regmedjournalРегенерация органов и тканейРегенерация органов и тканей2949-5938Общество регенеративной медицины10.60043/2949-5938-2024-4-68-80regmedjournal-91Research ArticleОРИГИНАЛЬНЫЕ СТАТЬИORIGINAL ARTICLESNotch-сигнальный путь как механизм регуляции остеогенной дифференцировкиThe Notch signaling pathway as a mechanism for regulation of osteogenic differentiationПереплетчиковаД. А.PerepletchikovaD. A.

Переплетчикова Дарья Александровна — м.н.с. Лаборатории регенеративной биомедицины

194064, Санкт-Петербург, Тихорецкий пр-т, 4

Perepletchikova Daria Aleksandrovna — Junior Researcher, Laboratory of Regenerative Biomedicine

194064, Saint Petersburg, Tikhoretsky Ave., 4

perepletchikova@incras.ruСмирноваД. В.SmirnovaD. V.

Смирнова Дарья Владимировна — м.н.с. Лаборатории регенеративной биомедицины

194064, Санкт-Петербург, Тихорецкий пр-т, 4

Smirnova Daria Vladimirovna — Junior Researcher, Laboratory of Regenerative Biomedicine

194064, Saint Petersburg, Tikhoretsky Ave., 4

АзаркинаК. Е.AzarkinaK. E.

Азаркина Ксения Евгеньевна — ст. лаб.-исслед. Лаборатории регенеративной биомедицины 

194064, Санкт-Петербург, Тихорецкий пр-т, 4

Azarkina Kseniia Evgenievna — Laboratory Assistant, Laboratory of Regenerative Biomedicine

194064, Saint Petersburg, Tikhoretsky Ave., 4

СеменихинВ. А.SemenikchinV. A.

Семенихин Вячеслав Алексеевич — гендиректор 

119021, Москва, Инновационный центр «Сколково», Большой бульвар 42, стр. 1, офис 136

Semenikhin Viacheslav Alexeyevich — CEO & Founder of Palmira Biopharma LLC

119021, Moscow, Skolkovo Innovation Center, Bolshoy Blvd 42, str. 1, office 136

МалашичеваА. Б.MalashichevaA. B.

Малашичева Анна Борисовна — д.б.н., г.н.с., зав. Лаборатории регенеративной биомедицины 

194064, Санкт-Петербург, Тихорецкий пр-т, 4

Malashicheva Anna Borisovna — Doctor of Biological Sciences, Chief Researcher, Head of the Laboratory of Regenerative Biomedicine

194064, Saint Petersburg, Tikhoretsky Ave., 4

ФГБУН «Институт цитологии Российской академии наук»РоссияInstitute of Cytology of the Russian Academy of SciencesRussian FederationООО «Пальмира Биофарма»РоссияPalmira Biopharma LLCRussian Federation202422122025246880Copyright © Переплетчикова Д.А., Смирнова Д.В., Азаркина К.Е., Семенихин В.А., Малашичева А.Б., 20252025Переплетчикова Д.А., Смирнова Д.В., Азаркина К.Е., Семенихин В.А., Малашичева А.Б.Perepletchikova D.A., Smirnova D.V., Azarkina K.E., Semenikchin V.A., Malashicheva A.B.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.regmed-journal.ru/jour/article/view/91

Остеогенная дифференцировка — ключевой процесс в формировании и регенерации костной ткани, строго контролируемый различными молекулярными механизмами. Одним из важнейших регуляторов этого процесса является сигнальный путь Notch, способный как подавлять, так и стимулировать остеогенез в зависимости от стадии дифференцировки. В данном обзоре рассматриваются основные этапы остеогенной дифференцировки, роль сигнального пути Notch в регуляции активности клеток костной ткани, а также потенциальные подходы в таргетной модуляции этого пути для терапии заболеваний, сопровождающихся нарушением костного ремоделирования и патологической кальцификацией.

