RMD/
Articles/
2607004787
  • Open Access
  • Review

Mechanosignaling Promotes Osteogenic-Angiogenic Coupling in Bone Tissue

  • Zizhuo Zheng 1,   
  • Shibo Liu 1,   
  • Linyi Liu 2,   
  • Wangyang Ying 3,   
  • En Luo 1,*,   
  • Hanghang Liu 1,*

Received: 28 May 2026 | Revised: 24 Jul 2026 | Accepted: 31 Jul 2026 | Published: 10 Aug 2026

Abstract

Osteogenesis-angiogenesis coupling is the bidirectional interaction between osteogenic and angiogenic processes. This coupling is the fundamental prerequisite for successful bone formation and post-fracture healing. While soluble biofactors are well-known mediators, mechanical stress has recently emerged as a potent driver of this coupled regeneration. However, the precise mechanotransduction cascades that translate physical forces into synchronized tissue growth remain to be fully elucidated. This review systematically summarizes the mechanisms by which mechanical stimuli activate and augment osteogenesis-angiogenesis coupling. Specifically, we detail the critical crosstalk within key mechanosensory networks. We highlight how the Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) nuclear translocation, Piezo1-mediated calcium influx, and Integrin-triggered Wnt/β-catenin signaling pathway synergistically synchronize endothelial neovascularization with osteoblast differentiation. Furthermore, we explore the clinical translation of these mechanisms. We emphasize how engineered biomaterials, particularly digitally customized 3D-printed smart scaffolds, can actively modulate these pathways in vivo. This material-driven modulation can maximize the therapeutic efficacy of osteogenesis-angiogenesis coupling. Ultimately, by linking macroscopic physical cues with microscopic biochemical cascades, this review offers highly translational perspectives for the personalized management of complex bone defects.

References 

  • 1.

    Shao, J.; Liu, S.; Zhang, M.; et al. A Dual Role of HIF1α in Regulating Osteogenesis–Angiogenesis Coupling. Stem Cell Res. Ther. 2022, 13, 59. https://doi.org/10.1186/s13287-022-02742-1.

  • 2.

    Tan, Z.; Zhou, B.; Zheng, J.; et al. Lithium and Copper Induce the Osteogenesis-Angiogenesis Coupling of Bone Marrow Mesenchymal Stem Cells via Crosstalk between Canonical Wnt and HIF-1α Signaling Pathways. Stem Cells Int. 2021, 2021, 6662164. https://doi.org/10.1155/2021/6662164.

  • 3.

    Dicarlo, M.; Bianchi, N.; Ferretti, C.; et al. Evidence Supporting a Paracrine Effect of IGF-1/VEGF on Human Mesenchymal Stromal Cell Commitment. Cells Tissues Organs 2016, 201, 333–341. https://doi.org/10.1159/000445346.

  • 4.

    Wildemann, B.; Kandziora, F.; Krummrey, G.; et al. Local and Controlled Release of Growth Factors (Combination of IGF-I and TGF-βI, and BMP-2 Alone) from a Polylactide Coating of Titanium Implants Does Not Lead to Ectopic Bone Formation in Sheep Muscle. J. Control. Release 2004, 95, 249–256. https://doi.org/10.1016/j.jconrel.2003.11.014.

  • 5.

    Pei, F.; Guo, T.; Zhang, M.; et al. FGF Signaling Modulates Mechanotransduction/WNT Signaling in Progenitors during Tooth Root Development. Bone Res. 2024, 12, 37. https://doi.org/10.1038/s41413-024-00345-5.

  • 6.

    Zhou, Y.; Chen, L.; Han, M.; et al. FGF9–FGFR2 Signaling via Osteocytes-Preosteoblasts Crosstalks to Mediate Mechanotransduction-Driven Intramembranous Osteogenesis in the Underdeveloped Maxilla. Adv. Sci. 2025, 12, e06954. https://doi.org/10.1002/advs.202506954.

  • 7.

    Ma, L.; Wang, X.; Zhao, N.; et al. Integrating 3D Printing and Biomimetic Mineralization for Personalized Enhanced Osteogenesis, Angiogenesis, and Osteointegration. ACS Appl. Mater. Interfaces 2018, 10, 42146–42154. https://doi.org/10.1021/acsami.8b17495.

  • 8.

    Liu, H.; Huang, L.; Liu, S.; et al. Evolution of Temporomandibular Joint Reconstruction: From Autologous Tissue Transplantation to Alloplastic Joint Replacement. Int. J. Oral Sci. 2025, 17, 17. https://doi.org/10.1038/s41368-024-00339-3.

