{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T21:20:10Z","timestamp":1790803210422,"version":"4.1.0"},"reference-count":109,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2020,2,19]],"date-time":"2020-02-19T00:00:00Z","timestamp":1582070400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100004917","name":"Cancer Prevention and Research Institute of Texas","doi-asserted-by":"publisher","award":["RP170488"],"award-info":[{"award-number":["RP170488"]}],"id":[{"id":"10.13039\/100004917","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>Skeletal development is a complex process which requires the tight regulation of gene activation and suppression in response to local signaling pathways. Among these pathways, Notch signaling is implicated in governing cell fate determination, proliferation, differentiation and apoptosis of skeletal cells-osteoblasts, osteoclasts, osteocytes and chondrocytes. Moreover, human genetic mutations in Notch components emphasize the critical roles of Notch signaling in skeletal development and homeostasis. In this review, we focus on the physiological roles of Notch signaling in skeletogenesis, postnatal bone and cartilage homeostasis and fracture repair. We also discuss the pathological gain- and loss-of-function of Notch signaling in bone and cartilage, resulting in osteosarcoma and age-related degenerative diseases, such as osteoporosis and osteoarthritis. Understanding the physiological and pathological function of Notch signaling in skeletal tissues using animal models and human genetics will provide new insights into disease pathogenesis and offer novel approaches for the treatment of bone\/cartilage diseases.<\/jats:p>","DOI":"10.3390\/biom10020332","type":"journal-article","created":{"date-parts":[[2020,2,21]],"date-time":"2020-02-21T10:49:16Z","timestamp":1582282156000},"page":"332","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":85,"title":["Notch Signaling in Skeletal Development, Homeostasis and Pathogenesis"],"prefix":"10.3390","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1650-1830","authenticated-orcid":false,"given":"Jennifer T.","family":"Zieba","sequence":"first","affiliation":[{"name":"Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi-Ting","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brendan H.","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yangjin","family":"Bae","sequence":"additional","affiliation":[{"name":"Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,2,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"275","DOI":"10.1016\/j.ajhg.2014.07.011","article-title":"Mutations in NOTCH1 cause Adams-Oliver syndrome","volume":"95","author":"Stittrich","year":"2014","journal-title":"Am. J. Hum. Genet."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"391","DOI":"10.1016\/j.ajhg.2012.07.005","article-title":"RBPJ mutations identified in two families affected by Adams-Oliver syndrome","volume":"91","author":"Hassed","year":"2012","journal-title":"Am. J. Hum. Genet."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"475","DOI":"10.1016\/j.ajhg.2015.07.015","article-title":"Heterozygous Loss-of-Function Mutations in DLL4 Cause Adams-Oliver Syndrome","volume":"97","author":"Meester","year":"2015","journal-title":"Am. J. Hum. Genet."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"822","DOI":"10.1002\/hep.510290331","article-title":"Features of Alagille syndrome in 92 patients: Frequency and relation to prognosis","volume":"29","author":"Emerick","year":"1999","journal-title":"Hepatology"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"594","DOI":"10.1002\/humu.21231","article-title":"Jagged1 (JAG1) mutations in patients with tetralogy of Fallot or pulmonic stenosis","volume":"31","author":"Bauer","year":"2010","journal-title":"Hum. Mutat."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1141","DOI":"10.1016\/S0016-5085(99)70017-X","article-title":"Mutations in JAGGED1 gene are predominantly sporadic in Alagille syndrome","volume":"116","author":"Crosnier","year":"1999","journal-title":"Gastroenterology"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"405","DOI":"10.1093\/hmg\/10.4.405","article-title":"Defective intracellular transport and processing of JAG1 missense mutations in Alagille syndrome","volume":"10","author":"Morrissette","year":"2001","journal-title":"Hum. Mol. Genet."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"2683","DOI":"10.1093\/hmg\/ddm222","article-title":"Biological function of mutant forms of JAGGED1 proteins in Alagille syndrome: Inhibitory effect on Notch signaling","volume":"16","author":"Driancourt","year":"2007","journal-title":"Hum. Mol. Genet."