Osteogenic differentiation is a key process in the formation and regeneration of bone tissue, tightly regulated by various molecular mechanisms. One of the major regulators of this process is the Notch signaling pathway, which can either inhibit or promote osteogenesis depending on the stage of differentiation. This review discusses the main stages of osteogenic differentiation, the role of the Notch signaling pathway in regulating the activity of bone-forming cells, and potential approaches to its targeted modulation for the treatment of diseases associated with impaired bone remodeling and pathological calcification.

остеогенная дифференцировкасигнальный путь Notchмезенхимные стволовые клеткиостеобластыпатологическая кальцификацияosteogenic differentiationNotch signaling pathwayosteoblastsmesenchymal stem cellspathological calcificationРабота выполнена при поддержке гранта Российского научного фонда 23-15-00320.This work was supported by a grant from the Russian Science Foundation 23-15-00320.ReferencesAli A, Yun S. Multifaceted Role of Notch Signaling in Vascular Health and Diseases. Biomedicines. 2025;4(13):837.Ali A, Yun S. Multifaceted Role of Notch Signaling in Vascular Health and Diseases. Biomedicines. 2025;4(13):837.Arias AM, Fiuza U-M. Cell and molecular biology of Notch. J Endocrinol. 2007;3(194):459–474.Arias AM, Fiuza U-M. Cell and molecular biology of Notch. J Endocrinol. 2007;3(194):459–474.Artigas N, et al. Mitogen-activated Protein Kinase(MAPK)-regulated Interactions between Osterix and Runx2 Are Critical for the Transcriptional Osteogenic Program. Journal of Biological Chemistry. 2014;39(289):27105–27117.Artigas N, et al. Mitogen-activated Protein Kinase(MAPK)-regulated Interactions between Osterix and Runx2 Are Critical for the Transcriptional Osteogenic Program. Journal of Biological Chemistry. 2014;39(289):27105–27117.Azarkina K, Gromova E, Malashicheva A. “A Friend Among Strangers” or the Ambiguous Roles of Runx2. Biomolecules. 2024;11(14):1392.Azarkina K, Gromova E, Malashicheva A. “A Friend Among Strangers” or the Ambiguous Roles of Runx2. Biomolecules. 2024;11(14):1392.Bixel MG, et al. Angiogenesis is uncoupled from osteogenesis during calvarial bone regeneration. Nature Communications. 2024;1(15):4575.Bixel MG, et al. Angiogenesis is uncoupled from osteogenesis during calvarial bone regeneration. Nature Communications. 2024;1(15):4575.Bray SJ, Bigas A. Modes of Notch signalling in development and disease. Nature Reviews Molecular Cell Biology. 2025.Bray SJ, Bigas A. Modes of Notch signalling in development and disease. Nature Reviews Molecular Cell Biology. 2025.Chen L, et al. MicroRNA-34a Inhibits Osteoblast Differentiation and In Vivo Bone Formation of Human Stromal Stem Cells. Stem Cells. 2014;4(32):902–912.Chen L, et al. MicroRNA-34a Inhibits Osteoblast Differentiation and In Vivo Bone Formation of Human Stromal Stem Cells. Stem Cells. 2014;4(32):902–912.Dilawar M, et al. Notch signaling pathway in osteogenesis, bone development, metabolism, and diseases. The FASEB Journal. 2025;4(39).Dilawar M, et al. Notch signaling pathway in osteogenesis, bone development, metabolism, and diseases. The FASEB Journal. 2025;4(39).Dishowitz MI, et al. Notch signaling components are upregulated during both endochondral and intramembranous bone regeneration. Journal of Orthopaedic Research. 2012;2(30):296–303.Dishowitz MI, et al. Notch signaling components are upregulated during both endochondral and intramembranous bone regeneration. Journal of Orthopaedic Research. 