  • 9.

    Schipani, E.; Maes, C.; Carmeliet, G.; et al. Regulation of Osteogenesis-Angiogenesis Coupling by HIFs and VEGF. J. Bone Miner. Res. 2009, 24, 1347–1353. https://doi.org/10.1359/jbmr.090602.

  • 10.

    Muppala, S.; Xiao, R.; Krukovets, I.; et al. Thrombospondin-4 Mediates TGF-β-Induced Angiogenesis. Oncogene 2017, 36, 5189–5198. https://doi.org/10.1038/onc.2017.140.

  • 11.

    Walzer, S.M.; Cetin, E.; Grübl-Barabas, R.; et al. Vascularization of Primary and Secondary Ossification Centres in the Human Growth Plate. BMC Dev. Biol. 2014, 14, 36. https://doi.org/10.1186/s12861-014-0036-7.

  • 12.

    Zhai, Y.; Zhou, Z.; Xing, X.; et al. Differential Bone and Vessel Type Formation at Superior and Dura Periosteum during Cranial Bone Defect Repair. Bone Res. 2025, 13, 8. https://doi.org/10.1038/s41413-024-00379-9.

  • 13.

    Zhang, J.; Pan, J.; Jing, W. Motivating Role of Type H Vessels in Bone Regeneration. Cell Prolif. 2020, 53, e12874. https://doi.org/10.1111/cpr.12874.

  • 14.

    Yun, H.M.; Ahn, S.J.; Park, K.R.; et al. Magnetic Nanocomposite Scaffolds Combined with Static Magnetic Field in the Stimulation of Osteoblastic Differentiation and Bone Formation. Biomaterials 2016, 85, 88–98. https://doi.org/10.1016/j.biomaterials.2016.01.035

  • 15.

    Yuan, S.; Li, Q.; Chen, K.; et al. Ridge Preservation Applying a Novel Hydrogel for Early Angiogenesis and Osteogenesis Evaluation: An Experimental Study in Canine. J. Biol. Eng. 2021, 15, 19. https://doi.org/10.1186/s13036-021-00271-8.

  • 16.

    Wang, B.; Wu, B.; Jia, Y.; et al. Neural Peptide Promotes the Angiogenesis and Osteogenesis around Oral Implants. Cell. Signal. 2021, 79, 109873. https://doi.org/10.1016/j.cellsig.2020.109873.

  • 17.

    Gao, S.Y.; Lin, R.B.; Huang, S.H.; et al. PDGF-BB Exhibited Therapeutic Effects on Rat Model of Bisphosphonate-Related Osteonecrosis of the Jaw by Enhancing Angiogenesis and Osteogenesis. Bone 2021, 144, 115117. https://doi.org/10.1016/j.bone.2019.115117.

  • 18.

    Ghimire, S.; Miramini, S.; Richardson, M.; et al. Role of Dynamic Loading on Early Stage of Bone Fracture Healing. Ann. Biomed. Eng. 2018, 46, 1768–1784. https://doi.org/10.1007/s10439-018-2083-x.

  • 19.

    Srivastava, M.; Deal, C. Osteoporosis in Elderly: Prevention and Treatment. Clin. Geriatr. Med. 2002, 18, 529–555. https://doi.org/10.1016/s0749-0690(02)00022-8.

  • 20.

    Zhang, F.; Huan, L.; Xu, T.; et al. Inflammatory Macrophages Facilitate Mechanical Stress-Induced Osteogenesis. Aging 2020, 12, 3617–3625. https://doi.org/10.18632/aging.102833.

  • 21.

    Liu, J.; Li, Q.; Liu, S.; et al. Periodontal Ligament Stem Cells in the Periodontitis Microenvironment Are Sensitive to Static Mechanical Strain. Stem Cells Int. 2017, 2017, 1380851. https://doi.org/10.1155/2017/1380851.

  • 22.

    Zambuzzi, W.F.; Ferreira, M.R. Dynamic Ion-Releasing Biomaterials Actively Shape the Microenvironment to Enhance Healing. J. Trace Elem. Med. Biol. 2025, 89, 127657. https://doi.org/10.1016/j.jtemb.2025.127657.

  • 23.

    Chen, Z.; Lv, Y. Gelatin/Sodium Alginate Composite Hydrogel with Dynamic Matrix Stiffening Ability for Bone Regeneration. Compos. Part B Eng. 2022, 243, 110162. https://doi.org/10.1016/j.compositesb.2022.110162.

  • 24.

