Epidermal growth factor signalling pathway in endochondral ossification: an evidence-based narrative review

References

• Galea GL, et al. Making and shaping endochondral and intramembranous bones. Dev Dyn. 2021;250(3):414–449.
   PubMed Web of Science ®Google Scholar
• Maes C, Carmeliet P, Moermans K, et al. Impaired angiogenesis and endochondral bone formation in mice lacking the vascular endothelial growth factor isoforms VEGF164 and VEGF188. Mech Dev. 2002;111(1–2):61–73.
   PubMed Web of Science ®Google Scholar
• Zelzer E, McLean W, Ng Y-S, et al. Skeletal defects in VEGF(120/120) mice reveal multiple roles for VEGF in skeletogenesis. Development. 2002;129(8):1893–1904.
   PubMed Web of Science ®Google Scholar
• Provot S, Schipani E. Molecular mechanisms of endochondral bone development. Biochem Biophys Res Commun. 2005;328(3):658–665.
   PubMed Web of Science ®Google Scholar
• Matsushita Y, Ono W, Ono N. Growth plate skeletal stem cells and their transition from cartilage to bone. Bone. 2020;136:115359.
   PubMed Web of Science ®Google Scholar
• Akiyama H, Chaboissier M-C, Martin JF, et al. The transcription factor Sox9 has essential roles in successive steps of the chondrocyte differentiation pathway and is required for expression of Sox5 and Sox6. Genes Dev. 2002;16(21):2813–2828.
   PubMed Web of Science ®Google Scholar
• Akiyama H, Lyons JP, Mori-Akiyama Y, et al. Interactions between Sox9 and beta-catenin control chondrocyte differentiation. Genes Dev. 2004;18(9):1072–1087.
   PubMed Web of Science ®Google Scholar
• Dy P, Wang W, Bhattaram P, et al. Sox9 directs hypertrophic maturation and blocks osteoblast differentiation of growth plate chondrocytes. Dev Cell. 2012;22(3):597–609.
   PubMed Web of Science ®Google Scholar
• Mangiavini L, Merceron C, Araldi E, et al. Loss of VHL in mesenchymal progenitors of the limb bud alters multiple steps of endochondral bone development. Dev Biol. 2014;393(1):124–136.
   PubMed Web of Science ®Google Scholar
• Schipani E, Mangiavini L, Merceron C. HIF-1α and growth plate development: what we really know. Bonekey Rep. 2015;4:730.
   PubMedGoogle Scholar
• Schipani E, Ryan HE, Didrickson S, et al. Hypoxia in cartilage: HIF-1alpha is essential for chondrocyte growth arrest and survival. Genes Dev. 2001;15(21):2865–2876.
   PubMed Web of Science ®Google Scholar
• Zelzer E, Mamluk R, Ferrara N, et al. VEGFA is necessary for chondrocyte survival during bone development. Development. 2004;131(9):2161–2171.
   PubMed Web of Science ®Google Scholar
• Karsenty G, Wagner EF. Reaching a genetic and molecular understanding of skeletal development. Dev Cell. 2002;2(4):389–406.
   PubMed Web of Science ®Google Scholar
• Kronenberg HM. Developmental regulation of the growth plate. Nature. 2003;423(6937):332–336.
   PubMed Web of Science ®Google Scholar
• Ornitz DM, Marie PJ. FGF signaling pathways in endochondral and intramembranous bone development and human genetic disease. Genes Dev. 2002;16(12):1446–1465.
   PubMed Web of Science ®Google Scholar
• Zhang X, Siclari VA, Lan S, et al. The critical role of the epidermal growth factor receptor in endochondral ossification. J Bone Miner Res. 2011;26(11):2622–2633.
   PubMed Web of Science ®Google Scholar
• Chim SM, Tickner J, Chow ST, et al. Angiogenic factors in bone local environment. Cytokine Growth Factor Rev. 2013;24(3):297–310.
