Українська English

ISSN 2522-9028 (Print)
ISSN 2522-9036 (Online)

Fiziologichnyi Zhurnal

is a scientific journal issued by the

Bogomoletz Institute of Physiology
National Academy of Sciences of Ukraine

Editor-in-chief: V.F. Sagach

The journal was founded in 1955 as
1955 – 1977 "Fiziolohichnyi zhurnal" (ISSN 0015 – 3311)
1978 – 1993 "Fiziologicheskii zhurnal" (ISSN 0201 – 8489)
1994 – 2016 "Fiziolohichnyi zhurnal" (ISSN 0201 – 8489)
2017 – "Fiziolohichnyi zhurnal" (ISSN 2522-9028)

Fiziol. Zh. 2023; 69(6): 108-119


N.V. Dedukh, N.V. Grygorieva

    State Institution “D.F. Chebotarev Institute of Gerontology of the NAMS of Ukraine”, Kyiv, Ukraine


The review summarizes current literature data on the importance of vitamin D in bone cell function. An analytical search was conducted in the PubMed, MEDLINE, Embase, Scopus, and Web of Science databases from January 1, 2018, to June 01, 2023. The vitamin D metabolite 1α,25(OH)2D3 plays an important role in the regulation of mineral homeostasis and bone metabolism. It has catabolic and anabolic actions on osteoblasts, osteocytes and mature osteoclasts. In this review, we describe the direct and indirect effects of 1α,25(OH)2D3 on the function of mesenchymal stromal cells (MSCs), osteoblasts, osteocytes, and osteoclasts. Among the targets of vitamin D action in bone cells are vitamin D receptor (VDR) and cytochrome P450 Family 27 Subfamily B Member 1 (CYP27B1). In osteoblasts and MSCs with CYP27B1 knockout, cell proliferation and differentiation are impaired, and in osteoclasts, the resorption activity and lifespan of these cells are increased. The role of VDR in bone cells was demonstrated in normal and VDR-knockout animal models. The relationship between 1α,25(OH)2D3 – VDR signal transduction by bone cells and calcium balance was analyzed. In osteocytes, as well as in osteoblasts, 1α,25(OH)2D3 regulates the expression of RANKL (receptor activator of nuclear factor kappa-B ligand)), and additionally in osteocytes regulates the expression of FGF-23. The interaction of many other factors in bone cells has been shown to control the biological activity of 1α,25(OH)2D3. Thus, the effect of vitamin D on bone cells is in the phase of active research and requires an in-depth study of the features of its autocrine and paracrine effects. Identification of the molecular links of the mechanism of action of 1α,25(OH)2D3 on bone metabolism will provide a fundamental basis for approaches to the treatment of vitamin D deficiency diseases.

Keywords: vitamin D; 1α,25(OH)2D3; vitamin D receptor (VDR); CYP27B1; CYP24A1; mesenchymal stromal cell; osteoblast; osteocyte; osteoclast.