    Zhan, H.; Shi, R.; Ni, H.; et al. Functional Requirements for Guided Bone Regeneration/Guided Tissue Regeneration Membrane Design: Progress and Challenges. Periodontol. 2000 2025. https://doi.org/10.1111/prd.70019.

  • 25.

    James, B.D.; Allen, J.B. Vascular Endothelial Cell Behavior in Complex Mechanical Microenvironments. ACS Biomater. Sci. Eng. 2018, 4, 3818–3842. https://doi.org/10.1021/acsbiomaterials.8b00628.

  • 26.

    Li, S.; Xue, C.; Hu, S.; et al. Dynamic Resilience Assessment of Single Cells under Cyclic Mechanical Loading Reveals Chemotherapy-Induced Cytoskeletal Microdamage. Anal. Chem. 2025, 97, 18499–18508. https://doi.org/10.1021/acs.analchem.5c02065.

  • 27.

    Mavčič, B.; Antolič, V. Optimal Mechanical Environment of the Healing Bone Fracture/Osteotomy. Int. Orthop. 2012, 36, 689–695. https://doi.org/10.1007/s00264-012-1487-8.

  • 28.

    Glatt, V.; Samchukov, M.; Cherkashin, A.; et al. Reverse Dynamization Accelerates Bone-Healing in a Large-Animal Osteotomy Model. J. Bone Joint Surg. 2021, 103, 257–263.

  • 29.

    Burger, E.H.; Klein-Nulend, J.; Veldhuijzen, J.P. Mechanical Stress and Osteogenesis in Vitro. J. Bone Miner. Res. 1992, 7, S397–S401. https://doi.org/10.1002/jbmr.5650071406.

  • 30.

    Maes, C.; Kobayashi, T.; Selig, M.K.; et al. Osteoblast Precursors, but Not Mature Osteoblasts, Move into Developing and Fractured Bones along with Invading Blood Vessels. Dev. Cell 2010, 19, 329–344. https://doi.org/10.1016/j.devcel.2010.07.010.

  • 31.

    Wang, H.; Yu, H.; Huang, T.; et al. Hippo-YAP/TAZ Signaling in Osteogenesis and Macrophage Polarization: Therapeutic Implications in Bone Defect Repair. Genes Dis. 2023, 10, 2528–2539. https://doi.org/10.1016/j.gendis.2022.12.012.

  • 32.

    Reichenbach, M.; Mendez, P.L.; da Silva Madaleno, C.; et al. Differential Impact of Fluid Shear Stress and YAP/TAZ on BMP/TGF-β Induced Osteogenic Target Genes. Adv. Biol. 2021, 5, e2000051. https://doi.org/10.1002/adbi.202000051.

  • 33.

    Nakajima, H.; Yamamoto, K.; Agarwala, S.; et al. Flow-Dependent Endothelial YAP Regulation Contributes to Vessel Maintenance. Dev. Cell 2017, 40, 523–536.e6. https://doi.org/10.1016/j.devcel.2017.02.019.

  • 34.

    Fischer, M.; Rikeit, P.; Knaus, P.; et al. YAP-Mediated Mechanotransduction in Skeletal Muscle. Front. Physiol. 2016, 7, 41. https://doi.org/10.3389/fphys.2016.00041.

  • 35.

    Dupont, S.; Morsut, L.; Aragona, M.; et al. Role of YAP/TAZ in Mechanotransduction. Nature 2011, 474, 179–183. https://doi.org/10.1038/nature10137.

  • 36.

    Collins, J.M.; Lang, A.; Parisi, C.; et al. YAP and TAZ Couple Osteoblast Precursor Mobilization to Angiogenesis and Mechanoregulation in Murine Bone Development. Dev. Cell 2024, 59, 211–227.e5. https://doi.org/10.1016/j.devcel.2023.11.029.

  • 37.

    Kegelman, C.D.; Nijsure, M.P.; Moharrer, Y.; et al. YAP and TAZ Promote Periosteal Osteoblast Precursor Expansion and Differentiation for Fracture Repair. J. Bone Miner. Res. 2021, 36, 143–157. https://doi.org/10.1002/jbmr.4166.

  • 38.

    Totaro, A.; Castellan, M.; Battilana, G.; et al. YAP/TAZ Link Cell Mechanics to Notch Signalling to Control Epidermal Stem Cell Fate. Nat. Commun. 2017, 8, 15206. https://doi.org/10.1038/ncomms15206.

  • 39.

