SIRT1 activation promotes bone repair by enhancing the coupling of type H vessel formation and osteogenesis

Abstract

Bone repair is intricately correlated with vascular regeneration, especially of type H vessels. Sirtuin 1 (SIRT1) expression is closely associated with endothelial function and vascular regeneration; however, the role of SIRT1 in enhancing the coupling of type H vessel formation with osteogenesis to promote bone repair needs to be investigated. A co-culture system combining human umbilical vein endothelial cells and osteoblasts was constructed, and a SIRT1 agonist was used to evaluate the effects of SIRT1 activity. The angiogenic and osteogenic capacities of the co-culture system were examined using short interfering RNA. Mouse models with bone defects in the femur or mandible were established to explore changes in type H vessel formation and bone repair following modulated SIRT1 activity. SIRT1 activation augmented the angiogenic and osteogenic capacities of the co-culture system by activating the PI3K/AKT/FOXO1 signalling pathway and did not significantly regulate osteoblast differentiation. Inhibition of the PI3K/AKT/FOXO1 pathway attenuated SIRT1-mediated effects. The SIRT1 activity in bone defects was positively correlated with the formation of type H vessels and bone repair in vivo, whereas SIRT1 inhibition substantially weakened vascular and bone formation. Thus, SIRT1 is crucial to the coupling of type H vessels with osteogenesis during bone repair.

References

[1] Di Maggio N, Banfi A. The osteo-angiogenic signaling crosstalk for bone regeneration: harmony out of complexity. Curr Opin Biotechnol. 2022;76:102750.

[2] Zhao J, Zhou YH, Zhao YQ, et al. Oral cavity-derived stem cells and preclinical models of jaw-bone defects for bone tissue engineering. Stem Cell Res Ther. 2023;14:39.

[3] Koons GL, Diba M, Mikos AG. Materials design for bone-tissue engineering. Nature Reviews Materials. 2020;5:584-603.

[4] Stucker S, Chen J, Watt FE, Kusumbe AP. Bone angiogenesis and vascular niche remodeling in stress, aging, and diseases. Front Cell Dev Biol. 2020;8:602269.

[5] Stegen S, van Gastel N, Carmeliet G. Bringing new life to damaged bone: the importance of angiogenesis in bone repair and regeneration. Bone. 2015;70:19-27.

[6] Kusumbe AP, Ramasamy SK, Adams RH. Coupling of angiogenesis and osteogenesis by a specific vessel subtype in bone. Nature. 2014;507:323-328.

[7] Peng Y, Wu S, Li Y, Crane JL. Type H blood vessels in bone modeling and remodeling. Theranostics. 2020;10:426-436.

[8] Zhang J, Pan J, Jing W. Motivating role of type H vessels in bone regeneration. Cell Prolif. 2020;53:e12874.

[9] Xu R, Yallowitz A, Qin A, et al. Targeting skeletal endothelium to ameliorate bone loss. Nat Med. 2018;24:823-833.

[10] Rindone AN, Liu X, Farhat S, et al. Quantitative 3D imaging of the cranial microvascular environment at single-cell resolution. Nat Commun. 2021;12:6219.

[11] Yao H, Guo J, Zhu W, et al. Controlled release of bone morphogenetic Protein-2 augments the coupling of angiogenesis and osteogenesis for accelerating mandibular defect repair. Pharmaceutics. 2022;14:14.

[12] Diomede F, Marconi GD, Cavalcanti M, et al. VEGF/VEGF-R/RUNX2 upregulation in human periodontal ligament stem cells seeded on dual acid etched titanium disk. Materials (Basel). 2020;13:706.

[13] Ramasamy SK, Kusumbe AP, Wang L, Adams RH. Endothelial notch activity promotes angiogenesis and osteogenesis in bone. Nature. 2014;507:376-380.

[14] Pizzicannella J, Cavalcanti M, Trubiani O, Diomede F. MicroRNA 210 mediates VEGF upregulation in human periodontal ligament stem cells cultured on 3DHydroxyapatite ceramic scaffold. Int J Mol Sci. 2018;19:3916.

[15] Bonkowski MS, Sinclair DA. Slowing ageing by design: the rise of NAD(+) and sirtuin-activating compounds. Nat Rev Mol Cell Biol. 2016;17:679-690.