  1. Florencio-Silva R, Sasso GR, Sasso-Cerri E, Simões MJ, Cerri PS. Biology of bone tissue: structure, function, and factors that influence bone cells. Biomed Res Int. 2015;2015:421746. CrossRef PubMed PubMedCentral
  2. Fakhry M, Hamade E, Badran B, Buchet R, Magne D. Molecular mechanisms of mesenchymal stem cell differentiation towards osteoblasts. World J Stem Cells. 2013;5(4):136-48. CrossRef PubMed PubMedCentral
  3. Povoroznyuk VV, Płudowski P, Balatska NI, Muts VYA, Klimovytskyi FV. Reznichenko NA, Sinenkyi OV, Mailyan EA. Pankiv IV. Vitamin D deficiency and insufficiency: epidemiology, diagnosis, prevention and treatment. Edited by VV Povoroznyuk, P. Płudowski. Kyiv. Publisher Zaslavsky OYu. 2014.
  4. Grugorieva NV, Tronko MD, Kovalenko VM, Komisarenko SV, Tatarchuk TF, Dedukh NV, Velikiy MM, Strafun SS, Komisarenko YuI, Kalashnikov AV, Orlenko VL, Pankiv VI, Shvets OV, Hogunska IV, Regeda SI. Diagnosis, prevention and treatment of vitamin D deficiency in adults: Consensus of Ukrainian experts. Pain Joints Spine. 2023;2:7-14.
  5. Bouillon R, Marcocci C, Carmeliet G, Bikle D, White JH, Dawson-Hughes B, Lips P, Munns CF, Lazaretti-Castro M, Giustina A, Bilezikian J. Skeletal and extraskeletal actions of vitamin D: current evidence and outstanding questions. Endocrin Rev. 2019 Aug 1;40(4):1109-51. CrossRef PubMed PubMedCentral
  6. Gil Á, Plaza-Diaz J, Mesa MD. Vitamin D: Classic and novel actions. Ann Nutr Metab. 2018;72(2):87-95. Lu M, Taylor BV, Körner H. Genomic Effects of the vitamin D receptor: potentially the link between vitamin D, immune cells, and multiple sclerosis. Front Immunol 2018;9:477. CrossRef PubMed PubMedCentral
  7. Mendes MM, Botelho PB, Ribeiro H. Vitamin D and musculoskeletal health: outstanding aspects to be considered in the light of current evidence. Endocrin Connect. 2022 Sep 26;11(10):e210596. CrossRef PubMed PubMedCentral
  8. Liu MC, Weng PW, Chen SC, Liu TH, Huang HW, Huang CT, Yang CT, Mishra VK, Yang MT. Immunologic, antiinflammatory, and anti-muscle damage profile of supplemented vitamin D3 in healthy adults on strenuous endurance exercise. Biology (Basel). 2023 Apr 26;12(5):657. CrossRef PubMed PubMedCentral
  9. Muresan GC, Hedesiu M, Lucaciu O, Boca S, Petrescu N. Effect of vitamin D on bone regeneration: A Review. Medicina (Kaunas). 2022 Sep 23;58(10):1337. CrossRef PubMed PubMedCentral
  10. Cignachi NP, Ribeiro A, Machado GDB, Cignachi AP, Kist LW, Bogo MR, Silva RBM, Campos MM. Bone regeneration in a mouse model of type 1 diabetes: Influence of sex, vitamin D3, and insulin. Life Sci. 2020;263:118593. CrossRef PubMed
  11. Kwiatek J, Jaroń A, Trybek G. Impact of the 25-hydroxycholecalciferol concentration and vitamin d deficiency treatment on changes in the bone level at the implant site during the process of osseointegration: A prospective, randomized, controlled clinical trial. J Clin Med. 2021;10:526. CrossRef PubMed PubMedCentral
  12. Carlberg C. Vitamin D and its target genes. Nutrients. 2022 Mar 24;14(7):1354. CrossRef PubMed PubMedCentral
  13. Christakos S, Li S, DeLa Cruz J, Verlinden L, Carmeliet G. Vitamin D and bone. Handb Exp Pharmacol. 2020;262:47-63. CrossRef PubMed
  14. El-Sharkawy A, Malki A. Vitamin D signaling in inflammation and cancer: molecular mechanisms and therapeutic implications. Molecules. 2020; 25(14):3219. CrossRef PubMed PubMedCentral
  15. Agostini D, Donati Zeppa S. Vitamin D, diet and musculoskeletal health. Nutrients. 2023, 15, 2902. CrossRef PubMed PubMedCentral
  16. Van Driel M, van Leeuwen JPTM. Vitamin D and bone: a story of endocrine and auto/paracrine action in osteoblasts. Nutrients. 2023;15:480. CrossRef PubMed PubMedCentral