    Wang, F.; Li, S.; Kong, L.; et al. Tensile Stress-Activated and Exosome-Transferred YAP/TAZ-Notch Circuit Specifies Type H Endothelial Cell for Segmental Bone Regeneration. Adv. Sci. 2024, 11, e2309133. https://doi.org/10.1002/advs.202309133.

  • 40.

    Zhao, Z.; Wang, Y.; Wang, Q.; et al. Radial Extracorporeal Shockwave Promotes Subchondral Bone Stem/Progenitor Cell Self-Renewal by Activating YAP/TAZ and Facilitates Cartilage Repair in Vivo. Stem Cell Res. Ther. 2021, 12, 19. https://doi.org/10.1186/s13287-020-02076-w.

  • 41.

    Wei, Q.; Holle, A.; Li, J.; et al. BMP-2 Signaling and Mechanotransduction Synergize to Drive Osteogenic Differentiation via YAP/TAZ. Adv. Sci. 2020, 7, 1902931. https://doi.org/10.1002/advs.201902931.

  • 42.

    Zhu, Y.; Li, Y.; Yang, Y.; et al. Mechanical Stimulus and Metabolic Responses by Cryo-Printing Anisotropic Scaffolds for Achieving Promoted Bone Regeneration. Adv. Funct. Mater. 2025, 35, 2416546. https://doi.org/10.1002/adfm.202416546.

  • 43.

    Izadyari Aghmiuni, A.; Heidari Keshel, S.; Sefat, F.; et al. Fabrication of 3D Hybrid Scaffold by Combination Technique of Electrospinning-like and Freeze-Drying to Create Mechanotransduction Signals and Mimic Extracellular Matrix Function of Skin. Mater. Sci. Eng. C 2021, 120, 111752. https://doi.org/10.1016/j.msec.2020.111752.

  • 44.

    Qin, Y.; Hu, X.-B.; Fan, W.-T.; et al. A Stretchable Scaffold with Electrochemical Sensing for 3D Culture, Mechanical Loading, and Real-Time Monitoring of Cells. Adv. Sci. 2021, 8, 2003738. https://doi.org/10.1002/advs.202003738.

  • 45.

    Wu, L.; Pei, X.; Zhang, B.; et al. 3D-Printed HAp Bone Regeneration Scaffolds Enable Nano-Scale Manipulation of Cellular Mechanotransduction Signals. Chem. Eng. J. 2023, 455, 140699. https://doi.org/10.1016/j.cej.2022.140699.

  • 46.

    Zonderland, J.; Moroni, L. Steering Cell Behavior through Mechanobiology in 3D: A Regenerative Medicine Perspective. Biomaterials 2021, 268, 120572. https://doi.org/10.1016/j.biomaterials.2020.120572.

  • 47.

    Jiang, S.; Lyu, C.; Zhao, P.; et al. Cryoprotectant Enables Structural Control of Porous Scaffolds for Exploration of Cellular Mechano-Responsiveness in 3D. Nat. Commun. 2019, 10, 3491. https://doi.org/10.1038/s41467-019-11397-1.

  • 48.

    Kang, H.; Hong, Z.; Zhong, M.; et al. Piezo1 Mediates Angiogenesis through Activation of MT1-MMP Signaling. Am. J. Physiol. Cell Physiol. 2019, 316, C92–C103. https://doi.org/10.1152/ajpcell.00346.2018.

  • 49.

    Guan, H.; Wang, W.; Jiang, Z.; et al. Magnetic Aggregation-Induced Bone-Targeting Nanocarrier with Effects of Piezo1 Activation and Osteogenic-Angiogenic Coupling for Osteoporotic Bone Repair. Adv. Mater. 2024, 36, e2312081. https://doi.org/10.1002/adma.202312081.

  • 50.

    Lewis, A.H.; Grandl, J. Mechanical Sensitivity of Piezo1 Ion Channels Can Be Tuned by Cellular Membrane Tension. eLife 2015, 4, e12088. https://doi.org/10.7554/eLife.12088.

  • 51.

    Jetta, D.; Gottlieb, P.A.; Verma, D.; et al. Shear Stress-Induced Nuclear Shrinkage through Activation of Piezo1 Channels in Epithelial Cells. J. Cell Sci. 2019, 132, jcs226076. https://doi.org/10.1242/jcs.226076.

  • 52.

    Savadipour, A.; Nims, R.J.; Rashidi, N.; et al. Membrane Stretch as the Mechanism of Activation of PIEZO1 Ion Channels in Chondrocytes. Proc. Natl. Acad. Sci. USA 2023, 120, e2221958120. https://doi.org/10.1073/pnas.2221958120.

  • 53.

