/s41514-021-00058-7 
  47. Ling M, Huang P, Islam S, Heruth DP, Li X, Zhang LQ, Li DY, Hu Z, Ye SQ. Epigenetic regulation of Runx2 transcription and osteoblast differentiation by nicotinamide phosphoribosyltransferase. Cell Biosci 2017;7:27. doi: 10.1186/s13578-017-0154-6 
  48. Li Y, He J, He X, Li Y, Lindgren U. Nampt expression increases during osteogenic differentiation of multi- and omnipotent progenitors. Biochem Biophys Res Commun 2013;434:117-23. doi: 10.1016/j.bbrc.2013.02.132 
  49. Hassan B, Baroukh B, Llorens A, Lesieur J, Ribbes S, Chaussain C, Saffar JL, Gosset M. NAMPT expression in osteoblasts controls osteoclast recruitment in alveolar bone remodeling. J Cell Physiol 2018;233:7402-14. doi: 10.1002/jcp.26584