   PubMed Web of Science ®Google Scholar
• Cohen S. Isolation of a mouse submaxillary gland protein accelerating incisor eruption and eyelid opening in the new-born animal. J Biol Chem. 1962;237:1555–1562.
   PubMed Web of Science ®Google Scholar
• Harris RC, Chung E, Coffey RJ. EGF receptor ligands. Exp Cell Res. 2003;284(1):2–13.
   PubMed Web of Science ®Google Scholar
• Carpenter G, Zendegui JG. Epidermal growth factor, its receptor, and related proteins. Exp Cell Res. 1986;164(1):1–10.
   PubMed Web of Science ®Google Scholar
• Savage CR, Jr., Hash JH, Cohen S. Epidermal growth factor. Location of disulfide bonds. J Biol Chem. 1973;248(22):7669–7672.
   PubMed Web of Science ®Google Scholar
• Zeng F, Harris RC. Epidermal growth factor, from gene organization to bedside. Semin Cell Dev Biol. 2014;28:2–11.
   PubMed Web of Science ®Google Scholar
• Wong RW. Transgenic and knock-out mice for deciphering the roles of EGFR ligands. Cell Mol Life Sci. 2003;60(1):113–118.
   PubMed Web of Science ®Google Scholar
• Xian CJ. Roles of epidermal growth factor family in the regulation of postnatal somatic growth. Endocr Rev. 2007;28(3):284–296.
   PubMed Web of Science ®Google Scholar
• Zanetti-Domingues LC, Bonner SE, Martin-Fernandez ML, et al. Mechanisms of action of EGFR tyrosine kinase receptor incorporated in extracellular vesicles. Cells. 2020;9(11):2505.
   PubMed Web of Science ®Google Scholar
• Gomez GG, Wykosky J, Zanca C, et al. Therapeutic resistance in cancer: microRNA regulation of EGFR signaling networks. Cancer Biol Med. 2013;10(4):192–205.
   PubMedGoogle Scholar
• Vergara D, Merlot B, Lucot J-P, et al. Epithelial-mesenchymal transition in ovarian cancer. Cancer Lett. 2010;291(1):59–66.
   PubMed Web of Science ®Google Scholar
• Kfoury Y, Scadden DT. Mesenchymal cell contributions to the stem cell niche. Cell Stem Cell. 2015;16(3):239–253.
   PubMed Web of Science ®Google Scholar
• Wang J, et al. Rho a regulates epidermal growth factor-induced human osteosarcoma MG63 cell migration. Int J Mol Sci. 2018;1;19(5):1437.
   Web of Science ®Google Scholar
• Li D, et al. Cyclic guanosine monophosphate (cGMP)-Dependent Protein Kinase II Blocks Epidermal Growth Factor (EGF)/Epidermal Growth Factor Receptor (EGFR)-Induced Biological Effects on Osteosarcoma Cells. Med Sci Monit. 2018;24:1997–2002.
   PubMed Web of Science ®Google Scholar
• Sevelda F, et al. EGFR is not a major driver for osteosarcoma cell growth in vitro but contributes to starvation and chemotherapy resistance. J Exp Clin Cancer Res. 2015;34:134.
   PubMed Web of Science ®Google Scholar
• Lee JA, Ko Y, Kim DH, et al. Epidermal growth factor receptor: is it a feasible target for the treatment of osteosarcoma? Cancer Res Treat. 2012;44(3):202–209.
   PubMed Web of Science ®Google Scholar
• Wen YH, et al. Epidermal growth factor receptor in osteosarcoma: expression and mutational analysis. Hum Pathol. 2007;38(8):1184–1191.
   PubMed Web of Science ®Google Scholar
• Lu X, Kang Y. Epidermal growth factor signalling and bone metastasis. Br J Cancer. 2010;102(3):457–461
   PubMed Web of Science ®Google Scholar
• Lu X, et al. ADAMTS1 and MMP1 proteolytically engage EGF-like ligands in an osteolytic signaling Cascade for bone metastasis. Genes Dev. 2009;23(16):1882–1894.