  17. Braziunas MD, Cortizo AM. Vitamin D-VDR signaling in bone cells. Physiol Mini Rev. 2014;7(6):77-90.
  18. Verlinden L, Janssens I, Doms S, Vanhevel J, Carmeliet G, Verstuyf A. VDR expression in osteoclast precursors is not critical in bone homeostasis. J Steroid Biochem Mol Biol. 2019;195:105478. CrossRef PubMed
  19. Mahdavi R, Belgheisi G, Haghbin-Nazarpak M, Omidi M, Khojasteh A, Solati-Hashjin M. Bone tissue engineering gelatin-hydroxyapatite/graphene oxide scaffolds with the ability to release vitamin D: fabrication, characterization, and in vitro study. J Mater Sci Mater Med. 2020 Oct 31;31(11):97. CrossRef PubMed
  20. Kitase Y, Prideaux M. Targeting osteocytes vs osteoblasts. Bone. 2023;170:116724. CrossRef PubMed
  21. Geng S, Zhou S, Bi Z, Glowacki J. Vitamin D metabolism in human bone marrow stromal (mesenchymal stem) cells. Metabolism. 2013 Jun;62(6):768-77. CrossRef PubMed PubMedCentral
  22. Jo S, Yoon S, Lee SY, Kim SY, Park H, Han J, Choi SH, Han JS, Yang JH, Kim TH. DKK1 induced by 1,25D3 is required for the mineralization of osteoblasts. Cells. 2020 Jan 17;9(1):236. CrossRef PubMed PubMedCentral
  23. Posa F, Di Benedetto A, Colaianni G, Cavalcanti-Adam EA, Brunetti G, Porro C, Trotta T, Grano M, Mori G. Vitamin D effects on osteoblastic differentiation of mesenchymal stem cells from dental tissues. Stem Cells Int. 2016;2016:9150819. CrossRef PubMed PubMedCentral
  24. Lou YR, Toh TC, Tee YH, Yu H. 25-Hydroxyvitamin D3 induces osteogenic differentiation of human mesenchymal stem cells. Sci Rep. 2017 Feb 17;7:42816. CrossRef PubMed PubMedCentral
  25. Borojević A, Jauković A, Kukolj T, Mojsilović S, Obradović H, Trivanović D, Živanović M, Zečević Ž, Simić M, Gobeljić B, Vujić D, Bugarski D. Vitamin D3 stimulates proliferation capacity, expression of pluripotency markers, and osteogenesis of human bone marrow mesenchymal stromal/stem cells, partly through SIRT1 signaling. Biomolecules. 2022 Feb 18;12(2):323. CrossRef PubMed PubMedCentral
  26. Yamamoto Y, Yoshizawa T, Fukuda T, Shirode-Fukuda Y, Yu T, Sekine K, Sato T, Kawano H, Aihara K, Nakamichi Y, Watanabe T, Shindo M, Inoue K, Inoue E, Tsuji N, Hoshino M, Karsenty G, Metzger D, Chambon P, Kato S, Imai Y. Vitamin D receptor in osteoblasts is a negative regulator of bone mass control. Endocrinology. 2013 Mar;154(3):1008-20. CrossRef PubMed
  27. Bikle DD, Patzek S, Wang Y. Physiologic and pathophysiologic roles of extra renal CYP27b1: Case report and review. Bone Rep. 2018 Feb 26;8:255-67. CrossRef PubMed PubMedCentral
  28. Zhou S, Geng S, Glowacki J. Histone deacetylation mediates the rejuvenation of osteoblastogenesis by the combination of 25(OH)D3 and parathyroid hormone in MSCs from elders. J Steroid Biochem Mol Biol. 2013 Jul;136:156-9. CrossRef PubMed PubMedCentral
  29. Mori T, Horibe K, Koide M, Uehara S, Yamamoto Y, Kato S, Yasuda H, Takahashi N, Udagawa N, Nakamichi Y. The vitamin D receptor in osteoblast-lineage cells is essential for the proresorptive activity of 1α,25(OH)2D3 in vivo. Endocrinology. 2020 Nov 1;161(11):bqaa178. CrossRef PubMed PubMedCentral
  30. Goltzman D. Functions of vitamin D in bone. Histochem Cell Biol. 2018 Apr;149(4):305-12. CrossRef PubMed
  31. Goltzman D, Hendy GN, White JH. Vitamin D and its receptor during late development. Biochim Biophys Acta. 2015 Feb;1849(2):171-80. CrossRef PubMed
  32. Xu D, Gao HJ, Lu CY, Tian HM, Yu XJ. Vitamin D inhibits bone loss in mice with thyrotoxicosis by activating the OPG/RANKL and Wnt/β-catenin signaling pathways. Front Endocrinol (Lausanne). 2022 Nov 30;13:1066089. CrossRef PubMed PubMedCentral