2012;2(30):296–303.Dong Z, et al. Gamma-Secretase Inhibitor(DAPT), a potential therapeutic target drug, caused neurotoxicity in planarian regeneration by inhibiting Notch signaling pathway. Science of The Total Environment. 2021;(781):146735.Dong Z, et al. Gamma-Secretase Inhibitor(DAPT), a potential therapeutic target drug, caused neurotoxicity in planarian regeneration by inhibiting Notch signaling pathway. Science of The Total Environment. 2021;(781):146735.Driscoll K, Cruz AD, Butcher JT. Inflammatory and Biomechanical Drivers of Endothelial-Interstitial Interactions in Calcific Aortic Valve Disease. Circulation Research. 2021;9(128):1344–1370.Driscoll K, Cruz AD, Butcher JT. Inflammatory and Biomechanical Drivers of Endothelial-Interstitial Interactions in Calcific Aortic Valve Disease. Circulation Research. 2021;9(128):1344–1370.Garg V, et al. Mutations in NOTCH1 cause aortic valve disease. Nature. 2005;7056(437):270–274.Garg V, et al. Mutations in NOTCH1 cause aortic valve disease. Nature. 2005;7056(437):270–274.Giuliani N, et al. New Insights into Osteogenic and Chondrogenic Differentiation of Human Bone Marrow Mesenchymal Stem Cells and Their Potential Clinical Applications for Bone Regeneration in Pediatric Orthopaedics. Stem Cells International. 2013;(2013):1–11.Giuliani N, et al. New Insights into Osteogenic and Chondrogenic Differentiation of Human Bone Marrow Mesenchymal Stem Cells and Their Potential Clinical Applications for Bone Regeneration in Pediatric Orthopaedics. Stem Cells International. 2013;(2013):1–11.Gordon WR, Arnett KL, Blacklow SC. The molecular logic of Notch signaling — a structural and biochemical perspective. Journal of Cell Science. 2008;19(121):3109–3119.Gordon WR, Arnett KL, Blacklow SC. The molecular logic of Notch signaling — a structural and biochemical perspective. Journal of Cell Science. 2008;19(121):3109–3119.Groth C, Fortini ME. Therapeutic approaches to modulating Notch signaling: Current challenges and future prospects. Seminars in Cell & Developmental Biology. 2012;4(23):465–472.Groth C, Fortini ME. Therapeutic approaches to modulating Notch signaling: Current challenges and future prospects. Seminars in Cell & Developmental Biology. 2012;4(23):465–472.He Y, Zou L. Notch-1 inhibition reduces proliferation and promotes osteogenic differentiation of bone marrow mesenchymal stem cells. Experimental and Therapeutic Medicine. 2019.He Y, Zou L. Notch-1 inhibition reduces proliferation and promotes osteogenic differentiation of bone marrow mesenchymal stem cells. Experimental and Therapeutic Medicine. 2019.Iline-Vul T, et al. Osteopontin regulates biomimetic calcium phosphate crystallization from disordered mineral layers covering apatite crystallites. Scientific Reports. 2020;1(10):15722.Iline-Vul T, et al. Osteopontin regulates biomimetic calcium phosphate crystallization from disordered mineral layers covering apatite crystallites. Scientific Reports. 2020;1(10):15722.Infante A, Rodríguez CI. Osteogenesis and aging: lessons from mesenchymal stem cells. Stem Cell Research & Therapy. 2018;1(9):244.Infante A, Rodríguez CI. Osteogenesis and aging: lessons from mesenchymal stem cells. Stem Cell Research & Therapy. 2018;1(9):244.James AW. Review of Signaling Pathways Governing MSC Osteogenic and Adipogenic Differentiation. Scientifica. 2013;(2013):1–17.James AW. Review of Signaling Pathways Governing MSC Osteogenic and Adipogenic Differentiation. Scientifica. 