   PubMed Web of Science ®Google Scholar
• Citri A, Yarden Y. EGF-ERBB signalling: towards the systems level. Nat Rev Mol Cell Biol. 2006;7(7):505–516.
   PubMed Web of Science ®Google Scholar
• Appleton CT, et al. Transforming growth factor alpha suppression of articular chondrocyte phenotype and Sox9 expression in a rat model of osteoarthritis. Arthritis Rheum. 2007;56(11):3693–3705.
   PubMedGoogle Scholar
• Staal B, et al. Cartilage-specific deletion of mig-6 results in osteoarthritis-like disorder with excessive articular chondrocyte proliferation. Proc Natl Acad Sci USA. 2014;111(7):2590–2595.
   PubMed Web of Science ®Google Scholar
• Zhang X, Zhu J, Liu F, et al. Reduced EGFR signaling enhances cartilage destruction in a mouse osteoarthritis model. Bone Res. 2014;2:14015.
   PubMed Web of Science ®Google Scholar
• Jia H, Ma X, Tong W, et al. EGFR signaling is critical for maintaining the superficial layer of articular cartilage and preventing osteoarthritis initiation. Proc Natl Acad Sci USA. 2016;113(50):14360–14365.
   PubMed Web of Science ®Google Scholar
• Pest MA, Russell BA, Zhang Y-W, et al. Disturbed cartilage and joint homeostasis resulting from a loss of mitogen-inducible gene 6 in a mouse model of joint dysfunction. Arthritis Rheumatol. 2014;66(10):2816–2827.
   PubMed Web of Science ®Google Scholar
• Shepard JB, Jeong J-W, Maihle NJ, et al. Transient anabolic effects accompany epidermal growth factor receptor signal activation in articular cartilage in vivo. Arthritis Res Ther. 2013;15(3):R60.
   PubMed Web of Science ®Google Scholar
• Wei Y, et al. Targeting cartilage EGFR pathway for osteoarthritis treatment. Sci Transl Med. 2021;13(576):eabb3946.
   Web of Science ®Google Scholar
• Sun H, Wu Y, Pan Z, et al. Gefitinib for epidermal growth factor receptor activated osteoarthritis subpopulation treatment. EBioMedicine. 2018;32:223–233.
   PubMed Web of Science ®Google Scholar
• Nickerson NK, Mohammad KS, Gilmore JL, et al. Decreased autocrine EGFR signaling in metastatic breast cancer cells inhibits tumor growth in bone and mammary fat pad. PLOS One. 2012;7(1):e30255.
   PubMed Web of Science ®Google Scholar
• Nakayama Y, Takahashi K, Noji S, et al. Functional modes of retinoic acid in mouse osteoblastic clone MC3T3-E1, proved as a target cell for retinoic acid. FEBS Lett. 1990;261(1):93–96.
   PubMed Web of Science ®Google Scholar
• Wang J, Chen X, Yang X, et al. Positive role of calcium phosphate ceramics regulated inflammation in the osteogenic differentiation of mesenchymal stem cells. J Biomed Mater Res A. 2020;108(6):1305–1320.
   PubMed Web of Science ®Google Scholar
• Tanaka U, Sanui T, Fukuda T, et al. Sprouty2 inhibition promotes proliferation and migration of periodontal ligament cells. Oral Dis. 2015;21(8):977–986.
   PubMed Web of Science ®Google Scholar
• Ng KW, Partridge NC, Niall M, et al. Stimulation of DNA synthesis by epidermal growth factor in osteoblast-like cells. Calcif Tissue Int. 1983;35(4–5):624–628.
   PubMed Web of Science ®Google Scholar
• Ng KW, Partridge NC, Niall M, et al. Epidermal growth factor receptors in clonal lines of a rat osteogenic sarcoma and in osteoblast-rich rat bone cells. Calcif Tissue Int. 1983;35(3):298–303.