    Chen, P.; Zhang, G.; Jiang, S.; et al. Mechanosensitive Piezo1 in Endothelial Cells Promotes Angiogenesis to Support Bone Fracture Repair. Cell Calcium 2021, 97, 102431. https://doi.org/10.1016/j.ceca.2021.102431.

  • 54.

    Liu, Y.; Tian, H.; Hu, Y.; et al. Mechanosensitive Piezo1 Is Crucial for Periosteal Stem Cell-Mediated Fracture Healing. Int. J. Biol. Sci. 2022, 18, 3961–3980. https://doi.org/10.7150/ijbs.71390.

  • 55.

    Yang, J.; Yuan, K.; Zhang, T.; et al. Accelerated Bone Reconstruction by the Yoda1 Bilayer Membrane via Promotion of Osteointegration and Angiogenesis. Adv. Healthc. Mater. 2023, 12, e2203105. https://doi.org/10.1002/adhm.202203105.

  • 56.

    Wang, B.; Li, G.; Zhu, Q.; et al. Bone Repairment via Mechanosensation of Piezo1 Using Wearable Pulsed Triboelectric Nanogenerator. Small 2022, 18, e2201056. https://doi.org/10.1002/smll.202201056.

  • 57.

    Hu, R.; Yang, Z.Y.; Li, Y.H.; et al. LIPUS Promotes Endothelial Differentiation and Angiogenesis of Periodontal Ligament Stem Cells by Activating Piezo1. Int. J. Stem Cells 2022, 15, 372–383. https://doi.org/10.15283/ijsc22024.

  • 58.

    Wang, B.; Shao, W.; Zhao, Y.; et al. Radial Extracorporeal Shockwave Promotes Osteogenesis-Angiogenesis Coupling of Bone Marrow Stromal Cells from Senile Osteoporosis via Activating the Piezo1/CaMKII/CREB Axis. Bone 2024, 187, 117196. https://doi.org/10.1016/j.bone.2024.117196.

  • 59.

    Tian, J.Q.; Wei, T.F.; Wei, Y.R.; et al. Effect of Whole Body Vibration Therapy in the Rat Model of Steroid-Induced Osteonecrosis of the Femoral Head. Front. Cell Dev. Biol. 2023, 11, 1251634. https://doi.org/10.3389/fcell.2023.1251634.

  • 60.

    Kang, T.; Yang, Z.; Zhou, M.; et al. The Role of the Piezo1 Channel in Osteoblasts under Cyclic Stretching: A Study on Osteogenic and Osteoclast Factors. Arch. Oral Biol. 2024, 163, 105963. https://doi.org/10.1016/j.archoralbio.2024.105963.

  • 61.

    Yu, Y.; Ji, Z.; Xu, H.; et al. Exosome-Mediated Piezo1 Activation in 3D-Printed Titanium Scaffolds Promotes Repair of Femoral Head Osteonecrosis. J. Nanobiotechnol. 2026, 24, 472. https://doi.org/10.1186/s12951-026-04424-z.

  • 62.

    Lee, J.-u.; Shin, W.; Lim, Y.; et al. Non-Contact Long-Range Magnetic Stimulation of Mechanosensitive Ion Channels in Freely Moving Animals. Nat. Mater. 2021, 20, 1029–1036. https://doi.org/10.1038/s41563-020-00896-y.

  • 63.

    Guo, X.; Tao, Z.; Dai, Z.; et al. Magnetically Guided Mechanoactive Mineralization Scaffolds for Enhanced Bone Regeneration. Adv. Funct. Mater. 2025, 35, 2503903. https://doi.org/10.1002/adfm.202503903.

  • 64.

    Beauchemin, H.; Shooshtarizadeh, P.; Vadnais, C.; et al. Gfi1b Controls Integrin Signaling-Dependent Cytoskeleton Dynamics and Organization in Megakaryocytes. Haematologica 2017, 102, 484–497. https://doi.org/10.3324/haematol.2016.150375.

  • 65.

    Li, S.; Nih, L.R.; Bachman, H.; et al. Hydrogels with Precisely Controlled Integrin Activation Dictate Vascular Patterning and Permeability. Nat. Mater. 2017, 16, 953–961. https://doi.org/10.1038/nmat4954.

  • 66.

    Davis, G.E.; Senger, D.R. Endothelial Extracellular Matrix: Biosynthesis, Remodeling, and Functions during Vascular Morphogenesis and Neovessel Stabilization. Circ. Res. 2005, 97, 1093–1107. https://doi.org/10.1161/01.RES.0000191547.64391.e3.

