Роль взаимодействия остеобластов и остеоцитов в условиях in vivo и в ходе процесса остеодифференцировки in vitro в ключе дальнейших перспектив применения для целей регенеративной медицины

Заболевания, ассоциированные с нарушением гомеостаза костной ткани, включая остеопороз, находятся среди патологий, которые лидируют по уровню летальности. Разработка и внедрение подходов тканевой инженерии, основанных на применении мезенхимных стволовых клеток, обещают стать высокоэффективным методом их терапии. Однако фундаментальные молекулярно-клеточные механизмы, нарушение которых приводит к развитию заболеваний костной ткани, требуют дополнительных исследований. Взаимодействия между остеобластами и остеоцитами костной ткани, несомненно, играют важную роль в поддержании баланса между процессами формирования кости и вовлечены в патогенез заболеваний костной ткани. Для более углубленного понимания различных аспектов этих взаимодействий необходима репрезентативная модель. Использование клеточных культур человека в качестве составной части такой модели более точно отображает физиологические нюансы, в отличие от клеточных культур, полученных из тканей модельных животных. Возможность создания систем совместного культивирования остеобластов и остеоцитов, полученных из мезенхимных стволовых клеток человека, и их применение в контексте трансляционной медицины находятся в фокусе внимания авторов настоящего обзора.

1. Zhivodernikov IV, Kirichenko TV, Markina YV, et al. Molecular and Cellular Mechanisms of Osteoporosis. Int J Mol Sci. 2023;24(21). DOI: 10.3390/ijms242115772.

2. Kenkre JS, Bassett J. The bone remodelling cycle. Ann Clin Biochem. 2018;55(3):308–27. DOI: 10.1177/0004563218759371.

3. Krasnova O, Neganova I. Assembling the Puzzle Pieces. Insights for in Vitro Bone Remodeling. Stem Cell Rev Rep. 2023;19(6):1635–1658. DOI: 10.1007/s12015-023-10558-6.

4. Ding P, Gao C, Gao Y, et al. Osteocytes regulate senescence of bone and bone marrow. Elife. 2022;11. DOI: 10.7554/eLife.81480.

5. Stains JP, Watkins MP, Grimston SK, et al. Molecular mechanisms of osteoblast/osteocyte regulation by connexin43. Calcif Tissue Int. 2013;94(1):55–67. DOI: 10.1007/s00223-013-9742-6.

6. Tu X, Delgado-Calle J, Condon KW, et al. Osteocytes mediate the anabolic actions of canonical Wnt/ beta-catenin signaling in bone. Proc Natl Acad Sci U S A. 2015;112(5):E478–86. DOI: 10.1073/pnas.1409857112

7. Rhee Y, Lee EY, Lezcano V, et al. Resorption controls bone anabolism driven by parathyroid hormone (PTH) receptor signaling in osteocytes. J Biol Chem. 2013;288(41):29809–20. DOI: 10.1074/jbc.M113.485938.

8. Chen Y, Xiao H, Liu Z, et al. Sirt1: An Increasingly Interesting Molecule with a Potential Role in Bone Metabolism and Osteoporosis. Biomolecules. 2024;14(8). DOI: 10.3390/biom14080970.

9. Udagawa N, Koide M, Nakamura M, et al. Osteoclast differentiation by RANKL and OPG signaling pathways. J Bone Miner Metab. 2021;39(1):19–26. DOI: 10.1007/s00774-020-01162-6.

10. Breathwaite E, Weaver J, Odanga J, et al. 3D Bioprinted Osteogenic Tissue Models for In Vitro Drug Screening. Molecules. 2020;25(15). DOI: 10.3390/molecules25153442.

11. Chen J, Liu D, Chen B, et al. The histone acetyltransferase Mof regulates Runx2 and Osterix for osteoblast differentiation. Cell Tissue Res. 2023;393(2):265–279. DOI: 10.1007/s00441-023-03791-5.

12. Riancho JA, Delgado-Calle J. [Osteoblast-osteoclast interaction mechanisms]. Reumatol Clin. 2011;7 Suppl 2:S1–4. DOI: 10.1016/j.reuma.2011.03.003.

13. Boyce BF. Advances in the regulation of osteoclasts and osteoclast functions. J Dent Res. 2013;92(10):860–7. DOI: 10.1177/0022034513500306.

