Cell and Organ Transplantology. 2024; 12(2):84-93 (e2024122173)
DOI: 10.22494/cot.v12i2.173
Correction of vitamin D deficiency and the role of BsmI (rs1544410) VDR gene polymorphism in mineral metabolism related to cartilage regeneration in osteoarthritis
Sokolova I.
, Berbets A., Fediv O., Sokolov B.
- Bukovinian State Medical University, Chernivtsi, Ukraine
Abstract
Mesenchymal stem cells, osteoblasts, osteocytes, and osteoclasts maintain the physiological stability of bone tissue. Their activity is regulated by numerous molecular factors, among which vitamin D plays a crucial role. Vitamin D influences the functional interactions between bone cells and their niche through autocrine and paracrine effects, as well as by regulating calcium-phosphorus homeostasis. However, the role of vitamin D deficiency in mineral metabolism in patients with osteoarthritis (OA) and the approaches to the treatment of such patients based on the genotype of the BsmI (rs1544410) VDR gene polymorphism remain inconclusive.
The aim of the study was to correct vitamin D deficiency and disturbances in calcium-phosphorus homeostasis, and to clarify the pathogenetic role of the BsmI (rs1544410) VDR gene polymorphism in mineral metabolism in patients with OA.
Material and methods. 60 patients with acute knee OA, Kellgren-Lawrence stages I–III, and vitamin D deficiency were examined. Vitamin D and parathyroid hormone levels in peripheral blood were measured using enzyme immunoassay, total calcium and phosphorus concentrations by biochemical analysis, ionized calcium by ion-selective method, and calcitonin by immunochemiluminescence. Measurements were taken before the treatment and after 3 months of cholecalciferol supplementation at a dose of 6000 IU. Additionally, the genotypes of the BsmI (rs1544410) polymorphism of the VDR gene were analyzed using PCR-RFLP.
Results. Among the participants, 44 patients (73.3 %) were carriers of the unfavorable A allele of the BsmI polymorphism. Specifically, 38.3 % had the GA genotype, and 35.0 % had the AA genotype. The unfavorable AA genotype was associated with significantly lower levels of key mineral metabolism indicators: total calcium was 10.0 % lower, ionized calcium was 16.0 % lower, and phosphorus was 20.0 % lower compared to the GG genotype. Calcitonin levels were also significantly reduced in the context of vitamin D deficiency. Compared to the physiological norm, calcitonin levels were lower, with a decrease of 28.5 % in patients with the GG genotype, 50.5 % in those with the GA genotype, and 36.9 % in patients with the AA genotype, compared to their respective control groups.
In patients with the GG genotype, the parathyroid hormone level was significantly 2.2 times higher than in the control group. In those with the AA genotype, the level was 30.9 % higher than in the GG genotype and 3.2 times higher than in the control group. Similarly, in patients with the GA genotype, the level was 20.0 % higher than in the GG genotype and 3 times higher than in the control group.
After treatment with cholecalciferol, optimal vitamin D levels were achieved and increased by 39.8 % in patients with the GG genotype or by 30.0 % in those with the pathological A allele. In patients with the GG genotype, indicators of mineral metabolism significantly improved and normalized. Patients with the GA and AA genotypes reached reference values for ionized calcium and parathyroid hormone. However, despite positive changes in dynamics, total calcium, phosphorus, and calcitonin levels in patients carrying the A allele did not normalize in response to the treatment.
Conclusions. When correcting vitamin D deficiency and calcium-phosphorus homeostasis disorders with cholecalciferol, patients with the GG genotype of the BsmI polymorphism of the VDR gene exhibited significantly higher levels of vitamin D, calcium-phosphorus homeostasis markers, and calcitonin, as well as significantly lower levels of parathyroid hormone compared to the patients with the pathological A allele.