  • 67.

    He, Y.; Tang, Y.; Zeng, B.; et al. Black Phosphorus Quantum Dot-Modified ADSCs as a Novel Therapeutic for Periodontitis Bone Loss Coupling of Osteogenesis and Osteoimmunomodulation. Mater. Today Bio 2024, 27, 101122. https://doi.org/10.1016/j.mtbio.2024.101122.

  • 68.

    Jo, M.H.; Li, J.; Jaumouillé, V.; et al. Single-Molecule Characterization of Subtype-Specific β1 Integrin Mechanics. Nat. Commun. 2022, 13, 7471. https://doi.org/10.1038/s41467-022-35173-w.

  • 69.

    Blatchley, M.R.; Gerecht, S. Integrin Binding: Sticking Around Vessels. Nat. Mater. 2017, 16, 881–883. https://doi.org/10.1038/nmat4977.

  • 70.

    Weis, S.M.; Cheresh, D.A. Tumor Angiogenesis: Molecular Pathways and Therapeutic Targets. Nat. Med. 2011, 17, 1359–1370. https://doi.org/10.1038/nm.2537.

  • 71.

    Kwakwa, K.A.; Sterling, J.A. Integrin αvβ3 Signaling in Tumor-Induced Bone Disease. Cancers 2017, 9, 84. https://doi.org/10.3390/cancers9070084.

  • 72.

    Geng, X.; Tang, Y.; Gu, C.; et al. Integrin αVβ3 Antagonist-c(RGDyk) Peptide Attenuates the Progression of Ossification of the Posterior Longitudinal Ligament by Inhibiting Osteogenesis and Angiogenesis. Mol. Med. 2024, 30, 57. https://doi.org/10.1186/s10020-024-00822-x.

  • 73.

    Jiang, M.; Shen, Q.; Zhou, Y.; et al. Fluid Shear Stress and Endothelial Cells Synergistically Promote Osteogenesis of Mesenchymal Stem Cells via Integrin β1-FAK-ERK1/2 Pathway. Turk. J. Biol. 2021, 45, 683–694. https://doi.org/10.3906/biy-2104-20.

  • 74.

    Akwii, R.G.; Sajib, M.S.; Zahra, F.T.; et al. Angiopoietin-2-Induced Lymphatic Endothelial Cell Migration Drives Lymphangiogenesis via the β1 Integrin-RhoA-Formin Axis. Angiogenesis 2022, 25, 373–396. https://doi.org/10.1007/s10456-022-09831-y.

  • 75.

    Oliver-Cervelló, L.; Cavalcanti-Adam, E.A.; Mas-Moruno, C. Modulating Integrin and Growth Factor Signaling with Peptides: Strategies to Synergistically Enhance Bone Tissue Regeneration. Adv. Sci. 2026, 13, e14782. https://doi.org/10.1002/advs.202514782.

  • 76.

    Pan, Y.; Li, J.; Wu, J.; et al. Hyperbaric Oxygen Therapy Enhances Osteointegration of Reimplanted Cranial Flap by Regulating Osteogenesis-Angiogenesis Coupling. J. Orthop. Res. 2024, 42, 2197–2209. https://doi.org/10.1002/jor.25875.

  • 77.

    Surman, M.; Wilczak, M.; Bzowska, M.; et al. The Proangiogenic Effects of Melanoma-Derived Ectosomes Are Mediated by αvβ5 Integrin Rather than αvβ3 Integrin. Cells 2024, 13, 1336. https://doi.org/10.3390/cells13161336.

  • 78.

    Gaur, T.; Lengner, C.J.; Hovhannisyan, H.; et al. Canonical WNT Signaling Promotes Osteogenesis by Directly Stimulating Runx2 Gene Expression. J. Biol. Chem. 2005, 280, 33132–33140. https://doi.org/10.1074/jbc.M500608200.

  • 79.

    Ko, F.C.; Moran, M.M.; Ross, R.D.; et al. Activation of Canonical Wnt Signaling Accelerates Intramembranous Bone Regeneration in Male Mice. J. Orthop. Res. 2022, 40, 1834–1843. https://doi.org/10.1002/jor.25217.

  • 80.

    Boström, K.I.; Rajamannan, N.M.; Towler, D.A. The Regulation of Valvular and Vascular Sclerosis by Osteogenic Morphogens. Circ. Res. 2011, 109, 564–577. https://doi.org/10.1161/circresaha.110.234278.

  • 81.

    Liu, F.; Kohlmeier, S.; Wang, C.Y. Wnt Signaling and Skeletal Development. Cell. Signal. 2008, 20, 999–1009. https://doi.org/10.1016/j.cellsig.2007.11.011.