2013;(2013):1–17.Ji Y, Ke Y, Gao S. Intermittent activation of notch signaling promotes bone formation. American journal of translational research. 2017;6(9):2933–2944.Ji Y, Ke Y, Gao S. Intermittent activation of notch signaling promotes bone formation. American journal of translational research. 2017;6(9):2933–2944.Kachanova OS, et al. Ex vivo model of pathological calcification of human aortic valve. Frontiers in Cardiovascular Medicine. 2024;(11).Kachanova OS, et al. Ex vivo model of pathological calcification of human aortic valve. Frontiers in Cardiovascular Medicine. 2024;(11).Kamalakar A, et al. Delivery of a Jagged1-PEG-MAL hydrogel with pediatric human bone cells regenerates critically sized craniofacial bone defects. eLife. 2024;(13).Kamalakar A, et al. Delivery of a Jagged1-PEG-MAL hydrogel with pediatric human bone cells regenerates critically sized craniofacial bone defects. eLife. 2024;(13).Kamath BM, et al. NOTCH2 mutations in Alagille syndrome. Journal of Medical Genetics. 2012;2(49):138–144.Kamath BM, et al. NOTCH2 mutations in Alagille syndrome. Journal of Medical Genetics. 2012;2(49):138–144.Kang J-H, et al. Vascular calcification and cellular signaling pathways as potential therapeutic targets. Life Sciences. 2024;(336):122309.Kang J-H, et al. Vascular calcification and cellular signaling pathways as potential therapeutic targets. Life Sciences. 2024;(336):122309.Klose R, et al. Soluble Notch ligand and receptor peptides act antagonistically during angiogenesis. Cardiovascular Research. 2015;1(107):153–163.Klose R, et al. Soluble Notch ligand and receptor peptides act antagonistically during angiogenesis. Cardiovascular Research. 2015;1(107):153–163.Komori T, et al. Targeted Disruption of Results in a Complete Lack of Bone Formation owing to Maturational Arrest of Osteoblasts. Cell. 1997;5(89):755–764.Komori T, et al. Targeted Disruption of Results in a Complete Lack of Bone Formation owing to Maturational Arrest of Osteoblasts. Cell. 1997;5(89):755–764.Komori T. Regulation of osteoblast differentiation by transcription factors. Journal of Cellular Biochemistry. 2006;5(99):1233–1239.Komori T. Regulation of osteoblast differentiation by transcription factors. Journal of Cellular Biochemistry. 2006;5(99):1233–1239.Kostina A, et al. Different Notch signaling in cells from calcified bicuspid and tricuspid aortic valves. Journal of Molecular and Cellular Cardiology. 2018;(114):211–219.Kostina A, et al. Different Notch signaling in cells from calcified bicuspid and tricuspid aortic valves. Journal of Molecular and Cellular Cardiology. 2018;(114):211–219.Kostina A, et al. Human aortic endothelial cells have osteogenic Notch-dependent properties in co-culture with aortic smooth muscle cells. Biochemical and Biophysical Research Communications. 2019;2(514):462–468.Kostina A, et al. Human aortic endothelial cells have osteogenic Notch-dependent properties in co-culture with aortic smooth muscle cells. Biochemical and Biophysical Research Communications. 2019;2(514):462–468.Kraler S, et al. Calcific aortic valve disease: from molecular and cellular mechanisms to medical therapy. European Heart Journal. 2022;7(43):683–697.Kraler S, et al. Calcific aortic valve disease: from molecular and cellular mechanisms to medical therapy. European Heart Journal. 2022;7(43):683–697.Lanzillotti C, et al. Long Non-coding RNAs and MicroRNAs Interplay in Osteogenic Differentiation of Mesenchymal Stem Cells. Frontiers in Cell and Developmental Biology. 