Keywords: VDR gene; BsmI polymorphism (rs1544410); vitamin D deficiency; cholecalciferol; mineral metabolism; parathyroid hormone; calcitonin
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| 1. Cherniavskyi VV, Bailo AIe, Onyshchuk LO, Tishchenko VV. Modern aspects of the practical use of symptomatic slow-acting drugs in the treatment of osteoarthritis Pain Joints Spine. 2024; 14(2):96-105. [in Ukrainian] https://doi.org/10.22141/pjs.14.2.2024.423 | ||||
| 2. Tripathy SK, Gantaguru A, Nanda SN, Velagada S, Srinivasan A, Mangaraj M. Association of vitamin D and knee osteoarthritis in younger individuals. World J Orthop. 2020; 11(10):418-25. https://doi.org/10.5312/wjo.v11.i10.418 PMid:33134104 PMCid:PMC7582112 |
||||
| 3. Kolesnichenko VA, Holka HH, Khanyk TIa, Veklich VM. Еpidemiology of knee osteoarthritis joint. Bulletin of Kharkiv National University named after V. N. Karazin. “Medicine” series. 2021; 43:115-26. [in Ukrainian] https://doi.org/10.26565/2313-6693-2021-43-12 | ||||
| 4. Rekalov DH, Holovach IIu., Dotsenko SIa, Daniuk IO, Kulynych RL, et al. (2023). Efficacy of undenatured type II collagen in osteoarthritis of the knee compared with the combination of glucosamine and chondroitin. Ukrainian Journal of Rheumatology. 2023;1(23):12-23. [in Ukrainian]. https://doi.org/10.32471/rheumatology.2707-6970.91.17717 |
||||
| 5. Zafeiris EP, Babis GC, Zafeiris CP, Chronopoulos E. Association of vitamin D, BMD and knee osteoarthritis in postmenopausal women. J Musculoskelet Neuronal Interact. 2021; 21(4):509-16. PMID: 34854390; PMCID: PMC8672405 | ||||
| 6. Lee WS, Kim HJ, Kim KI, Kim GB, Jin W. Intra-Articular Injection of Autologous Adipose Tissue-Derived Mesenchymal Stem Cells for the Treatment of Knee Osteoarthritis: A Phase IIb, Randomized, Placebo-Controlled Clinical Trial. Stem Cells Transl Med. 2019; 8(6):504-11. https://doi.org/10.1002/sctm.18-0122 PMid:30835956 PMCid:PMC6525553 |
||||
| 7. Yu H, Huang Y, Yang L. Research progress in the use of mesenchymal stem cells and their derived exosomes in the treatment of osteoarthritis. Ageing Res Rev. 2022; 80:101684. https://doi.org/10.1016/j.arr.2022.101684 PMid:35809775 |
||||
| 8. Giorgino R, Albano D, Fusco S, Peretti GM, Mangiavini L, Messina C. Knee Osteoarthritis: Epidemiology, Pathogenesis, and Mesenchymal Stem Cells: What Else Is New? An Update. Int J Mol Sci. 2023; 24(7):6405. https://doi.org/10.3390/ijms24076405 PMid:37047377 PMCid:PMC10094836 |
||||
| 9. Wei P, Bao R. Intra-Articular Mesenchymal Stem Cell Injection for Knee Osteoarthritis: Mechanisms and Clinical Evidence. Int J Mol Sci. 2022; 24(1):59. https://doi.org/10.3390/ijms24010059 PMid:36613502 PMCid:PMC9819973 |
||||
| 10. Drobotun OV, Kolotylov NN, Konovalenko VF, Ternovyi NK. Evaluation of the effect of dalargin on the level of vitamin D and melatonin in blood serum in patients with malignant bone tumors and polymorbidity. Pain Joints Spine. 2024;1(14):36-41. [in Ukrainian] https://doi.org/10.22141/pjs.14.1.2024.411 | ||||
| 11. Tripathy SK, Gantaguru A, Nanda SN, Velagada S, Srinivasan A, Mangaraj M. Association of vitamin D and knee osteoarthritis in younger individuals. World J Orthop. 2020; 11(10):418-25. https://doi.org/10.5312/wjo.v11.i10.418 PMid:33134104 PMCid:PMC7582112 |
||||
| 12. Hryhorieva NV, Solonenko TIu, Musiienko AS. Vitamin D deficiency during the COVID-19 pandemic and the war in Ukraine. Pain Joints Spine. 2023; 1(13):7-14. [in Ukrainian] https://doi.org/10.22141/pjs.13.1.2023.352 | ||||