[16] Wang H, Hu Z, Wu J, et al. Sirt1 promotes osteogenic differentiation and increases alveolar bone mass via Bmi1 activation in mice. J Bone Miner Res. 2019;34:1169-1181.

[17] Xia J, Hu JN, Zhang RB, et al. Icariin exhibits protective effects on cisplatin-induced cardiotoxicity via ROS-mediated oxidative stress injury in vivo and in vitro. Phytomedicine. 2022;104:154331.

[18] Dou YQ, Kong P, Li CL, et al. Smooth muscle SIRT1 reprograms endothelial cells to suppress angiogenesis after ischemia. Theranostics. 2020;10:1197-1212.

[19] Zhang W, Zhou X, Hou W, et al. Reversing the imbalance in bone homeostasis via sustained release of SIRT-1 agonist to promote bone healing under osteoporotic condition. Bioactive Materials. 2023;19:429-443.

[20] Shah AR, Wenke JC, Agrawal CM. Manipulation of human primary endothelial cell and osteoblast coculture ratios to augment Vasculogenesis and mineralization. Ann Plast Surg. 2016;77:122-128.

[21] De Moor L, Merovci I, Baetens S, et al. High-throughput fabrication of vascularized spheroids for bioprinting. Biofabrication. 2018;10:035009.

[22] Ma J, van den Beucken JJ, Yang F, et al. Coculture of osteoblasts and endothelial cells: optimization of culture medium and cell ratio. Tissue Eng Part C Methods. 2011;17:349-357.

[23] Liu S, Zhou H, Liu H, Ji H, Fei W, Luo E. Fluorine-contained hydroxyapatite suppresses bone resorption through inhibiting osteoclasts differentiation and function in vitro and in vivo. Cell Prolif. 2019;52:e12613.

[24] Tong F, Shen W, Zhao J, et al. Silencing information regulator 1 ameliorates lipopolysaccharide-induced acute lung injury in rats via the upregulation of caveolin-1. Biomed Pharmacother. 2023;165:115018.

[25] Li H, Daculsi R, Bareille R, Bourget C, Amedee J. uPA and MMP-2 were involved in self-assembled network formation in a two dimensional co-culture model of bone marrow stromal cells and endothelial cells. J Cell Biochem. 2013;114:650-657.

[26] Stefanowski J, Lang A, Rauch A, et al. Spatial distribution of macrophages during callus formation and maturation reveals close crosstalk between macrophages and newly forming vessels. Front Immunol. 2019;10:2588.

[27] Shen Z, Dong W, Chen Z, et al. Total flavonoids of Rhizoma Drynariae enhances CD31(hi)Emcn(hi) vessel formation and subsequent bone regeneration in rat models of distraction osteogenesis by activating PDGF-BB/VEGF/RUNX2/OSX signaling axis. Int J Mol Med. 2022;50:1-13.

[28] Yang M, Li CJ, Xiao Y, et al. Ophiopogonin D promotes bone regeneration by stimulating CD31(hi) EMCN(hi) vessel formation. Cell Prolif. 2020;53:e12784.

[29] Cui Z, Wu H, Xiao Y, et al. Endothelial PDGF-BB/PDGFR-β signaling promotes osteoarthritis by enhancing angiogenesis-dependent abnormal subchondral bone formation. Bone Res. 2022;10:58.

[30] Winnik S, Auwerx J, Sinclair DA, Matter CM. Protective effects of sirtuins in cardiovascular diseases: from bench to bedside. Eur Heart J. 2015;36:3404-3412.

[31] Jia G, Aroor AR, Jia C, Sowers JR. Endothelial cell senescence in aging-related vascular dysfunction. Biochim Biophys Acta Mol Basis Dis. 2019;1865:1802-1809.

[32] Tuckermann J, Adams RH. The endothelium-bone axis in development, homeostasis and bone and joint disease. Nat Rev Rheumatol. 2021;17:608-620.

[33] Huang J, Yin H, Rao SS, et al. Harmine enhances type H vessel formation and prevents bone loss in ovariectomized mice. Theranostics. 2018;8:2435-2446.

[34] Zhu L, Guo Z, Zhang J, et al. Recombinant human Arresten and Canstatin inhibit angiogenic behaviors of HUVECs via inhibiting the PI3K/Akt signaling pathway. Int J Mol Sci. 2022;23:8995.