2021;(9).Lanzillotti C, et al. Long Non-coding RNAs and MicroRNAs Interplay in Osteogenic Differentiation of Mesenchymal Stem Cells. Frontiers in Cell and Developmental Biology. 2021;(9).Li G, et al. Abnormal mechanical stress on bicuspid aortic valve induces valvular calcification and inhibits Notch1/NICD/Runx2 signal. PeerJ. 2023;(11):e14950.Li G, et al. Abnormal mechanical stress on bicuspid aortic valve induces valvular calcification and inhibits Notch1/NICD/Runx2 signal. PeerJ. 2023;(11):e14950.Liang X, et al. Key regulators of vascular calcification in chronic kidney disease: Hyperphosphatemia, BMP2, and RUNX2. PeerJ. 2024;(12):e18063.Liang X, et al. Key regulators of vascular calcification in chronic kidney disease: Hyperphosphatemia, BMP2, and RUNX2. PeerJ. 2024;(12):e18063.Lin X, et al. The Bone Extracellular Matrix in Bone Formation and Regeneration. Frontiers in Pharmacology. 2020;(11).Lin X, et al. The Bone Extracellular Matrix in Bone Formation and Regeneration. Frontiers in Pharmacology. 2020;(11).Liu J, et al. The management of bone defect using long non-coding RNA as a potential biomarker for regulating the osteogenic differentiation process. Molecular Biology Reports. 2022;3(49):2443–2453.Liu J, et al. The management of bone defect using long non-coding RNA as a potential biomarker for regulating the osteogenic differentiation process. Molecular Biology Reports. 2022;3(49):2443–2453.Liu P, et al. Anabolic actions of Notch on mature bone. Proceedings of the National Academy of Sciences. 2016;15(113).Liu P, et al. Anabolic actions of Notch on mature bone. Proceedings of the National Academy of Sciences. 2016;15(113).Lobov A, et al. Mesenchymal Cells Retain the Specificity of Embryonal Origin During Osteogenic Differentiation. Stem Cells. 2024;1(42):76–89.Lobov A, et al. Mesenchymal Cells Retain the Specificity of Embryonal Origin During Osteogenic Differentiation. Stem Cells. 2024;1(42):76–89.Lobov A, et al. Similar, but not the same: multiomics comparison of human valve interstitial cells and osteoblast osteogenic differentiation expanded with an estimation of data-dependent and data-independent PASEF proteomics. GigaScience. 2025;(14).Lobov A, et al. Similar, but not the same: multiomics comparison of human valve interstitial cells and osteoblast osteogenic differentiation expanded with an estimation of data-dependent and data-independent PASEF proteomics. GigaScience. 2025;(14).Lobov AA, et al. Crenigacestat(LY3039478) inhibits osteogenic differentiation of human valve interstitial cells from patients with aortic valve calcification in vitro. Frontiers in Cardiovascular Medicine. 2022;(9).Lobov AA, et al. Crenigacestat(LY3039478) inhibits osteogenic differentiation of human valve interstitial cells from patients with aortic valve calcification in vitro. Frontiers in Cardiovascular Medicine. 2022;(9).McDaniell R, et al. NOTCH2 Mutations Cause Alagille Syndrome, a Heterogeneous Disorder of the Notch Signaling Pathway. The American Journal of Human Genetics. 2006;1(79):169–173.McDaniell R, et al. NOTCH2 Mutations Cause Alagille Syndrome, a Heterogeneous Disorder of the Notch Signaling Pathway. The American Journal of Human Genetics. 2006;1(79):169–173.Menon V, Lincoln J. The Genetic Regulation of Aortic Valve Development and Calcific Disease. Frontiers in Cardiovascular Medicine. 2018;(5).Menon V, Lincoln J. The Genetic Regulation of Aortic Valve Development and Calcific Disease. Frontiers in Cardiovascular Medicine. 