Angiogenesis and osteogenesis are integral to the process of bone growth, development, and repair and reconstruction. The close spatial and temporal association between osteogenesis and angiogenesis is known as "angiogenesis-osteogenesis coupling". Vascular invasion is a prerequisite for bone formation, and their mutual coupling is a key factor in bone formation. Vessels not only provide nutrients, transport oxygen, growth factors and metabolic wastes to bone tissue, but also regulate the various stages of angiogenesis and bone formation through vascular endothelial growth factor and angiopoietin. With the extensive research on tissue engineering in recent years, the role of signaling molecules related to angiogenesis-osteogenesis coupling in bone tissue engineering has been broadened. In this paper, we intend to review the relevant research results in order to provide ideas for tissue engineering bone vascularization.

Tiantian Zhu, Wuxikun Wuran, Xiayidan Aihemaitijiang, Huiyu He. Research progress on the angiogenic-osteogenic coupling signaling molecules of bone tissue engineering. Frontiers in Medical Science Research (2023) Vol. 5, Issue 5: 79-84. https://doi.org/10.25236/FMSR.2023.050512.

[1] de Silva L, Bernal PN, Rosenberg A, Malda J, Levato R, Gawlitta D. Biofabricating the vascular tree in engineered bone tissue [J]. Acta Biomater. 2023; 156:250-268. 

[2] Rademakers T, Horvath JM, van Blitterswijk CA, LaPointe VLS. Oxygen and nutrient delivery in tissue engineering: Approaches to graft vascularization [J]. J Tissue Eng Regen Med. 2019; 13(10): 1815-1829.

[3] Qin Q, Lee S, Patel N, et al. Neurovascular coupling in bone regeneration [J]. Exp Mol Med. 2022; 54(11): 1844-1849. 

[4] Zhai Y, Schilling K, Wang T, et al. Spatiotemporal blood vessel specification at the osteogenesis and angiogenesis interface of biomimetic nanofiber-enabled bone tissue engineering [J]. Biomaterials. 2021; 276:121041. 

[5] Ouyang Z, Tan T, Zhang X, et al. LncRNA ENST00000563492 promoting the osteogenesis- angiogenesis coupling process in bone mesenchymal stem cells (BMSCs) by functions as a ceRNA for miR-205-5p [J]. Cell Death Dis. 2020; 11(6):486.

[6] Carmeliet P, Jain RK. Molecular mechanisms and clinical applications of angiogenesis [J]. Nature. 2011; 473(7347):298-307. 

[7] Eelen G, Treps L, Li X, Carmeliet P. Basic and Therapeutic Aspects of Angiogenesis Updated [J]. Circ Res. 2020; 127(2):310-329. 

[8] Gianni-Barrera R, Di Maggio N, Melly L, et al. Therapeutic vascularization in regenerative medicine [J]. Stem Cells Transl Med. 2020; 9(4):433-444. 

[9] Cheng K, Liu CF, Rao GW. Anti-angiogenic Agents: A Review on Vascular Endothelial Growth Factor Receptor-2 (VEGFR-2) Inhibitors [J]. Curr Med Chem. 2021; 28(13):2540-2564. 

[10] Hu K, Olsen BR. Osteoblast-derived VEGF regulates osteoblast differentiation and bone formation during bone repair [J]. J Clin Invest. 2016; 126(2):509-526. 

[11] Burger MG, Grosso A, Briquez PS, et al. Robust coupling of angiogenesis and osteogenesis by VEGF-decorated matrices for bone regeneration [J]. Acta Biomater. 2022; 149:111-125. 

[12] Poldervaart MT, Gremmels H, van Deventer K, et al. Prolonged presence of VEGF promotes vascularization in 3D bioprinted scaffolds with defined architecture [J]. J Control Release. 2014; 184: 58-66. 

[13] Largo RD, Burger MG, Harschnitz O, et al. VEGF Over-Expression by Engineered BMSC Accelerates Functional Perfusion, Improving Tissue Density and In-Growth in Clinical-Size Osteogenic Grafts [J]. Front Bioeng Biotechnol. 2020; 8: 755. 

[14] Schumacher M, Habibović P, van Rijt S. Peptide-Modified Nano-Bioactive Glass for Targeted Immobilization of Native VEGF [J]. ACS Appl Mater Interfaces. 2022; 14(4):4959-4968.