   PubMed Web of Science ®Google Scholar
• Satomura K, Derubeis AR, Fedarko NS, et al. Receptor tyrosine kinase expression in human bone marrow stromal cells. J Cell Physiol. 1998;177(3):426–438.
   PubMed Web of Science ®Google Scholar
• Beech D, Pollock RE, Tsan R, et al. Epidermal growth factor receptor and insulin-like growth factor-I receptor expression and function in human soft-tissue sarcoma cells. Int J Oncol. 1998;12(2):329–336.
   PubMed Web of Science ®Google Scholar
• Laflamme C, Curt S, Rouabhia M. Epidermal growth factor and bone morphogenetic proteins upregulate osteoblast proliferation and osteoblastic markers and inhibit bone nodule formation. Arch Oral Biol. 2010;55(9):689–701.
   PubMed Web of Science ®Google Scholar
• Hu F, Wang X, Liang G, et al. Effects of epidermal growth factor and basic fibroblast growth factor on the proliferation and osteogenic and neural differentiation of adipose-derived stem cells. Cell Reprogram. 2013;15(3):224–232.
   PubMed Web of Science ®Google Scholar
• Lim K-T, Kim J, Seonwoo H, et al. Enhanced osteogenesis of human alveolar bone-derived mesenchymal stem cells for tooth tissue engineering using fluid shear stress in a rocking culture method. Tissue Eng Part C Methods. 2013;19(2):128–145.
   PubMed Web of Science ®Google Scholar
• Keeve PL, Dittmar T, Gassmann G, et al. Characterization and analysis of migration patterns of dentospheres derived from periodontal tissue and the palate. J Periodontal Res. 2013;48(3):276–285.
   PubMed Web of Science ®Google Scholar
• Chieregato K, Castegnaro S, Madeo D, et al. Epidermal growth factor, basic fibroblast growth factor and platelet-derived growth factor-bb can substitute for fetal bovine serum and compete with human platelet-rich plasma in the ex vivo expansion of mesenchymal stromal cells derived from adipose tissue. Cytotherapy. 2011;13(8):933–943.
   PubMed Web of Science ®Google Scholar
• Solmesky L, Lefler S, Jacob-Hirsch J, et al. Serum free cultured bone marrow mesenchymal stem cells as a platform to characterize the effects of specific molecules. PLOS One. 2010;5(9):e12689.
   PubMed Web of Science ®Google Scholar
• Ai G, Shao X, Meng M, et al. Epidermal growth factor promotes proliferation and maintains multipotency of continuous cultured adipose stem cells via activating STAT signal pathway in vitro. Medicine. 2017;96(30):e7607.
   PubMed Web of Science ®Google Scholar
• Felthaus O, Gosau M, Ettl T, et al. Migration of human dental follicle cells in vitro. J Periodontal Res. 2014;49(2):205–212.
   PubMed Web of Science ®Google Scholar
• Lin H-T, Tarng Y-W, Chen Y-C, et al. Using human plasma supplemented medium to cultivate human bone marrow-derived mesenchymal stem cell and evaluation of its multiple-lineage potential. Transplant Proc. 2005;37(10):4504–4505.
   PubMed Web of Science ®Google Scholar
• Tamama K, Fan VH, Griffith LG, et al. Epidermal growth factor as a candidate for ex vivo expansion of bone marrow-derived mesenchymal stem cells. Stem Cells. 2006;24(3):686–695.
   PubMed Web of Science ®Google Scholar
• Ozaki Y, Nishimura M, Sekiya K, et al. Comprehensive analysis of chemotactic factors for bone marrow mesenchymal stem cells. Stem Cells Dev. 2007;16(1):119–129.
   PubMed Web of Science ®Google Scholar
• Cheon SJ, Kim JI, Lee JS. Effects of growth factors and kinase inhibitors on the properties of human adipose-stromal cells in different culture conditions. Cell Biol Int. 2008;32(7):784–791.