14. Florencio-Silva R, Sasso GR, Sasso-Cerri E, et al. Biology of BoneTissue: Structure, Function, and FactorsThat Influence Bone Cells. Biomed Res Int. 2015;2015:421746. DOI: 10.1155/2015/421746.

15. Sims NA, Vrahnas C. Regulation of cortical and trabecular bone mass by communication between osteoblasts, osteocytes and osteoclasts. Arch Biochem Biophys. 2014;561:22–8. DOI: 10.1016/j.abb.2014.05.015.

16. Kitase Y, Prideaux M. Targeting osteocytes vs osteoblasts. Bone. 2023;170:116724. DOI: 10.1016/j.bone.2023.116724.

17. Bruderer M, Richards RG, Alini M, Stoddart MJ. Role and regulation of RUNX2 in osteogenesis. Eur Cell Mater. 2014;28:269–286. DOI: 10.22203/ecm.v028a19.

18. Capulli M, Paone R, Rucci N. Osteoblast and osteocyte: games without frontiers. Arch Biochem Biophys. 2014;561:3–12. DOI: 10.1016/j.abb.2014.05.003.

19. Ponzetti M, Rucci N. Osteoblast Differentiation and Signaling: Established Concepts and Emerging Topics. Int J Mol Sci. 2021;22(13). DOI: 10.3390/ijms22136651.

20. Heng BC, Cao T, Stanton LW, et al. Strategies for directing the differentiation of stem cells into the osteogenic lineage in vitro. J Bone Miner Res. 2004;19(9):1379–1394. DOI: 10.1359/JBMR.040714.

21. Valdoz JC, Johnson BC, Jacobs DJ, et al. The ECM: To Scaffold, or Not to Scaffold, That Is the Question. Int J Mol Sci. 2021;22(23):12690. DOI: 10.3390/ijms222312690.

22. Xing Q, Qian Z, Kannan B, et al. Osteogenic Differentiation Evaluation of an Engineered Extracellular Matrix Based Tissue Sheet for Potential Periosteum Replacement.ACSApplMaterInterfaces.2015;7(41):23239–47. DOI: 10.1021/acsami.5b07386.

23. Sauer H, Wartenberg M, Hescheler J. Reactive oxygen species as intracellular messengers during cell growth and differentiation. Cell Physiol Biochem. 2001;11(4):173–186. DOI: 10.1159/000047804.

24. Zhang M, Dai GC, Zhang YW, et al. Enhancing osteogenic differentiation of diabetic tendon stem/ progenitor cells through hyperoxia: Unveiling ROS/HIF-1alpha signalling axis. J Cell Mol Med. 2024;28(20):e70127. DOI: 10.1111/jcmm.70127.

25. Sheppard AJ, Barfield AM, Barton S, Dong Y. Understanding Reactive Oxygen Species in Bone Regeneration: A Glance at Potential Therapeutics and Bioengineering Applications. Front Bioeng Biotechnol. 2022;10:836764. DOI:10.3389/fbioe.2022.836764.

26. Lim KT, Hexiu J, Kim J, et al. Synergistic effects of orbital shear stress on in vitro growth and osteogenic differentiation of human alveolar bone-derived mesenchymal stem cells. Biomed Res Int. 2014;2014:316803. DOI: 10.1155/2014/316803.

27. Lim K, Kim J, Seonwoo H, et al. In vitro effects of low-intensity pulsed ultrasound stimulation on the osteogenic differentiation of human alveolar bone-derived mesenchymal stem cells for tooth tissue engineering. Biomed Res Int. 2013;2013:269724. DOI: 10.1155/2013/269724.

28. Tangporncharoen R, Silathapanasakul A, Tragoonlugkana P, et al. The extracts of osteoblast developed from adipose-derived stem cell and its role in osteogenesis. J Orthop Surg Res. 2024;19(1):255. DOI: 10.1186/s13018-024-04747-3.

29. Han Y, Yang J, Fang J, et al. The secretion profile of mesenchymal stem cells and potential applications in treating human diseases. Signal Transduct Target Ther. 2022;7(1):92. DOI: 10.1038/s41392-022-00932-0.

30. Mollentze J, Durandt C, Pepper MS. An In Vitro and In Vivo Comparison of Osteogenic Differentiation of Human Mesenchymal Stromal/Stem Cells. Stem Cells Int. 2021;2021:9919361. DOI: 10.1155/2021/9919361.