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"138","DOI":"10.1136\/jmedgenet-2011-100544","article-title":"NOTCH2 mutations in Alagille syndrome","volume":"49","author":"Kamath","year":"2012","journal-title":"J. Med. Genet."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1086\/505332","article-title":"NOTCH2 mutations cause Alagille syndrome, a heterogeneous disorder of the notch signaling pathway","volume":"79","author":"McDaniell","year":"2006","journal-title":"Am. J. Hum. Genet."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"723","DOI":"10.1093\/hmg\/8.5.723","article-title":"Embryonic lethality and vascular defects in mice lacking the Notch ligand Jagged1","volume":"8","author":"Xue","year":"1999","journal-title":"Hum. Mol. Genet."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1075","DOI":"10.1242\/dev.129.4.1075","article-title":"A mouse model of Alagille syndrome: Notch2 as a genetic modifier of Jag1 haploinsufficiency","volume":"129","author":"McCright","year":"2002","journal-title":"Development"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"948","DOI":"10.1016\/0002-9343(68)90193-9","article-title":"Spondylocostal dysplasia. A dominantly inherited form of short-trunked dwarfism","volume":"45","author":"Rimoin","year":"1968","journal-title":"Am. J. Med."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"333","DOI":"10.1136\/jmg.40.5.333","article-title":"Novel mutations in DLL3, a somitogenesis gene encoding a ligand for the Notch signalling pathway, cause a consistent pattern of abnormal vertebral segmentation in spondylocostal dysostosis","volume":"40","author":"Turnpenny","year":"2003","journal-title":"J. Med. Genet."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1249","DOI":"10.1086\/421053","article-title":"Mutated MESP2 causes spondylocostal dysostosis in humans","volume":"74","author":"Whittock","year":"2004","journal-title":"Am. J. Hum. Genet."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"3761","DOI":"10.1093\/hmg\/ddn272","article-title":"Mutation of Hairy-and-Enhancer-of-Split-7 in humans causes spondylocostal dysostosis","volume":"17","author":"Sparrow","year":"2008","journal-title":"Hum. Mol Genet."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1086\/498879","article-title":"Mutation of the LUNATIC FRINGE gene in humans causes spondylocostal dysostosis with a severe vertebral phenotype","volume":"78","author":"Sparrow","year":"2006","journal-title":"Am. J. Hum. Genet."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"2642","DOI":"10.1101\/gad.930601","article-title":"Dynamic expression and essential functions of Hes7 in somite segmentation","volume":"15","author":"Bessho","year":"2001","journal-title":"Genes. Dev."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1141","DOI":"10.1038\/ncomms2133","article-title":"Lfng regulates the synchronized oscillation of the mouse segmentation clock via trans-repression of Notch signalling","volume":"3","author":"Okubo","year":"2013","journal-title":"Nat. Commun."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"674","DOI":"10.1038\/ejhg.2009.241","article-title":"Two novel missense mutations in HAIRY-AND-ENHANCER-OF-SPLIT-7 in a family with spondylocostal dysostosis","volume":"18","author":"Sparrow","year":"2010","journal-title":"Eur. J. Hum. Genet."},{"key":"ref_21","first-page":"110","article-title":"A novel NOTCH2 mutation identified in a Korean family with Hajdu-Cheney syndrome showing phenotypic diversity","volume":"45","author":"Han","year":"2015","journal-title":"Ann. Clin. Lab. Sci."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1114","DOI":"10.1002\/humu.21546","article-title":"Mutations in NOTCH2 in families with Hajdu-Cheney syndrome","volume":"32","author":"Majewski","year":"2011","journal-title":"Hum. Mutat."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1538","DOI":"10.1074\/jbc.M115.685453","article-title":"Hajdu Cheney Mouse Mutants Exhibit Osteopenia, Increased Osteoclastogenesis, and Bone Resorption","volume":"291","author":"Canalis","year":"2016","journal-title":"J. Biol. Chem."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1016\/S0022-3476(77)80763-4","article-title":"Familial osteosclerosis with abnormalities of the nervous system and meninges","volume":"90","author":"Lehman","year":"1977","journal-title":"J. Pediatr."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1002\/(SICI)1096-8628(19970613)70:3<229::AID-AJMG4>3.0.CO;2-R","article-title":"Lateral meningocele syndrome: Three new patients and review of the literature","volume":"70","author":"Gripp","year":"1997","journal-title":"Am. J. Med. Genet."