   PubMed Web of Science ®Google Scholar
• McCarty RC, Gronthos S, Zannettino AC, et al. Characterisation and developmental potential of ovine bone marrow derived mesenchymal stem cells. J Cell Physiol. 2009;219(2):324–333.
   PubMed Web of Science ®Google Scholar
• Qin L, Partridge NC. Stimulation of amphiregulin expression in osteoblastic cells by parathyroid hormone requires the protein kinase a and cAMP response element-binding protein signaling pathway. J Cell Biochem. 2005;96(3):632–640.
   PubMed Web of Science ®Google Scholar
• Zhu J, Siclari VA, Liu F, et al. Amphiregulin-EGFR signaling mediates the migration of bone marrow mesenchymal progenitors toward PTH-stimulated osteoblasts and osteocytes. PLoS One. 2012;7(12):e50099.
   PubMed Web of Science ®Google Scholar
• Kuek V, Yang Z, Chim SM, et al. NPNT is expressed by osteoblasts and mediates angiogenesis via the activation of extracellular signal-regulated kinase. Sci Rep. 2016;6:36210.
   PubMed Web of Science ®Google Scholar
• Sun Y, Kuek V, Qiu H, et al. The emerging role of NPNT in tissue injury repair and bone homeostasis. J Cell Physiol. 2018;233(3):1887–1894.
   PubMed Web of Science ®Google Scholar
• Zhu J, Shimizu E, Zhang X, et al. EGFR signaling suppresses osteoblast differentiation and inhibits expression of master osteoblastic transcription factors Runx2 and osterix. J Cell Biochem. 2011;112(7):1749–1760.
   PubMed Web of Science ®Google Scholar
• Yu S, Geng Q, Ma J, et al. Heparin-binding EGF-like growth factor and miR-1192 exert opposite effect on Runx2-induced osteogenic differentiation. Cell Death Dis. 2013;4:e868.
   PubMed Web of Science ®Google Scholar
• Lee H-L, Park H-J, Kwon A, et al. Smurf1 plays a role in EGF inhibition of BMP2-induced osteogenic differentiation. Exp Cell Res. 2014;323(2):276–287.
   PubMed Web of Science ®Google Scholar
• Boonanantanasarn K, Lee H-L, Baek K, et al. EGF inhibits Wnt/β-catenin-induced osteoblast differentiation by promoting β-catenin degradation. J Cell Biochem. 2015;116(12):2849–2857.
   PubMed Web of Science ®Google Scholar
• Go YY, Kim SE, Cho GJ, et al. Differential effects of amnion and chorion membrane extracts on osteoblast-like cells due to the different growth factor composition of the extracts. PLOS One. 2017;12(8):e0182716.
   PubMed Web of Science ®Google Scholar
• Yang M, Pan Y, Zhou Y. miR-96 promotes osteogenic differentiation by suppressing HBEGF-EGFR signaling in osteoblastic cells. FEBS Lett. 2014;588(24):4761–4768.
   PubMed Web of Science ®Google Scholar
• Zou W, Rohatgi N, Brestoff JR, et al. Ablation of fat cells in adult mice induces massive bone gain. Cell Metab. 2020;32(5):801–813 e6.
   PubMed Web of Science ®Google Scholar
• Liu X, Qin J, Luo Q, et al. Cross-talk between EGF and BMP9 signalling pathways regulates the osteogenic differentiation of mesenchymal stem cells. J Cell Mol Med. 2013;17(9):1160–1172.
   PubMed Web of Science ®Google Scholar
• Platt MO, Roman AJ, Wells A, et al. Sustained epidermal growth factor receptor levels and activation by tethered ligand binding enhances osteogenic differentiation of multi-potent marrow stromal cells. J Cell Physiol. 2009;221(2):306–317.
   PubMed Web of Science ®Google Scholar
• Grasser WA, Orlic I, Borovecki F, et al. BMP-6 exerts its osteoinductive effect through activation of IGF-I and EGF pathways. Int Orthop. 2007;31(6):759–765.