31. Langenbach F, Handschel J. Effects of dexamethasone, ascorbic acid and beta-glycerophosphate on the osteogenic differentiation of stem cells in vitro. Stem Cell Res Ther. 2013;4:117. DOI: 10.1186/scrt328.

32. Lyu LX, Zhang XF, Deegan AJ, et al. Comparing hydroxyapatite with osteogenic medium for the osteogenic differentiation of mesenchymal stem cells on PHBV nanofibrous scaffolds. J Biomater Sci Polym Ed. 2019;30(2):150–161. DOI: 10.1080/09205063.2018.1558485.

33. Wang L, Li ZY, Wang YP, et al. Dynamic Expression Profiles of Marker Genes in Osteogenic Differentiation of Human Bone Marrow-derived Mesenchymal Stem Cells. Chin Med Sci J. 2015;30(2):108–113. DOI: 10.1016/s1001-9294(15)30021-3.

34. Kostina D, Lobov A, Klausen P, et al. Isolation of Human Osteoblast Cells Capable for Mineralization and Synthetizing Bone-Related Proteins In Vitro from Adult Bone. Cells. 2022;11(21):3356. DOI: 10.3390/cells11213356.

35. Choi KM, Seo YK, Yoon HH, et al. Effect of ascorbic acid on bone marrow-derived mesenchymal stem cell proliferation and differentiation. J Biosci Bioeng. 2008;105(6):586–594. DOI: 10.1263/jbb.105.586.

36. Porter RM, Huckle WR, Goldstein AS. Effect of dexamethasone withdrawal on osteoblastic differentiation of bone marrow stromal cells. J Cell Biochem. 2003;90(1):13–22. DOI: 10.1002/jcb.10592.

37. Fiorentini E, Granchi D, Leonardi E, et al. Effects of osteogenic differentiation inducers on in vitro expanded adult mesenchymal stromal cells. Int J Artif Organs. 2011;34(10):998–1011. DOI: 10.5301/ijao.5000001.

38. Brown C, McKee C, Bakshi S, et al. Mesenchymal stem cells: Cell therapy and regeneration potential. J Tissue Eng Regen Med. 2019;13(9):1738–1755. DOI: 10.1002/term.2914.

39. Pino AM, Rosen CJ, Rodriguez JP. In osteoporosis, differentiation of mesenchymal stem cells (MSCs) improves bone marrow adipogenesis. Biol Res. 2012;45(3):279–287. DOI: 10.4067/S0716-97602012000300009.

40. PrallWC, Haasters F, Heggebo J, et al. Mesenchymal stem cells from osteoporotic patients feature impaired signal transduction but sustained osteoinduction in response to BMP-2 stimulation. Biochem Biophys Res Commun. 2013;440(4):617–622. DOI: 10.1016/j.bbrc.2013.09.114.

41. Lin H, Sohn J, Shen H, et al. Bone marrow mesenchymal stem cells: Aging and tissue engineering applications to enhance bone healing. Biomaterials. 2019;203:96–110. DOI: 10.1016/j.biomaterials.2018.06.026.

42. Qin L, Liu W, Cao H, Xiao G. Molecular mechanosensors in osteocytes. Bone Res. 2020;8:23. DOI: 10.1038/s41413-020-0099-y.

43. Delgado-Calle J, Bellido T. The osteocyte as a signaling cell. Physiol Rev. 2022;102(1):379–410. DOI: 10.1152/physrev.00043.2020.

44. Hart NH, Newton RU, Tan J, et al. Biological basis of bone strength: anatomy, physiology and measurement. J Musculoskelet Neuronal Interact. 2020;20(3):347–71. http://www.ismni.org/jmni/pdf/81/jmni_20_347.pdf

45. Marahleh A, Kitaura H, Ohori F, et al. The osteocyte and its osteoclastogenic potential. Front Endocrinol (Lausanne). 2023;14:1121727. DOI: 10.3389/fendo.2023.1121727.

46. Palander A, Fauch L, Turunen MJ, et al. Molecular Quantity Variations in Human-Mandibular-Bone Osteoid. Calcif Tissue Int. 2022;111(6):547–558. DOI: 10.1007/s00223-022-01017-4.

47. Sanchez-de-Diego C, Artigas N, Pimenta-Lopes C, et al. Glucose Restriction Promotes Osteocyte Specification by Activating a PGC-1alpha-Dependent Transcriptional Program. iScience. 2019;15:79–94. DOI: 10.1016/j.isci.2019.04.015.