2018;(5).Nakashima K, et al. The Novel Zinc Finger-Containing Transcription Factor Osterix Is Required for Osteoblast Differentiation and Bone Formation. Cell. 2002;1(108):17–29.Nakashima K, et al. The Novel Zinc Finger-Containing Transcription Factor Osterix Is Required for Osteoblast Differentiation and Bone Formation. Cell. 2002;1(108):17–29.Niu Z, et al. Vascular Calcification: New Insights Into BMP Type I Receptor A. Frontiers in Pharmacology. 2022;(13).Niu Z, et al. Vascular Calcification: New Insights Into BMP Type I Receptor A. Frontiers in Pharmacology. 2022;(13).Novak S, et al. Endothelial to mesenchymal Notch signaling regulates skeletal repair. JCI insight. 2024;12(9).Novak S, et al. Endothelial to mesenchymal Notch signaling regulates skeletal repair. JCI insight. 2024;12(9).Osathanon T, et al. Jagged1 promotes mineralization in human bone-derived cells. Archives of Oral Biology. 2019;(99):134–140.Osathanon T, et al. Jagged1 promotes mineralization in human bone-derived cells. Archives of Oral Biology. 2019;(99):134–140.Pakvasa M, et al. Notch signaling: Its essential roles in bone and craniofacial development. Genes & Diseases. 2021;1(8):8–24.Pakvasa M, et al. Notch signaling: Its essential roles in bone and craniofacial development. Genes & Diseases. 2021;1(8):8–24.Perepletchikova D, et al. Endothelial-mesenchymal crosstalk drives osteogenic differentiation of human osteoblasts through Notch signaling. Cell Communication and Signaling. 2025;1(23):100.Perepletchikova D, et al. Endothelial-mesenchymal crosstalk drives osteogenic differentiation of human osteoblasts through Notch signaling. Cell Communication and Signaling. 2025;1(23):100.Perepletchikova D, Malashicheva A. Communication between endothelial cells and osteoblasts in regulation of bone homeostasis: Notch players. Stem Cell Research & Therapy. 2025;1(16):56.Perepletchikova D, Malashicheva A. Communication between endothelial cells and osteoblasts in regulation of bone homeostasis: Notch players. Stem Cell Research & Therapy. 2025;1(16):56.Qu Y, et al. The crucial role of SPP1 in osteoporosis, osteoarthritis, and cancer. Pharmaceutical Science Advances. 2025;(3):100074.Qu Y, et al. The crucial role of SPP1 in osteoporosis, osteoarthritis, and cancer. Pharmaceutical Science Advances. 2025;(3):100074.Ramasamy SK, et al. Endothelial Notch activity promotes angiogenesis and osteogenesis in bone. Nature. 2014;7492(507):376–380.Ramasamy SK, et al. Endothelial Notch activity promotes angiogenesis and osteogenesis in bone. Nature. 2014;7492(507):376–380.Remark LH, et al. Loss of Notch signaling in skeletal stem cells enhances bone formation with aging. Bone Research. 2023;1(11):50.Remark LH, et al. Loss of Notch signaling in skeletal stem cells enhances bone formation with aging. Bone Research. 2023;1(11):50.Rosset EM, Bradshaw AD. SPARC/osteonectin in mineralized tissue. Matrix Biology. 2016.(52–54):78–87.Rosset EM, Bradshaw AD. SPARC/osteonectin in mineralized tissue. Matrix Biology. 2016.(52–54):78–87.Rutkovskiy A, et al. Valve Interstitial Cells: The Key to Understanding the Pathophysiology of Heart Valve Calcification. Journal of the American Heart Association. 2017;9(6).Rutkovskiy A, et al. Valve Interstitial Cells: The Key to Understanding the Pathophysiology of Heart Valve Calcification. Journal of the American Heart Association. 2017;9(6).Salhotra A, et al. Mechanisms of bone development and repair. Nature Reviews Molecular Cell Biology. 2020;11(21):696–711.Salhotra A, et al. Mechanisms of bone development and repair. Nature Reviews Molecular Cell Biology. 