| 13. Hryhorieva NV, Tronko MD, Kovalenko VM, Komisarenko SV, Tatarchuk TF, et al. Diagnosis, prevention and treatment of vitamin D deficiency in adults: Consensus of Ukrainian experts. Pain Joints Spine. 2023; 2(13):60-76. [in Ukrainian]. https://doi.org/10.22141/pjs.13.2.2023.368 |
||||
| 14. Charoenngam N. Vitamin D and Rheumatic Diseases: A Review of Clinical Evidence. Int J Mol Sci. 2021; 22(19):10659. https://doi.org/10.3390/ijms221910659 PMid:34639000 PMCid:PMC8508879 |
||||
| 15. Kaminskyi OV. Dosage of vitamin D. International Journal of Endocrinology. 2021; 5(17):435-442. [in Ukrainian]. https://doi.org/10.22141/2224-0721.17.5.2021.241524 |
||||
| 16. Usategui-Martín R, De Luis-Román DA, Fernández-Gómez JM, Ruiz-Mambrilla M, Pérez-Castrillón JL. Vitamin D Receptor (VDR) Gene Polymorphisms Modify the Response to Vitamin D Supplementation: A Systematic Review and Meta-Analysis. Nutrients. 2022; 14(2):360. https://doi.org/10.3390/nu14020360 PMid:35057541 PMCid:PMC8780067 |
||||
| 17. Lazaruk TIu. Correction of disorders of vitamin D deficiency and calcium-phosphorus homeostasis in patients with comorbid pathology: chronic pancreatitis and chronic obstructive pulmonary disease taking into account the BsmI polymorphism of the VDR gene. Journal of marine medicine. 2021; 2(91): 31-7 [in Ukrainian]. | ||||
| 18. Retamoso VR, Barbisan F, Moro GM, Maurer P, Rubio DV, et al. VDR, SOD-2, and CYP24A1 Gene Expression in Different Genotypes of BsmI SNP of the Vitamin D Receptor Gene in Individuals with Hypovitaminosis. Nutrients. 2023; 15(16):3565. https://doi.org/10.3390/nu15163565 PMid:37630755 PMCid:PMC10459192 |
||||
| 19. Li HM, Liu Y, Zhang RJ, Ding JY, Shen CL. Vitamin D receptor gene polymorphisms and osteoarthritis: A meta-analysis. Rheumatology. 2021; 60:538-48. [in English]. https://doi.org/10.1093/rheumatology/keaa644 PMid:33147632 |
||||
| 20. Kohn MD, Sassoon AA, Fernando ND. Classifications in Brief: Kellgren-Lawrence Classification of Osteoarthritis. Clin Orthop Relat Res. 2016; 474(8):1886-93. https://doi.org/10.1007/s11999-016-4732-4 PMid:26872913 PMCid:PMC4925407 |
||||
| 21. On the approval and implementation of medical and technological documents on the standardization of medical care for hypertension. Order of the Ministry of Health dated May 24, 2012 No. 384. Kyiv: Ministry of Health of Ukraine. 2012; 15-16. https://www.dec.gov.ua/wp-content/uploads/2019/11/384_2012_kn_ag.pdf [in Ukrainian]. | ||||
| 22. On the approval and implementation of medical and technological documents on the standardization of medical care for type 2 diabetes. Order of the Ministry of Health dated December 21, 2012 No. 1118. Kyiv: Ministry of Health of Ukraine. 2012; 15-16. https://www.dec.gov.ua/wp-content/uploads/2019/11/2012_1118ykpmd.pdf [in Ukrainian]. | ||||
| 23. Vina ER, Kwoh CK. Epidemiology of osteoarthritis: literature update. Curr Opin Rheumatol. 2018; 30(2):160-167. https://doi.org/10.1097/BOR.0000000000000479 PMid:29227353 PMCid:PMC5832048 |
||||
| 24. Uitterlinden AG, Fang Y, van Meurs JB, van Leeuwen H, Pols HA. Vitamin D receptor gene polymorphisms in relation to Vitamin D related disease states. J Steroid Biochem Mol Biol. 2004; 89-90(1-5):187-93. https://doi.org/10.1016/j.jsbmb.2004.03.083 PMid:15225770 |
||||
| 25. Chen J, Zhang J, Li J, Qin R, Lu N, Goltzman D, Miao D, Yang R. 1,25-Dihydroxyvitamin D Deficiency Accelerates Aging-related Osteoarthritis via Downregulation of Sirt1 in Mice. Int J Biol Sci. 2023; 19(2):610-24. https://doi.org/10.7150/ijbs.78785 PMid:36632467 PMCid:PMC9830508 |