  • 82.

    Liu, N.; Zhou, M.; Zhang, Q.; et al. Stiffness Regulates the Proliferation and Osteogenic/Odontogenic Differentiation of Human Dental Pulp Stem Cells via the WNT Signalling Pathway. Cell Prolif. 2018, 51, e12435. https://doi.org/10.1111/cpr.12435.

  • 83.

    Arnsdorf, E.J.; Tummala, P.; Jacobs, C.R. Non-Canonical Wnt Signaling and N-Cadherin Related β-Catenin Signaling Play a Role in Mechanically Induced Osteogenic Cell Fate. PLoS ONE 2009, 4, e5388. https://doi.org/10.1371/journal.pone.0005388.

  • 84.

    Tu, X.; Joeng, K.S.; Nakayama, K.I.; et al. Noncanonical Wnt Signaling through G Protein-Linked PKCδ Activation Promotes Bone Formation. Dev. Cell 2007, 12, 113–127. https://doi.org/10.1016/j.devcel.2006.11.003.

  • 85.

    Shen, J.; Sun, Y.; Liu, X.; et al. EGFL6 Regulates Angiogenesis and Osteogenesis in Distraction Osteogenesis via Wnt/β-Catenin Signaling. Stem Cell Res. Ther. 2021, 12, 415. https://doi.org/10.1186/s13287-021-02487-3.

  • 86.

    He, X.; Han, Z.; Jiang, W.; et al. Hypoxia Improved Vasculogenesis in Distraction Osteogenesis through Mesenchymal-Epithelial Transition (MET), Wnt/β-Catenin Signaling Pathway, and Autophagy. Acta Histochem. 2020, 122, 151593. https://doi.org/10.1016/j.acthis.2020.151593.

  • 87.

    Zhang, L.; Liu, W.; Zhao, J.; et al. Mechanical Stress Regulates Osteogenic Differentiation and RANKL/OPG Ratio in Periodontal Ligament Stem Cells by the Wnt/β-Catenin Pathway. Biochim. Biophys. Acta 2016, 1860, 2211–2219. https://doi.org/10.1016/j.bbagen.2016.05.003.

  • 88.

    Liu, L.; Guo, J.; Tong, X.; et al. Mechanical Strain Regulates Osteogenesis via Antxr1/LncRNA H19/Wnt/β-Catenin Axis. J. Cell. Physiol. 2024, 239, e31214. https://doi.org/10.1002/jcp.31214.

  • 89.

    Nelson, A.L.; Fontana, G.; Miclau, E.; et al. Therapeutic Approaches to Activate the Canonical Wnt Pathway for Bone Regeneration. J. Tissue Eng. Regener. Med. 2022, 16, 961–976. https://doi.org/10.1002/term.3349.

  • 90.

    Niu, Q.; Li, F.; Zhang, L.; et al. Role of the Wnt/β-Catenin Signaling Pathway in the Response of Chondrocytes to Mechanical Loading. Int. J. Mol. Med. 2016, 37, 755–762. https://doi.org/10.3892/ijmm.2016.2463.

  • 91.

    Tang, L.; Guo, H.; Wang, K.; et al. Low-Intensity Pulsed Ultrasound Enhances the Positive Effects of High-Intensity Treadmill Exercise on Bone in Rats. J. Bone Miner. Metab. 2023, 41, 592–605. https://doi.org/10.1007/s00774-023-01439-6.

  • 92.

    Zhao, Y.; Bai, L.; Zhang, Y.; et al. Type I Collagen Decorated Nanoporous Network on Titanium Implant Surface Promotes Osseointegration through Mediating Immunomodulation, Angiogenesis, and Osteogenesis. Biomaterials 2022, 288, 121684. https://doi.org/10.1016/j.biomaterials.2022.121684.

  • 93.

    Lu, C.; Dong, X.; Yu, W.P.; et al. Inorganic Phosphate-Osteogenic Induction Medium Promotes Osteogenic Differentiation of Valvular Interstitial Cells via the BMP-2/Smad1/5/9 and RhoA/ROCK-1 Signaling Pathways. Am. J. Transl. Res. 2020, 12, 3329–3345.

  • 94.

    Yang, Q.; Liu, S.; Liu, H.; et al. A New Paradigm in Bone Tissue Biomaterials: Enhanced Osteogenesis–Angiogenic Coupling by Targeting H-Type Blood Vessels. Biomaterials 2026, 324, 123423. https://doi.org/10.1016/j.biomaterials.2025.123423.