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"271","DOI":"10.1002\/ajmg.a.36863","article-title":"Truncating mutations in the last exon of NOTCH3 cause lateral meningocele syndrome","volume":"167","author":"Gripp","year":"2015","journal-title":"Am. J. Med. Genet. A"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"3593","DOI":"10.1242\/dev.063610","article-title":"Notch signaling: Simplicity in design, versatility in function","volume":"138","author":"Andersson","year":"2011","journal-title":"Development"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"625","DOI":"10.1007\/s00467-009-1368-6","article-title":"Transcriptional networks controlling chondrocyte proliferation and differentiation during endochondral ossification","volume":"25","author":"Wuelling","year":"2010","journal-title":"Pediatr. Nephrol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1126\/scisignal.3146re9","article-title":"Fibroblast growth factor receptor signaling crosstalk in skeletogenesis","volume":"3","author":"Miraoui","year":"2010","journal-title":"Sci. Signal."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1081","DOI":"10.1016\/j.joca.2011.05.003","article-title":"The relationship between fibrogenic TGFbeta1 signaling in the joint and cartilage degradation in post-injury osteoarthritis","volume":"19","author":"Plaas","year":"2011","journal-title":"Osteoarthr. Cartil."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1146\/annurev-genom-082908-150158","article-title":"Signaling pathways in human skeletal dysplasias","volume":"11","author":"Baldridge","year":"2010","journal-title":"Annu. Rev. Genom. Hum. Genet."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"344","DOI":"10.1007\/s00774-003-0428-4","article-title":"Suppression of differentiation and proliferation of early chondrogenic cells by Notch","volume":"21","author":"Watanabe","year":"2003","journal-title":"J. Bone Miner. Metab."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1461","DOI":"10.1242\/dev.042911","article-title":"RBPjkappa-dependent Notch signaling regulates mesenchymal progenitor cell proliferation and differentiation during skeletal development","volume":"137","author":"Dong","year":"2010","journal-title":"Development"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"191","DOI":"10.1007\/s00774-005-0671-y","article-title":"Involvement of Notch signaling in initiation of prechondrogenic condensation and nodule formation in limb bud micromass cultures","volume":"24","author":"Fujimaki","year":"2006","journal-title":"J. Bone Miner. Metab."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"2754","DOI":"10.1002\/art.23730","article-title":"Repression of chondrogenesis through binding of notch signaling proteins HES-1 and HEY-1 to N-box domains in the COL2A1 enhancer site","volume":"58","author":"Grogan","year":"2008","journal-title":"Arthritis Rheum."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"14420","DOI":"10.1073\/pnas.0902306106","article-title":"Notch pathway regulation of chondrocyte differentiation and proliferation during appendicular and axial skeleton development","volume":"106","author":"Mead","year":"2009","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"987","DOI":"10.1242\/dev.126.5.987","article-title":"Delta-1 negatively regulates the transition from prehypertrophic to hypertrophic chondrocytes during cartilage formation","volume":"126","author":"Crowe","year":"1999","journal-title":"Development"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"2145","DOI":"10.1242\/jcs.181271","article-title":"HES factors regulate specific aspects of chondrogenesis and chondrocyte hypertrophy during cartilage development","volume":"129","author":"Rutkowski","year":"2016","journal-title":"J. Cell Sci."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1159\/000280416","article-title":"HES1 and HES5 are dispensable for cartilage and endochondral bone formation","volume":"192","author":"Karlsson","year":"2010","journal-title":"Cells Tissues Organs."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1016\/j.mce.2015.01.015","article-title":"Notch inhibits chondrogenic differentiation of mesenchymal progenitor cells by targeting Twist1","volume":"403","author":"Tian","year":"2015","journal-title":"Mol. Cell Endocrinol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"306","DOI":"10.1038\/nm1716","article-title":"Notch signaling maintains bone marrow mesenchymal progenitors by suppressing osteoblast differentiation","volume":"14","author":"Hilton","year":"2008","journal-title":"Nat. Med."