||||
| 26. Portales-Castillo I, Simic P. PTH, FGF-23, Klotho and Vitamin D as regulators of calcium and phosphorus: Genetics, epigenetics and beyond. Front Endocrinol (Lausanne). 2022; 13:992666. https://doi.org/10.3389/fendo.2022.992666 PMid:36246903 PMCid:PMC9558279 |
||||
| 27. Seuter S, Pehkonen P, Heikkinen S, Carlberg C. Dynamics of 1α,25-dihydroxyvitamin D3-dependent chromatin accessibility of early vitamin D receptor target genes. Biochim Biophys Acta. 2013; 1829(12):1266-75. https://doi.org/10.1016/j.bbagrm.2013.10.003 PMid:24185200 |
||||
| 28. Nurminen V, Neme A, Seuter S, Carlberg C. The impact of the vitamin D-modulated epigenome on VDR target gene regulation. Biochim Biophys Acta Gene Regul Mech. 2018; 1861(8):697-705. https://doi.org/10.1016/j.bbagrm.2018.05.006 PMid:30018005 |
||||
| 29. Khatami F, Gorji A, Khoshchehreh M, Mashhadi R, Pishkuhi MA, Khajavi A, et al. Correlation between promoter hypermethylation of VDR, CLDN and CasR genes and recurrent stone formation. BMC Med Genomics. 2022; 15(1):1-9. https://doi.org/10.1186/s12920-022-01265-1 PMid:35546405 PMCid:PMC9092793 |
||||
| 30. Santos BR, Mascarenhas LP, Satler F, Boguszewski MC, Spritzer PM. Vitamin D deficiency in girls from South Brazil: a cross-sectional study on prevalence and association with vitamin D receptor gene variants. BMC Pediatr. 2012; 12:62. https://doi.org/10.1186/1471-2431-12-62 PMid:22681928 PMCid:PMC3464685 |
||||
| 31. Cipriani C, Pepe J, Colangelo L, Minisola S. Vitamin D and Secondary Hyperparathyroid States. Front Horm Res. 2018; 50:138-48. https://doi.org/10.1159/000486077 PMid:29597237 |
||||
| 32. Komisarenko SV, Vasylevska VM, Ivonin SP, Lisakovska OO, Labudzynskyi DO, et al. The combined effect of pyrazole-containing bisphosphonates and vitamin D3 in the correction of mineral metabolism disorders due to alimentary osteoporosis in rats. Medical and clinical chemistry. 2020; 22(3):5-16. [in Ukrainian]. https://doi.org/10.11603/mcch.2410-681X.2020.v.i3.11513 |
||||
| 33. Diedukh NV, Hryhorieva NV. The role of vitamin D in the functioning of bone cells. Physiological journal. 2023; 69(6):108-19. [in Ukrainian]. https://doi.org/10.15407/fz69.06.108 |
||||
| 34. Nakamichi Y, Udagawa N, Horibe K, Mizoguchi T, Yamamoto Y, et al. VDR in Osteoblast-Lineage Cells Primarily Mediates Vitamin D Treatment-Induced Increase in Bone Mass by Suppressing Bone Resorption. J. Bone Miner. Res. 2017; 32:1297-308. https://doi.org/10.1002/jbmr.3096 PMid:28177161 |
||||
| 35. Zarei A, Morovat A, Javaid K, Brown CP. Vitamin D receptor expression in human bone tissue and dose-dependent activation in resorbing osteoclasts. Bone Res. 2016; 4:16030. https://doi.org/10.1038/boneres.2016.30 PMid:27785371 PMCid:PMC5057180 |
||||
| 36. Driel M, Leeuwen J. Vitamin D and Bone: A Story of Endocrine and Auto/Paracrine Action in Osteoblasts. Nutrients. 2023; 15(3):480. https://doi.org/10.3390/nu15030480 PMid:36771187 PMCid:PMC9919888 |
||||
| 37. Geng S, Zhou S, Glowacki J. Age-related decline in 1α-hydroxylase/CYP27B1 and osteoblasto-genesis in human mesenchymal stem cells; Stimulation by PTH. Aging Cell. 2011; 10:962-71. https://doi.org/10.1111/j.1474-9726.2011.00735.x PMid:21824271 PMCid:PMC3215854 |
||||
| 38. 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; 136:156-9. https://doi.org/10.1016/j.jsbmb.2012.09.002 PMid:22982627 PMCid:PMC3548026 |