  • 95.

    Xu, Z.; Kusumbe, A.P.; Cai, H.; et al. Type H Blood Vessels in Coupling Angiogenesis-Osteogenesis and Its Application in Bone Tissue Engineering. J. Biomed. Mater. Res. Part B Appl. Biomater. 2023, 111, 1434–1446. https://doi.org/10.1002/jbm.b.35243.

  • 96.

    Song, S.; Zhang, G.; Chen, X.; et al. HIF-1α Increases the Osteogenic Capacity of ADSCs by Coupling Angiogenesis and Osteogenesis via the HIF-1α/VEGF/AKT/mTOR Signaling Pathway. J. Nanobiotechnol. 2023, 21, 257. https://doi.org/10.1186/s12951-020-02320-z.

  • 97.

    Zhang, Y.; Huang, J.; Wang, C.; et al. Application of HIF-1α by Gene Therapy Enhances Angiogenesis and Osteogenesis in Alveolar Bone Defect Regeneration. J. Gene Med. 2016, 18, 57–64. https://doi.org/10.1002/jgm.2876.

  • 98.

    Pagnotti, G.M.; Thompson, W.R.; Guise, T.A.; et al. Suppression of Cancer-Associated Bone Loss through Dynamic Mechanical Loading. Bone 2021, 150, 115998. https://doi.org/10.1016/j.bone.2021.115998.

  • 99.

    Li, S.; Cai, X.; Guo, J.; et al. Cell Communication and Relevant Signaling Pathways in Osteogenesis-Angiogenesis Coupling. Bone Res. 2025, 13, 45. https://doi.org/10.1038/s41413-025-00417-0.

  • 100.

    Koo, J.H.; Guan, K.L. Interplay between YAP/TAZ and Metabolism. Cell Metab. 2018, 28, 196–206. https://doi.org/10.1016/j.cmet.2018.07.010.

  • 101.

    Aronson, J.; Harp, J.H. Mechanical Forces as Predictors of Healing during Tibial Lengthening by Distraction Osteogenesis. Clin. Orthop. Relat. Res. 1994, 301, 73–79.

  • 102.

    Ramasamy, S.K.; Kusumbe, A.P.; Schiller, M.; et al. Blood Flow Controls Bone Vascular Function and Osteogenesis. Nat. Commun. 2016, 7, 13601. https://doi.org/10.1038/ncomms13601.

  • 103.

    Liu, H.; Zhou, H.; Fan, Y.; et al. Macrophages Regulate Angiogenesis-Osteogenesis Coupling Induced by Mechanical Loading through the Piezo1 Pathway. J. Bone Miner. Res. 2025, 40, 725–737. https://doi.org/10.1093/jbmr/zjae198.

  • 104.

    Veeriah, V.; Paone, R.; Chatterjee, S.; et al. Osteoblasts Regulate Angiogenesis in Response to Mechanical Unloading. Calcif. Tissue Int. 2019, 104, 344–354. https://doi.org/10.1007/s00223-018-0496-z.

  • 105.

    Marrelli, M.; Codispoti, B.; Shelton, R.M.; et al. Dental Pulp Stem Cell Mechanoresponsiveness: Effects of Mechanical Stimuli on Dental Pulp Stem Cell Behavior. Front. Physiol. 2018, 9, 1685. https://doi.org/10.3389/fphys.2018.01685.

  • 106.

    Xu, C.; Cheng, P.; Wang, J.; et al. Unveiling the Power of Magnetic-Driven Regenerative Medicine: Bone Regeneration and Functional Reconstruction. Research 2025, 8, 0707. https://doi.org/10.34133/research.0707.

  • 107.

    Coato, D.; Dolino, G.; Berardo, A.; et al. Synthetic 3D Printed Tibial Plateau with Gradient Material Properties for Biomechanical Accuracy. Front. Bioeng. Biotechnol. 2025, 13, 1707380. https://doi.org/10.3389/fbioe.2025.1707380.

Share this article:
Download PDF
DOI
10.53941/rmd.2026.100012
Issue
Volume 3, Issue 3
How to Cite
Zheng, Z.; Liu, S.; Liu, L.; Ying, W.; Luo, E.; Liu, H. Mechanosignaling Promotes Osteogenic-Angiogenic Coupling in Bone Tissue. Regenerative Medicine and Dentistry 2026, 3 (3), 12. https://doi.org/10.53941/rmd.2026.100012.
RIS
BibTex
Copyright & License
article copyright Image
Copyright (c) 2026 by the authors.