[35] Thiel A, Reumann MK, Boskey A, Wischmann J, von Eisenhart-Rothe R, Mayer-Kuckuk P. Osteoblast migration in vertebrate bone. Biol Rev Camb Philos Soc. 2018;93:350-363.

[36] van Gastel N, Carmeliet G. Metabolic regulation of skeletal cell fate and function in physiology and disease. Nat Metab. 2021;3:11-20.

[37] Li B, Wang Y, Fan Y, Ouchi T, Zhao Z, Li L. Cranial suture mesenchymal stem cells: insights and advances. Biomolecules. 2021;11:1129.

[38] Zainabadi K. Drugs targeting SIRT1, a new generation of therapeutics for osteoporosis and other bone related disorders?Pharmacol Res. 2019;143:97-105.

[39] Chen Y, Zhou F, Liu H, et al. SIRT1, a promising regulator of bone homeostasis. Life Sci. 2021;269:119041.

[40] Louvet L, Leterme D, Delplace S, et al. Sirtuin 1 deficiency decreases bone mass and increases bone marrow adiposity in a mouse model of chronic energy deficiency. Bone. 2020;136:115361.

[41] Simic P, Zainabadi K, Bell E, et al. SIRT1 regulates differentiation of mesenchymal stem cells by deacetylating β-catenin. EMBO mol Med. 2013;5:430-440.

[42] Fang H, Sun Q, Zhou J, et al. M(6)a methylation reader IGF2BP2 activates endothelial cells to promote angiogenesis and metastasis of lung adenocarcinoma. Mol Cancer. 2023;22:99.

[43] Zhang M, Xu T, Tong D, et al. Research advances in endometriosis-related signaling pathways: a review. Biomed Pharmacother. 2023;164:114909.

[44] Maloney SC, Antecka E, Granner T, et al. Expression of SIRT1 in choroidal neovascular membranes. Retina. 2013;33:862-866.

[45] Lim JH, Lee YM, Chun YS, Chen J, Kim JE, Park JW. Sirtuin 1 modulates cellular responses to hypoxia by deacetylating hypoxia-inducible factor 1alpha. Mol Cell. 2010;38:864-878.

[46] Wang S, Zhang X, Yuan Y, et al. BRG1 expression is increased in thoracic aortic aneurysms and regulates proliferation and apoptosis of vascular smooth muscle cells through the long non-coding RNA HIF1A-AS1 in vitro. Eur J Cardiothorac Surg. 2015;47:439-446.

[47] Arderiu G, Peña E, Aledo R, et al. MicroRNA-145 regulates the differentiation of adipose stem cells toward microvascular endothelial cells and promotes angiogenesis. Circ Res. 2019;125:74-89.

[48] Li Y, Jiang X, Zhang Z, et al. Autophagy promotes directed migration of HUVEC in response to electric fields through the ROS/SIRT1/FOXO1 pathway. Free Radic Biol Med. 2022;192:213-223.

[49] Wang Z, Feng C, Liu H, et al. Exosomes from circ-Astn1-modified adipose-derived mesenchymal stem cells enhance wound healing through miR-138-5p/SIRT1/FOXO1 axis regulation. World J Stem Cells. 2023;15:476-489.

[50] Chen W, Wu P, Yu F, Luo G, Qing L, Tang J. HIF-1α regulates bone homeostasis and angiogenesis, participating in the occurrence of bone metabolic diseases. Cell. 2022;11:3552.

[51] Zhang J, Feng Z, Wei J, et al. Repair of critical-sized mandible defects in aged rat using hypoxia preconditioned BMSCs with up-regulation of Hif-1α. Int J Biol Sci. 2018;14:449-460.

[52] Li S, Song C, Yang S, et al. Supercritical CO(2) foamed composite scaffolds incorporating bioactive lipids promote vascularized bone regeneration via Hif-1α upregulation and enhanced type H vessel formation. Acta Biomater. 2019;94:253-267.

[53] Yang M, Li CJ, Sun X, et al. MiR-497~195 cluster regulates angiogenesis during coupling with osteogenesis by maintaining endothelial notch and HIF-1α activity. Nat Commun. 2017;8:16003.

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2024 2024 The Authors. Cell Proliferation published by Beijing Institute for Stem Cell and Regenerative Medicine and John Wiley & Sons Ltd.