||||
| 39. Liu Y, Zhang X, Chen X, Zhang B, Dai L, et al. MiR146a modulates chondrogenesis of bone marrow mesenchymal stem cells by modulating Lsm11 expression. Am J Physiol Cell Physiol. 2023; 324(5):1007-16. https://doi.org/10.1152/ajpcell.00460.2022 PMid:36939200 PMCid:PMC10110697 |
||||
| 40. Merimi M, Lewalle P, Meuleman N, Agha DM, El-Kehdy H, et al. Mesenchymal Stem/Stromal Cell Therapeutic Features: The Bridge between the Bench and the Clinic. J Clin Med. 2021; 10(5):905. https://doi.org/10.3390/jcm10050905 PMid:33668878 PMCid:PMC7956428 |
||||
| 41. Girousse A, Mathieu M, Sastourné-Arrey Q, Monferran S, Casteilla L, et al. Endogenous Mobilization of Mesenchymal Stromal Cells: A Pathway for Interorgan Communication? Front. Cell Dev. Biol. 2021; 8:1534. https://doi.org/10.3389/fcell.2020.598520 PMid:33490065 PMCid:PMC7820193 |
||||
| 42. Vu AA, Bose S. Vitamin D(3) Release from Traditionally and Additively Manufactured Tricalcium Phosphate Bone Tissue Engineering Scaffolds. Ann Biomed Eng. 2020; 48:1025-33. https://doi.org/10.1007/s10439-019-02292-3 PMid:31168676 |
||||
| 43. Chen H, Ji M, Ding Z, Yan Y. Vitamin D3-loaded calcium citrate/calcium sulfate composite cement with enhanced physicochemical properties, drug release, and cytocompatibility. J Biomater Appl. 2020; 34:1343-1354. https://doi.org/10.1177/0885328220904498 PMid:32050854 |
||||
| 44. Borojevic A, Jaukovic A, Kukolj T, Mojsilovic S, Obradoviv H, et al. 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; 12(2):323. https://doi.org/10.3390/biom12020323 PMid:35204824 PMCid:PMC8868595 |
||||
| 45. Jiang H, Tang Q, Zheng D, Gu Y, Man C. Parathyroid hormone enhances the therapeutic effect of mesenchymal stem cells on temporomandibular joint osteoarthritis in rats. Am J Stem Cells. 2023; 12(4):73-82. PMID: 38021454; PMCID: PMC10658131. | ||||
| 46. Chen J, Zhang J, Li J, Qin R, Lu N, Goltzman D, et al. 1,25-Dihydroxyvitamin D Deficiency Accelerates Aging-related Osteoarthritis via Downregulation of Sirt1 in Mice. Int J Biol Sci. 2023; 19(2):610-24. https://doi.org/10.7150/ijbs.78785 PMid:36632467 PMCid:PMC9830508 |
||||
| 47. Chen K, Aenlle KK, Curtis KM, Roos BA, Howard GA. Hepatocyte growth factor (HGF) and 1,25-dihydroxyvitamin D together stimulate human bone marrow-derived stem cells toward the osteogenic phenotype by HGF-induced up-regulation of VDR. Bone. 2012; 51(1):69-77. https://doi.org/10.1016/j.bone.2012.04.002 PMid:22521434 |
||||
| 48. Badrachalam R, Mani V, Kumar R, Shafiulla A. Vitamin D receptor (BsmI) gene polymorphism and allele frequency among chronic kidney disease patients in south Indian population. Bioinformation. 2023; 19(4):380-4. https://doi.org/10.6026/97320630019380 PMid:37822821 PMCid:PMC10563556 |
||||
| 49. Malinovska TM, Orlenko VL, Popova VV, Sokolova LK, Kravchenko VI, Buldyhina VI. Vitamin D and VDR gene polymorphism as possible links in the genetic pathogenesis of obesity and diabetes in children and adolescents. Endocrinology. 2023; 28(3):276-87. [in Ukrainian]. https://doi.org/10.31793/1680-1466.2023.28-3.276 |
||||
Sokolova I, Berbets A, Fediv O, Sokolov B. Correction of vitamin D deficiency and the role of BsmI (rs1544410) VDR gene polymorphism in mineral metabolism related to cartilage regeneration in osteoarthritis. Cell Organ Transpl. 2024; 12(2):84-93 (e2024122173). doi: https://doi.org/10.22494/cot.v12i2.173
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