   PubMed Web of Science ®Google Scholar
• Joos UE, Fehrenbach E, Hogh-Janovsky K, et al. Effects of a new bone-inducing biomaterial on mesenchymal cells in vitro. Artif Organs. 1992;16(4):354–360.
   PubMed Web of Science ®Google Scholar
• Elabd C, Chiellini C, Massoudi A, et al. Human adipose tissue-derived multipotent stem cells differentiate in vitro and in vivo into osteocyte-like cells. Biochem Biophys Res Commun. 2007;361(2):342–348.
   PubMed Web of Science ®Google Scholar
• Yarram SJ, Tasman C, Gidley J, et al. Epidermal growth factor and calcitriol synergistically induce osteoblast maturation. Mol Cell Endocrinol. 2004;220(1–2):9–20.
   PubMed Web of Science ®Google Scholar
• Del Angel-Mosqueda C, Gutiérrez-Puente Y, López-Lozano AP, et al. Epidermal growth factor enhances osteogenic differentiation of dental pulp stem cells in vitro. Head Face Med. 2015;11:29.
   PubMed Web of Science ®Google Scholar
• Lee JH, Jang S-J, Baek H-R, et al. Synergistic induction of early stage of bone formation by combination of recombinant human bone morphogenetic protein-2 and epidermal growth factor. J Tissue Eng Regen Med. 2015;9(4):447–459.
   PubMed Web of Science ®Google Scholar
• Lee JH, Baek H-R, Lee KM, et al. Enhanced osteoinductivity of recombinant human bone morphogenetic protein-2 in combination with epidermal growth factor in a rabbit tibial defect model. Growth Factors. 2015;33(1):31–39.
   PubMed Web of Science ®Google Scholar
• Takahashi N, MacDonald BR, Hon J, et al. Recombinant human transforming growth factor-alpha stimulates the formation of osteoclast-like cells in long-term human marrow cultures. J Clin Invest. 1986;78(4):894–898.
   PubMed Web of Science ®Google Scholar
• Ibbotson KJ, Harrod J, Gowen M, et al. Human recombinant transforming growth factor alpha stimulates bone resorption and inhibits formation in vitro. Proc Natl Acad Sci USA. 1986;83(7):2228–2232.
   PubMed Web of Science ®Google Scholar
• Zhu J, Jia X, Xiao G, et al. EGF-like ligands stimulate osteoclastogenesis by regulating expression of osteoclast regulatory factors by osteoblasts: implications for osteolytic bone metastases. J Biol Chem. 2007;282(37):26656–26664.
   PubMed Web of Science ®Google Scholar
• Marcantonio NA, Boehm CA, Rozic RJ, et al. The influence of tethered epidermal growth factor on connective tissue progenitor colony formation. Biomaterials. 2009;30(27):4629–4638.
   PubMed Web of Science ®Google Scholar
• Tamama K, Kawasaki H, Wells A. Epidermal growth factor (EGF) treatment on multipotential stromal cells (MSCs). possible enhancement of therapeutic potential of MSC. J Biomed Biotechnol. 2010;2010:795385.
   PubMedGoogle Scholar
• Pruvot B, Curé Y, Djiotsa J, et al. Developmental defects in zebrafish for classification of EGF pathway inhibitors. Toxicol Appl Pharmacol. 2014;274(2):339–349.
   PubMed Web of Science ®Google Scholar
• Monsonego E, Halevy O, Gertler A, et al. Growth hormone inhibits differentiation of avian epiphyseal growth-plate chondrocytes. Mol Cell Endocrinol. 1995;114(1–2):35–42.
   PubMed Web of Science ®Google Scholar
• Dealy CN, Scranton V, Cheng HC. Roles of transforming growth factor-alpha and epidermal growth factor in chick limb development. Dev Biol. 1998;202(1):43–55.