[15] Han Su, Guohua Tang. Research Progress on PDGF/PDGFRβ Pathway Coupling with Osteogenesis and Angiogenesis [J].Journal of Oral Science Research. 2022, 38(02):113-115.

[16] Gao B, Deng R, Chai Y, et al. Macrophage-lineage TRAP+ cells recruit periosteum-derived cells for periosteal osteogenesis and regeneration [J]. J Clin Invest. 2019; 129(6):2578-2594. 

[17] Lee J, Lee S, Ahmad T, et al. Human adipose-derived stem cell spheroids incorporating platelet-derived growth factor (PDGF) and bio-minerals for vascularized bone tissue engineering [J]. Biomaterials. 2020; 255:120192. 

[18] Wu Z, Yuan K, Zhang Q, Guo JJ, Yang H, Zhou F. Antioxidant PDA-PEG nanoparticles alleviate early osteoarthritis by inhibiting osteoclastogenesis and angiogenesis in subchondral bone [J]. J Nanobiotechnology. 2022; 20(1):479. 

[19] Li J, Chen X, Ren L, et al. Type H vessel/platelet-derived growth factor receptor β+ perivascular cell disintegration is involved in vascular injury and bone loss in radiation-induced bone damage [J]. Cell Prolif. 2023; e13406.

[20] Cao H, Shi K, Long J, et al. PDGF-BB prevents destructive repair and promotes reparative osteogenesis of steroid-associated osteonecrosis of the femoral head in rabbits. Bone [J]. 2023; 167: 116645.

[21] Gao SY, Lin RB, Huang SH, et al. PDGF-BB exhibited therapeutic effects on rat model of bisphosphonate-related osteonecrosis of the jaw by enhancing angiogenesis and osteogenesis [J]. Bone. 2021; 144:115117. 

[22] Kang H, Aryal Ac S, Barnes AM, et al. Antagonism Between PEDF and TGF-β Contributes to Type VI Osteogenesis Imperfecta Bone and Vascular Pathogenesis [J]. J Bone Miner Res. 2022; 37(5): 925-937. 

[23] Tang Y, Hu M, Xu Y, et al. Megakaryocytes promote bone formation through coupling osteogenesis with angiogenesis by secreting TGF-β1 [J]. Theranostics. 2020; 10(5):2229-2242. 

[24] Elimelech R, Khoury N, Tamari T, Blumenfeld I, Gutmacher Z, Zigdon-Giladi H. Use of transforming growth factor-β loaded onto β-tricalcium phosphate scaffold in a bone regeneration rat calvaria model [J]. Clin Implant Dent Relat Res. 2019; 21(4):593-601. 

[25] Korhonen EA, Lampinen A, Giri H, et al. Tie1 controls angiopoietin function in vascular remodeling and inflammation [J]. J Clin Invest. 2016; 126(9):3495-3510. 

[26] Saharinen P, Eklund L, Alitalo K. Therapeutic targeting of the angiopoietin-TIE pathway [J]. Nat Rev Drug Discov. 2017; 16(9):635-661.

[27] Shen J, Frye M, Lee BL, et al. Targeting VE-PTP activates TIE2 and stabilizes the ocular vasculature [J]. J Clin Invest. 2014; 124(10):4564-4576. 

[28] Sanchez V, Golyardi F, Mayaki D, et al. Negative regulation of angiogenesis by novel micro RNAs [J]. Pharmacol Res. 2019; 139:173-181. 

[29] Jeong BC, Kim HJ, Bae IH, et al. COMP-Ang1, a chimeric form of Angiopoietin 1, enhances BMP2-induced osteoblast differentiation and bone formation [J]. Bone. 2010; 46(2):479-486. 

[30] Suzuki T, Miyamoto T, Fujita N, et al. Osteoblast-specific Angiopoietin 1 overexpression increases bone mass [J]. Biochem Biophys Res Commun. 2007; 362(4):1019-1025. 

[31] Zhen Wang, Peng Wen, Xiaomin Fang, et al. Angiogenin-1 promoting BMSCs combined yith PLGA/HA scaffold for radial defect in rabbits [J].Chinese Journal of Clinical Oncology and Rehabilitation. 2018; 25(11):1288-1290.