2020;11(21):696–711.Selvaraj V, et al. Type 1 collagen: Synthesis, structure and key functions in bone mineralization. Differentiation. 2024;(136):100757.Selvaraj V, et al. Type 1 collagen: Synthesis, structure and key functions in bone mineralization. Differentiation. 2024;(136):100757.Semenova D, et al. Dose-dependent mechanism of Notch action in promoting osteogenic differentiation of mesenchymal stem cells. Cell and Tissue Research. 2020;1(379):169–179.Semenova D, et al. Dose-dependent mechanism of Notch action in promoting osteogenic differentiation of mesenchymal stem cells. Cell and Tissue Research. 2020;1(379):169–179.Semenova D, et al. Multi-omics of in vitro aortic valve calcification. Frontiers in Cardiovascular Medicine. 2022;(9).Semenova D, et al. Multi-omics of in vitro aortic valve calcification. Frontiers in Cardiovascular Medicine. 2022;(9).Singh M, et al. Molecular Signaling Pathways and MicroRNAs in Bone Remodeling: A Narrative Review. Diseases. 2024;10(12):252.Singh M, et al. Molecular Signaling Pathways and MicroRNAs in Bone Remodeling: A Narrative Review. Diseases. 2024;10(12):252.Sprinzak D, Blacklow S. Biophysics of Notch Signaling. Annual Review of Biophysics. 2021;1(50):157–189.Sprinzak D, Blacklow S. Biophysics of Notch Signaling. Annual Review of Biophysics. 2021;1(50):157–189.Thomas S, Jaganathan BG. Signaling network regulating osteogenesis in mesenchymal stem cells. Journal of Cell Communication and Signaling. 2022;1(16):47–61.Thomas S, Jaganathan BG. Signaling network regulating osteogenesis in mesenchymal stem cells. Journal of Cell Communication and Signaling. 2022;1(16):47–61.Toshima T, et al. Therapeutic inhibition of microRNA-34a ameliorates aortic valve calcification via modulation of Notch1-Runx2 signalling. Cardiovascular Research. 2019.Toshima T, et al. Therapeutic inhibition of microRNA-34a ameliorates aortic valve calcification via modulation of Notch1-Runx2 signalling. Cardiovascular Research. 2019.Vimalraj S. Alkaline phosphatase: Structure, expression and its function in bone mineralization. Gene. 2020;(754):144855.Vimalraj S. Alkaline phosphatase: Structure, expression and its function in bone mineralization. Gene. 2020;(754):144855.Wang Y, et al. NOTCH Signaling in Aortic Valve Development and Calcific Aortic Valve Disease. Frontiers in Cardiovascular Medicine. 2021;(8).Wang Y, et al. NOTCH Signaling in Aortic Valve Development and Calcific Aortic Valve Disease. Frontiers in Cardiovascular Medicine. 2021;(8).Wilson HM, et al. Notch signaling in osteoblast progenitor cells is required for BMP-induced bone formation. Bone. 2025;(194):117425.Wilson HM, et al. Notch signaling in osteoblast progenitor cells is required for BMP-induced bone formation. Bone. 2025;(194):117425.Wu Z, et al. Regulation of bone homeostasis: signaling pathways and therapeutic targets. MedComm. 2024;8(5).Wu Z, et al. Regulation of bone homeostasis: signaling pathways and therapeutic targets. MedComm. 2024;8(5).Xu C, et al. Induction of osteogenesis by bone-targeted Notch activation. eLife. 2022;(11).Xu C, et al. Induction of osteogenesis by bone-targeted Notch activation. eLife. 2022;(11).Xu Y, et al. Notch activation promotes osteoblast mineralization by inhibition of apoptosis. Journal of Cellular Physiology. 2018;10(233):6921–6928.Xu Y, et al. Notch activation promotes osteoblast mineralization by inhibition of apoptosis. Journal of Cellular Physiology. 