   PubMed Web of Science ®Google Scholar
• Huang L, Solursh M, Sandra A. The role of transforming growth factor alpha in rat craniofacial development and chondrogenesis. J Anat. 1996;189(Pt 1):73–86.
   PubMedGoogle Scholar
• Yoon YM, Oh CD, Kim DY, et al. Epidermal growth factor negatively regulates chondrogenesis of mesenchymal cells by modulating the protein kinase C-alpha, erk-1, and p38 MAPK signaling pathways. J Biol Chem. 2000;275(16):12353–12359.
   PubMed Web of Science ®Google Scholar
• Bonassar LJ, Trippel SB. Interaction of epidermal growth factor and insulin-like growth factor-I in the regulation of growth plate chondrocytes. Exp Cell Res. 1997;234(1):1–6.
   PubMed Web of Science ®Google Scholar
• Genetos DC, Rao RR, Vidal MA. Betacellulin inhibits osteogenic differentiation and stimulates proliferation through HIF-1alpha. Cell Tissue Res. 2010;340(1):81–89.
   PubMed Web of Science ®Google Scholar
• Miettinen PJ, Berger JE, Meneses J, et al. Epithelial immaturity and multiorgan failure in mice lacking epidermal growth factor receptor. Nature. 1995;376(6538):337–341.
   PubMed Web of Science ®Google Scholar
• Threadgill DW, Dlugosz AA, Hansen LA, et al. Targeted disruption of mouse EGF receptor: effect of genetic background on mutant phenotype. Science. 1995;269(5221):230–234.
   PubMed Web of Science ®Google Scholar
• Chenevix-Trench G, Jones K, Green AC, et al. Cleft lip with or without cleft palate: associations with transforming growth factor alpha and retinoic acid receptor loci. Am J Hum Genet. 1992;51(6):1377–1385.
   PubMed Web of Science ®Google Scholar
• Miettinen PJ, Chin JR, Shum L, et al. Epidermal growth factor receptor function is necessary for normal craniofacial development and palate closure. Nat Genet. 1999;22(1):69–73.
   PubMed Web of Science ®Google Scholar
• Wolf CJ, Belair DG, Becker CM, et al. Development of an organotypic stem cell model for the study of human embryonic palatal fusion. Birth Defects Res. 2018;110(17):1322–1334.
   PubMedGoogle Scholar
• Lin Y-C, Niceta M, Muto V, et al. SCUBE3 loss-of-function causes a recognizable recessive developmental disorder due to defective bone morphogenetic protein signaling. Am J Hum Genet. 2021;108(1):115–133.
   PubMed Web of Science ®Google Scholar
• Lin Y-C, Roffler SR, Yan Y-T, et al. Disruption of Scube2 impairs endochondral bone formation. J Bone Miner Res. 2015;30(7):1255–1267.
   PubMed Web of Science ®Google Scholar
• Sibilia M, Wagner B, Hoebertz A, et al. Correction: Mice humanised for the EGF receptor display hypomorphic phenotypes in skin, bone and heart. Development. 2016;143(24):4755.
   PubMed Web of Science ®Google Scholar
• Sibilia M, Wagner B, Hoebertz A, et al. Mice humanised for the EGF receptor display hypomorphic phenotypes in skin, bone and heart. Development. 2003;130(19):4515–4525.
   PubMed Web of Science ®Google Scholar
• Chan SY, Wong RW. Expression of epidermal growth factor in transgenic mice causes growth retardation. J Biol Chem. 2000;275(49):38693–38698.
   PubMed Web of Science ®Google Scholar
• Wang K, Yamamoto H, Chin JR, et al. Epidermal growth factor receptor-deficient mice have delayed primary endochondral ossification because of defective osteoclast recruitment. J Biol Chem. 2004;279(51):53848–53856.
   PubMed Web of Science ®Google Scholar
• Chim SM, Kuek V, Chow ST, et al. EGFL7 is expressed in bone microenvironment and promotes angiogenesis via ERK, STAT3, and integrin signaling Cascades. J Cell Physiol. 2015;230(1):82–94.