48. Prideaux M, Loveridge N, Pitsillides AA, Farquharson C. Extracellular matrix mineralization promotes E11/gp38 glycoprotein expression and drives osteocytic differentiation. PLoS One. 2012;7(5):e36786. DOI: 10.1371/journal.pone.0036786.

49. Donmez BO, Karagur ER, Donmez AC, et al. Calciumdependent activation of PHEX, MEPE and DMP1 in osteocytes. Mol Med Rep. 2022;26(6):359. DOI: 10.3892/mmr.2022.12876.

50. Dussold C, Gerber C, White S, et al. DMP1 prevents osteocyte alterations, FGF23 elevation and left ventricular hypertrophy in mice with chronic kidney disease. Bone Res. 2019;7:12. DOI: 10.1038/s41413-019-0051-1.

51. Verbruggen SW. Role of the osteocyte in bone metastasis – The importance of networking. J Bone Oncol. 2024;44:100526. DOI: 10.1016/j.jbo.2024.100526.

52. Choi JUA, Kijas AW, Lauko J, Rowan AE. The Mechanosensory Role of Osteocytes and Implications for Bone Health and Disease States. Front Cell Dev Biol. 2022;9:770143. DOI: 10.3389/fcell.2021.770143.

53. Bernhardt A, Skottke J, von Witzleben M, Gelinsky M. Triple Culture of Primary Human Osteoblasts, Osteoclasts and Osteocytes as an In Vitro Bone Model. Int J Mol Sci. 2021;22(14) :7316. DOI: 10.3390/ijms22147316.

54. van der Plas A, Aarden EM, Feijen JH, et al. Characteristics and properties of osteocytes in culture. J Bone Miner Res. 1994;9(11):1697–1704. DOI: 10.1002/jbmr.5650091105.

55. Nasello G, Alaman-Diez P, Schiavi J, et al. Primary Human Osteoblasts Cultured in a 3D Microenvironment Create a Unique Representative Model of Their Differentiation Into Osteocytes. Front Bioeng Biotechnol. 2020;8:336. DOI: 10.3389/fbioe.2020.00336.

56. Kim J, Adachi T. Cell-fate decision of mesenchymal stem cells toward osteocyte differentiation is committed by spheroid culture. Sci Rep. 2021;11(1):13204. DOI: 10.1038/s41598-021-92607-z.

57. Kim J, Adachi T. Cell Condensation Triggers the Differentiation of Osteoblast Precursor Cells to Osteocyte-Like Cells. Front Bioeng Biotechnol. 2019;7:288. DOI: 10.3389/fbioe.2019.00288.

58. Shah KM, Stern MM, Stern AR, et al. Osteocyte isolation and culture methods. Bonekey Rep. 2016;5:838. DOI: 10.1038/bonekey.2016.65.

59. Mc Garrigle MJ, Mullen CA, Haugh MG, et al. Osteocyte differentiation and the formation of an interconnected cellular network in vitro. Eur Cell Mater. 2016;31:323–340. DOI: 10.22203/ecm.v031a21.

60. Greggi C, Cariati I, Onorato F, et al. PTX3 Effects on Osteogenic Differentiation in Osteoporosis: An In Vitro Study. Int J Mol Sci. 2021;22(11):5944. DOI: 10.3390/ijms22115944.

61. Skottke J, Gelinsky M, Bernhardt A. In Vitro Co-culture Model of Primary Human Osteoblasts and Osteocytes in Collagen Gels. Int J Mol Sci. 2019;20(8):1998. DOI: 10.3390/ijms20081998.

62. Yvanoff C, Willaert RG. Development of bone cell microarrays in microfluidic chips for studying osteocyte-osteoblast communication under fluid flow mechanical loading. Biofabrication. 2022;14(2). DOI: 10.1088/1758-5090/ac516e.

63. Zhou YH, Guo Y, Zhu JY, et al. Spheroid co-culture of BMSCs with osteocytes yields ring-shaped bone-like tissue that enhances alveolar bone regeneration. Sci Rep. 2022;12(1):14636. DOI: 10.1038/s41598-022-18675-x.

64. Vazquez M, Evans BA, Riccardi D, et al. A new method to investigate how mechanical loading of osteocytes controls osteoblasts. Front Endocrinol (Lausanne). 2014;5:208. DOI: 10.3389/fendo.2014.00208.