2018;10(233):6921–6928.Yang M, et al. MiR-497~195 cluster regulates angiogenesis during coupling with osteogenesis by maintaining endothelial Notch and HIF-1α activity. Nature Communications. 2017;1(8):16003.Yang M, et al. MiR-497~195 cluster regulates angiogenesis during coupling with osteogenesis by maintaining endothelial Notch and HIF-1α activity. Nature Communications. 2017;1(8):16003.Youngstrom DW, et al. Jagged1 expression by osteoblast-lineage cells regulates trabecular bone mass and periosteal expansion in mice. Bone. 2016;(91):64–74.Youngstrom DW, et al. Jagged1 expression by osteoblast-lineage cells regulates trabecular bone mass and periosteal expansion in mice. Bone. 2016;(91):64–74.Youngstrom DW, et al. Intraoperative delivery of the Notch ligand Jagged-1 regenerates appendicular and craniofacial bone defects. npj Regenerative Medicine. 2017;1(2):32.Youngstrom DW, et al. Intraoperative delivery of the Notch ligand Jagged-1 regenerates appendicular and craniofacial bone defects. npj Regenerative Medicine. 2017;1(2):32.Youngstrom DW, Hankenson KD. Contextual Regulation of Skeletal Physiology by Notch Signaling. Current Osteoporosis Reports. 2019;4(17):217–225.Youngstrom DW, Hankenson KD. Contextual Regulation of Skeletal Physiology by Notch Signaling. Current Osteoporosis Reports. 2019;4(17):217–225.Zhang S, et al. Notch Signaling Hydrogels Enable Rapid Vascularization and Promote Dental Pulp Tissue Regeneration. Advanced Science. 2024.Zhang S, et al. Notch Signaling Hydrogels Enable Rapid Vascularization and Promote Dental Pulp Tissue Regeneration. Advanced Science. 2024.Zhang Z, et al. Preosteoblast-enriched lnc-Evf2 facilitates osteogenic differentiation by targeting Notch. Acta Biochimica et Biophysica Sinica. 2021;2(53):179–188.Zhang Z, et al. Preosteoblast-enriched lnc-Evf2 facilitates osteogenic differentiation by targeting Notch. Acta Biochimica et Biophysica Sinica. 2021;2(53):179–188.Zhao Y, et al. Probing Notch1-Dll4 signaling in regulating osteogenic differentiation of human mesenchymal stem cells using single cell nanobiosensor. Scientific Reports. 2022;1(12):10315.Zhao Y, et al. Probing Notch1-Dll4 signaling in regulating osteogenic differentiation of human mesenchymal stem cells using single cell nanobiosensor. Scientific Reports. 2022;1(12):10315.Zhou B, et al. Notch signaling pathway: architecture, disease, and therapeutics. Signal Transduction and Targeted Therapy. 2022;1(7):95.Zhou B, et al. Notch signaling pathway: architecture, disease, and therapeutics. Signal Transduction and Targeted Therapy. 2022;1(7):95.Zhou Z, Hossain MS, Liu D. Involvement of the long noncoding RNA H19 in osteogenic differentiation and bone regeneration. Stem Cell Research & Therapy. 2021;1(12):74.Zhou Z, Hossain MS, Liu D. Involvement of the long noncoding RNA H19 in osteogenic differentiation and bone regeneration. Stem Cell Research & Therapy. 2021;1(12):74.Zhu S, et al. Cell signaling and transcriptional regulation of osteoblast lineage commitment, differentiation, bone formation, and homeostasis. Cell Discovery. 2024;1(10):71.Zhu S, et al. Cell signaling and transcriptional regulation of osteoblast lineage commitment, differentiation, bone formation, and homeostasis. Cell Discovery. 2024;1(10):71.Zoch ML, Clemens TL, Riddle R. New insights into the biology of osteocalcin. Bone. 2016;(82):42–49.Zoch ML, Clemens TL, Riddle R. New insights into the biology of osteocalcin. Bone. 2016;(82):42–49.

The authors declare that there are no conflicts of interest present.