  33. Van der Meijden K, Lips P, van Driel M, Heijboer AC, Schulten EA, den Heijer M, Bravenboer N. Primary human osteoblasts in response to 25-hydroxyvitamin D3, 1,25-dihydroxyvitamin D3 and 24R,25-dihydroxyvitamin D3. PLoS One. 2014 Oct 17;9(10):e110283. CrossRef PubMed PubMedCentral
  34. Yao P, Sun L, Xiong Q, Xu X, Li H, Lin X. Cholecalciferol supplementation promotes bone turnover in Chinese adults with vitamin D deficiency. J Nutr. 2018 May 1;148(5):746-51. CrossRef PubMed
  35. Wang D, Song J, Ma H. An in vitro experimental insight into the osteoblast responses to vitamin D3 and its metabolites. Pharmacology. 2018;101(5-6):225-35. CrossRef PubMed
  36. Vu AA, Bose S. Effects of vitamin D3 release from 3D printed calcium phosphate scaffolds on osteoblast and osteoclast cell proliferation for bone tissue engineering. RSC Adv. 2019;9(60):34847-53. CrossRef PubMed PubMedCentral
  37. Lieben L, Masuyama R, Torrekens S, Van Looveren R, Schrooten J, Baatsen P, Lafage-Proust MH, Dresselaers T, Feng JQ, Bonewald LF, Meyer MB, Pike JW, Bouillon R, Carmeliet G. Normocalcemia is maintained in mice under conditions of calcium malabsorption by vitamin Dinduced inhibition of bone mineralization. J Clin Invest. 2012 May;122(5):1803-15. CrossRef PubMed PubMedCentral
  38. Hemmatian H, Bakker AD, Klein-Nulend J, van Lenthe GH. Alterations in osteocyte lacunar morphology affect local bone tissue strains. J Mech Behav Biomed Mater. 2021 Nov;123:104730. CrossRef PubMed
  39. Al-Bari AA, Al-Mamun A. Current advances in regulation of bone homeostasis. FASEB Bioadv. 2020 Sep 19;2(11):668-79. CrossRef PubMed PubMedCentral
  40. Razzaque MS. Interactions between FGF23 and vitamin D. Endocr Connect. 2022 Sep 26;11(10):e220239. CrossRef PubMed PubMedCentral
  41. Lanske B, Densmore MJ, Erben RG. Vitamin D endocrine system and osteocytes. Bonekey Rep. 2014 Feb 5;3:494. CrossRef PubMed PubMedCentral
  42. Kato H, Ochiai-Shino H, Onodera S, Saito A, Shibahara T, Azuma T. Promoting effect of 1,25(OH)2 vitamin D3 in osteogenic differentiation from induced pluripotent stem cells to osteocyte-like cells. Open Biol. 2015;5:140201. CrossRef PubMed PubMedCentral
  43. Yajima A, Tsuchiya K, Burr DB, Wallace JM, Damrath JD, Inaba M, Tominaga Y, Satoh S, Nakayama T, Tanizawa T, Ogawa H, Ito A, Nitta K. The importance of biologically active vitamin D for mineralization by osteocytes after parathyroidectomy for renal hyperparathyroidism. JBMR Plus. 2019 Oct 23;3(11):e10234. CrossRef PubMed PubMedCentral
  44. Yuan Y, Jagga S, Martins JS, Rana R, Pajevic PD, Liu ES. Impaired 1,25 dihydroxyvitamin D3 action and hypophosphatemia underlie the altered lacuno-canalicular remodeling observed in the Hyp mouse model of XLH. PLoS One. 2021 May 27;16(5):e0252348. CrossRef PubMed PubMedCentral
  45. Lieben L, Carmeliet G. Vitamin D signaling in osteocytes: effects on bone and mineral homeostasis. Bone. 2013 Jun;54(2):237-43. CrossRef PubMed
  46. Rolvien T, Krause M, Jeschke A, Yorgan T, Puschel K, Schinke T, Busse B, Demay MB, Amling M. Vitamin D regulates osteocyte survival and perilacunar remodeling in human and murine bone. Bone. 2017;103:78-87. CrossRef PubMed
  47. Milovanovic P, Busse B. Phenomenon of osteocyte lacunar mineralization: indicator of former osteocyte death and a novel marker of impaired bone quality? Endocr Connect. 2020 Apr;9(4):R70-R80. CrossRef PubMed PubMedCentral
  48. Nakamichi Y, Udagawa N, Suda T, Takahashi N. Mechanisms involved in bone resorption regulated by vitamin D. J Steroid Biochem Mol Biol. 2018;177:70-6. CrossRef PubMed