65. Wirsig K, Kilian D, von Witzleben M, et al. Impact of Sr(2+) and hypoxia on 3D triple cultures of primary human osteoblasts, osteocytes and osteoclasts. Eur J Cell Biol. 2022;101(3):151256. DOI: 10.1016/j.ejcb.2022.151256.

66. Wirsig K, Bacova J, Richter RF, et al. Cellular response of advanced triple cultures of human osteocytes, osteoblasts and osteoclasts to high sulfated hyaluronan (sHA3). Mater Today Bio. 2024;25:101006. DOI: 10.1016/j.mtbio.2024.101006.

67. Remmers SJA, de Wildt BWM, Vis MAM, et al. Osteoblast-osteoclast co-cultures: A systematic review and map of available literature. PLoS One. 2021;16(11):e0257724. DOI: 10.1371/journal.pone.0257724.

68. Lambertini E, Penolazzi L, Pandolfi A, et al. Human osteoclasts/osteoblasts 3D dynamic coculture system to study the beneficial effects of glucosamine on bone microenvironment. Int J Mol Med. 2021;47(4):57. DOI: 10.3892/ijmm.2021.4890.

69. Zhu S, Haussling V, Aspera-Werz RH, et al. Bisphosphonates Reduce Smoking-Induced Osteoporotic-Like Alterations by Regulating RANKL/OPG in an Osteoblast and Osteoclast Co-Culture Model. Int J Mol Sci. 2020;22(1):53. DOI: 10.3390/ijms22010053.

70. Sieberath A, Della Bella E, Ferreira AM, et al. A Comparison of Osteoblast and Osteoclast In Vitro Co-Culture Models and Their Translation for Preclinical Drug Testing Applications. Int J Mol Sci. 2020;21(3):912. DOI: 10.3390/ijms21030912.

71. XieC,LiangR,YeJ,etal.High-efficientengineering of osteo-callus organoids for rapid bone regeneration within one month. Biomaterials. 2022;288:121741. DOI: 10.1016/j.biomaterials.2022.121741.

72. Confalonieri D, Schwab A, Walles H, Ehlicke F. Advanced Therapy Medicinal Products: A Guide for Bone Marrow-derived MSC Application in Bone and Cartilage Tissue Engineering. Tissue Eng Part B Rev. 2018;24(2):155–169. DOI: 10.1089/ten.TEB.2017.0305.

73. Shanbhag S, Kampleitner C, Al-Sharabi N, et al. Functionalizing Collagen Membranes with MSC-Conditioned Media Promotes Guided Bone Regeneration in Rat Calvarial Defects. Cells. 2023;12(5):767. DOI: 10.3390/cells12050767.

74. Conrad B, Yang F. Hydroxyapatite-coated gelatin microribbon scaffolds induce rapid endogenous cranial bone regeneration in vivo. Biomater Adv. 2022;140:213050. DOI: 10.1016/j.bioadv.2022.213050.

75. Arjmand B, Sarvari M, Alavi-Moghadam S, et al. Prospect of Stem Cell Therapy and Regenerative Medicine in Osteoporosis. Front Endocrinol (Lausanne). 2020;11:430. DOI: 10.3389/fendo.2020.00430.

76. Phetfong J, Sanvoranart T, Nartprayut K, et al. Osteoporosis: the current status of mesenchymal stem cell-based therapy. Cell Mol Biol Lett. 2016;21:12. DOI: 10.1186/s11658-016-0013-1.

77. Theodosaki AM, Tzemi M, Galanis N, et al. Bone Regeneration with Mesenchymal Stem Cells in Scaffolds: Systematic Review of Human Clinical Trials. Stem Cell Rev Rep. 2024;20(4):938–966. DOI: 10.1007/s12015-024-10696-5.

78. Ansari S, Ito K, Hofmann S. Cell Sources for Human In vitro Bone Models. Curr Osteoporos Rep. 2021;19(1):88–100. DOI: 10.1007/s11914-020-00648-6.

79. Fong ELS, Toh TB, Yu H, Chow EK. 3D Culture as a Clinically Relevant Model for Personalized Medicine. SLAS Technol. 2017;22(3):245–253. DOI: 10.1177/2472630317697251.

80. Rodriguez JP, Rios S, Fernandez M, Santibanez JF. Differential activation of ERK1,2 MAP kinase signaling pathway in mesenchymal stem cell from control and osteoporotic postmenopausal women. J Cell Biochem. 2004;92(4):745–754. DOI: 10.1002/jcb.20119.