   PubMed Web of Science ®Google Scholar
• Usmani SE, Pest MA, Kim G, et al. Transforming growth factor alpha controls the transition from hypertrophic cartilage to bone during endochondral bone growth. Bone. 2012;51(1):131–141.
   PubMed Web of Science ®Google Scholar
• Schneider MR, Dahlhoff M, Herbach N, et al. Betacellulin overexpression in transgenic mice causes disproportionate growth, pulmonary hemorrhage syndrome, and complex eye pathology. Endocrinology. 2005;146(12):5237–5246.
   PubMed Web of Science ®Google Scholar
• Schneider MR, Mayer-Roenne B, Dahlhoff M, et al. High cortical bone mass phenotype in betacellulin transgenic mice is EGFR dependent. J Bone Miner Res. 2009;24(3):455–467.
   PubMed Web of Science ®Google Scholar
• Fisher MC, Clinton GM, Maihle NJ, et al. Requirement for ErbB2/ErbB signaling in developing cartilage and bone. Dev Growth Differ. 2007;49(6):503–513.
   PubMed Web of Science ®Google Scholar
• Hall KC, Hill D, Otero M, et al. ADAM17 controls endochondral ossification by regulating terminal differentiation of chondrocytes. Mol Cell Biol. 2013;33(16):3077–3090.
   PubMed Web of Science ®Google Scholar
• Fang R, Haxaire C, Otero M, et al. Role of iRhoms 1 and 2 in endochondral ossification. IJMS. 2020;21(22):8732.
   Google Scholar
• Saito K, Horiuchi K, Kimura T, et al. Conditional inactivation of TNFα-converting enzyme in chondrocytes results in an elongated growth plate and shorter long bones. PLOS One. 2013;8(1):e54853.
   PubMed Web of Science ®Google Scholar
• Zhang X, Tamasi J, Lu X, et al. Epidermal growth factor receptor plays an anabolic role in bone metabolism in vivo. J Bone Miner Res. 2011;26(5):1022–1034.
   PubMed Web of Science ®Google Scholar
• Li P, Deng Q, Liu J, et al. Roles for HB-EGF in mesenchymal stromal cell proliferation and differentiation during skeletal growth. J Bone Miner Res. 2019;34(2):295–309.
   PubMed Web of Science ®Google Scholar
• Rodriguez-Merchan EC. A review of recent developments in the molecular mechanisms of bone healing. Int J Mol Sci. 2021;22(2):767.
   Web of Science ®Google Scholar
• Rodriguez-Merchan EC, Forriol F. Nonunion: general principles and experimental data. Clin Orthop Relat Res. 2004;419:4–12.
   PubMedGoogle Scholar
• El-Fiqi A, Mandakhbayar N, Jo SB, et al. Nanotherapeutics for regeneration of degenerated tissue infected by bacteria through the multiple delivery of bioactive ions and growth factor with antibacterial/angiogenic and osteogenic/odontogenic capacity. Bioact Mater. 2021;6(1):123–136.
   PubMed Web of Science ®Google Scholar
• Liu L, Chen Y, Song D, et al. BMP9 is a potential therapeutic agent for use in oral and maxillofacial bone tissue engineering. Biochem Soc Trans. 2020;48(3):1269–1285.
   PubMed Web of Science ®Google Scholar
• Mishra R, Sefcik RS, Bishop TJ, et al. Growth factor dose tuning for bone progenitor cell proliferation and differentiation on resorbable poly(propylene fumarate) scaffolds. Tissue Eng Part C Methods. 2016;22(9):904–913.
   PubMed Web of Science ®Google Scholar
• Eyckmans J, Roberts SJ, Bolander J, et al. Mapping calcium phosphate activated gene networks as a strategy for targeted osteoinduction of human progenitors. Biomaterials. 2013;34(19):4612–4621.
   PubMed Web of Science ®Google Scholar