  49. Ahmadi A, Mazloomnejad R, Kasravi M, Gholamine B, Bahrami S, Sarzaeem MM, Niknejad H. Recent advances on small molecules in osteogenic differentiation of stem cells and the underlying signaling pathways. Stem Cell Res Ther. 2022 Nov 12;13(1):518. CrossRef PubMed PubMedCentral
  50. Khalaf RM, Almudhi AA. The effect of vitamin D deficiency on the RANKL/OPG ratio in rats. J Oral Biol Craniofac Res. 2022 Mar-Apr;12(2):228-32. CrossRef PubMed PubMedCentral
  51. Gu J, Tong XS, Chen GH, Wang D, Chen Y, Yuan Y, Liu XZ, Bian JC, Liu ZP. Effects of 1α,25-(OH)2D3 on the formation and activity of osteoclasts in RAW264.7 cells. J Steroid Biochem Mol Biol. 2015 Aug;152:25-33. CrossRef PubMed
  52. Gu J, Tong X, Chen Y, Zhang C, Ma T, Li S, Min W, Yuan Y, Liu X, Bian J, Liu Z. Vitamin D inhibition of TRPV5 expression during osteoclast differentiation. Int J Endocrinol Metab. 2019 Oct 14;17(4):e91583. CrossRef PubMed PubMedCentral
  53. Haussler MR, Livingston S, Sabir ZL, Haussler CA, Jurutka PW. Vitamin D receptor mediates a myriad of biological actions dependent on its 1,25-dihydroxyvitamin D ligand: distinct regulatory themes revealed by induction of klotho and fibroblast growth factor-23. JBMR Plus. 2020 Dec 3;5(1):e10432. CrossRef PubMed PubMedCentral
  54. Kogawa M, Findlay DM, Anderson PH, Atkins GJ. Modulation of osteoclastic migration by metabolism of 25OH-vitamin D3. J Steroid Biochem Mol Biol. 2013 Jul;136:59-61. CrossRef PubMed
  55. Lu CL, Shyu JF, Wu CC, Hung CF, Liao MT, Liu WC, Zheng CM, Hou YC, Lin YF, Lu KC. Association of anabolic effect of calcitriol with osteoclast-derived Wnt10b secretion. Nutrients. 2018 Aug 25;10(9):1164. CrossRef PubMed PubMedCentral
  56. Starczak Y, Reinke DC, Barratt KR, Russell PK, Clarke MV, Davey RA, Atkins GJ, Anderson PH. Vitamin D receptor expression in mature osteoclasts reduces bone loss due to low dietary calcium intake in male mice. J Steroid Biochem Mol Biol. 2021 Jun;210:105857. CrossRef PubMed
  57. Verlinden L, Carmeliet G. Integrated view on the role of vitamin D actions on bone and growth plate homeostasis. JBMR Plus. 2021 Nov 18;5(12):e10577. CrossRef PubMed PubMedCentral
  58. Starczak Y, Reinke DC, Barratt KR, et al. Absence of vitamin D receptor in mature osteoclasts results in altered osteoclastic activity and bone loss. J Steroid Biochem Mol Biol. 2018;177:77-82. CrossRef PubMed
  59. Reinke DC, Kogawa M, Barratt KR, Morris HA, Anderson PH, Atkins GJ. Evidence for altered osteoclastogenesis in splenocyte cultures from Cyp27b1 knockout mice. J Steroid Biochem Mol Biol. 2016. Nov;164:353-60. CrossRef PubMed
  60. Perkins RS, Singh R, Abell AN, Krum SA, MirandaCarboni GA. The role of WNT10B in physiology and disease: A 10-year update. Front Cell Dev Biol. 2023 Feb 6;11:1120365. CrossRef PubMed PubMedCentral
  61. Cook CV, Islam MA, Smith BJ, Versypt ANF. Mathematical modeling of the effects of Wnt-10b on bone metabolism. Aiche J Am Institute Chemical Engineers, 18 Jun 2022, 68(12):e17809. CrossRef PubMed PubMedCentral
  62. Xu L, Qian Z, Wang S, Wang R, Pu X, Yang B, Zhou Q, Du C, Chen Q, Feng Z, Xu L, Zhu Z, Qiu Y, Sun X. Galectin-3 enhances osteogenic differentiation of precursor cells from patients with diffuse idiopathic skeletal hyperostosis via Wnt/β-catenin signaling. J Bone Miner Res. 2022 Apr;37(4):724-39. CrossRef PubMed
  63. Gu J, Zhang X, Zhang C, Li Y, Bian J, Liu X, Yuan Y, Zou H, Tong X, Liu Z. Galectin-3 contributes to the inhibitory effect of lα,25-(OH)2D3 on osteoclastogenesis. Int J Mol Sci. 2021 Dec 11;22(24):13334. CrossRef PubMed PubMedCentral

© National Academy of Sciences of Ukraine, Bogomoletz Institute of Physiology, 2014-2024.