[32] Xudong Liu, Le Cao, Zhuang Jang, et al. Repair of radial segmental bonedefects bycombined angiopoietin-1 gene transfected bone marrow mesenchymal stem cells and platelet-rich plasma tissue engineered bone in rabbits [J].Chinese Journal of Reparative and Reconstructive Surgery. 2011; 25(09): 1115-1119.

[33] Xie Y, Su N, Yang J, et al. FGF/FGFR signaling in health and disease [J]. Signal Transduct Target Ther. 2020; 5(1):181. 

[34] Kuttappan S, Mathew D, Jo JI, et al. Dual release of growth factor from nanocomposite fibrous scaffold promotes vascularisation and bone regeneration in rat critical sized calvarial defect [J]. Acta Biomater. 2018; 78:36-47. 

[35] Yang S, Guo Y, Zhang W, Zhang J, Zhang Y, Xu P. Effect of FGF-21 on implant bone defects through hepatocyte growth factor (HGF)-mediated PI3K/AKT signaling pathway [J]. Biomed Pharmacother. 2019; 109: 1259-1267. 

[36] Lai WY, Chen YJ, Lee AK, Lin YH, Liu YW, Shie MY. Therapeutic Effects of the Addition of Fibroblast Growth Factor-2 to Biodegradable Gelatin/Magnesium-Doped Calcium Silicate Hybrid 3D-Printed Scaffold with Enhanced Osteogenic Capabilities for Critical Bone Defect Restoration [J]. Biomedicines. 2021; 9(7):712. 

[37] O'Brien J, Hayder H, Zayed Y, Peng C. Overview of MicroRNA Biogenesis, Mechanisms of Actions, and Circulation [J]. Front Endocrinol (Lausanne). 2018; 9:402. 

[38] Noue K, Nakano S, Zhao B. Osteoclastic microRNAs and their translational potential in skeletal diseases [J]. Semin Immunopathol. 2019; 41(5):573-582. 

[39] Kir D, Schnettler E, Modi S, Ramakrishnan S. Regulation of angiogenesis by microRNAs in cardiovascular diseases [J]. Angiogenesis. 2018; 21(4):699-710. 

[40] Hao C, Yang S, Xu W, et al. MiR-708 promotes steroid-induced osteonecrosis of femoral head, suppresses osteogenic differentiation by targeting SMAD3 [J]. Sci Rep. 2016; 6:22599. 

[41] Liu X, Xu X. MicroRNA-137 dysregulation predisposes to osteoporotic fracture by impeding ALP activity and expression via suppression of leucine-rich repeat-containing G-protein-coupled receptor 4 expression [J]. Int J Mol Med. 2018; 42(2):1026-1033. 

[42] Lu Y, Heng X, Yu J, et al. miR-137 regulates the migration of human umbilical vein endothelial cells by targeting ephrin-type A receptor 7 [J]. Mol Med Rep. 2014; 10(3):1475-1480. 

[43] Yang W, Zhu W, Yang Y, et al. Exosomal miR-100-5p inhibits osteogenesis of hBMSCs and angiogenesis of HUVECs by suppressing the BMPR2/Smad1/5/9 signalling pathway [J]. Stem Cell Res Ther. 2021; 12(1):390.

[44] Zhang B, Li Y, Yu Y, et al. MicroRNA-378 Promotes Osteogenesis-Angiogenesis Coupling in BMMSCs for Potential Bone Regeneration [J]. Anal Cell Pathol (Amst). 2018; 2018:8402390.

[45] Nan K, Zhang Y, Zhang X, et al. Exosomes from miRNA-378-modified adipose-derived stem cells prevent glucocorticoid-induced osteonecrosis of the femoral head by enhancing angiogenesis and osteogenesis via targeting miR-378 negatively regulated suppressor of fused (Sufu) [J]. Stem Cell Res Ther. 2021; 12(1):331.

[46] Jiang W, Zhu P, Zhang T, et al. MicroRNA-205 mediates endothelial progenitor functions in distraction osteogenesis by targeting the transcription regulator NOTCH2 [J]. Stem Cell Res Ther. 2021; 12(1):101.