},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Tu, X., Chen, J., Lim, J., Karner, C.M., Lee, S.Y., Heisig, J., Wiese, C., Surendran, K., Kopan, R., and Gessler, M. (2018). Physiological notch signaling maintains bone homeostasis via RBPjk and Hey upstream of NFATc1. PLoS Genet., 8.","DOI":"10.1371\/journal.pgen.1002577"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"377","DOI":"10.1002\/(SICI)1097-0177(199708)209:4<377::AID-AJA5>3.0.CO;2-F","article-title":"Parallel expression of Sox9 and Col2a1 in cells undergoing chondrogenesis","volume":"209","author":"Zhao","year":"1997","journal-title":"Dev. Dyn."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"649","DOI":"10.1002\/jbmr.1770","article-title":"Notch gain of function inhibits chondrocyte differentiation via Rbpj-dependent suppression of Sox9","volume":"28","author":"Chen","year":"2013","journal-title":"J. Bone Miner. Res."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"6089","DOI":"10.1242\/dev.00834","article-title":"Functional Notch signaling is required for BMP4-induced inhibition of myogenic differentiation","volume":"130","author":"Dahlqvist","year":"2003","journal-title":"Development"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"541","DOI":"10.1038\/sj.emboj.7600065","article-title":"Synergy and antagonism between Notch and BMP receptor signaling pathways in endothelial cells","volume":"23","author":"Itoh","year":"2004","journal-title":"EMBO J."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"723","DOI":"10.1083\/jcb.200305112","article-title":"Cross-talk between the Notch and TGF-beta signaling pathways mediated by interaction of the Notch intracellular domain with Smad3","volume":"163","author":"Blokzijl","year":"2003","journal-title":"J. Cell Biol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"7537","DOI":"10.1128\/MCB.21.22.7537-7544.2001","article-title":"The notch intracellular domain can function as a coactivator for LEF-1","volume":"21","author":"Ross","year":"2001","journal-title":"Mol. Cell Biol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1826","DOI":"10.1126\/science.271.5257.1826","article-title":"Interaction between Wingless and Notch signaling pathways mediated by dishevelled","volume":"271","author":"Axelrod","year":"1996","journal-title":"Science"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"1819","DOI":"10.1242\/dev.01724","article-title":"Notch modulates Wnt signalling by associating with Armadillo\/beta-catenin and regulating its transcriptional activity","volume":"132","author":"Hayward","year":"2005","journal-title":"Development"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"1000","DOI":"10.1038\/sj.emboj.7600996","article-title":"Notch3 and pre-TCR interaction unveils distinct NF-kappaB pathways in T-cell development and leukemia","volume":"25","author":"Vacca","year":"2006","journal-title":"EMBO J."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1038\/nm1524","article-title":"Targeting the NF-kappaB signaling pathway in Notch1-induced T-cell leukemia","volume":"13","author":"Vilimas","year":"2007","journal-title":"Nat. Med."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"289","DOI":"10.4049\/jimmunol.167.1.289","article-title":"Human Notch-1 inhibits NF-kappa B activity in the nucleus through a direct interaction involving a novel domain","volume":"167","author":"Wang","year":"2001","journal-title":"J. Immunol."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"1198","DOI":"10.1242\/dev.070649","article-title":"Cartilage-specific RBPjkappa-dependent and -independent Notch signals regulate cartilage and bone development","volume":"139","author":"Kohn","year":"2012","journal-title":"Development"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"332","DOI":"10.1038\/nature01657","article-title":"Developmental regulation of the growth plate","volume":"423","author":"Kronenberg","year":"2003","journal-title":"Nature"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"626","DOI":"10.1002\/jcp.21258","article-title":"Osteoarthritis","volume":"213","author":"Goldring","year":"2007","journal-title":"J. Cell Physiol."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"224","DOI":"10.1186\/ar2592","article-title":"Cartilage homeostasis in health and rheumatic diseases","volume":"11","author":"Goldring","year":"2009","journal-title":"Arthritis Res. Ther."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"237","DOI":"10.1002\/bdrc.20050","article-title":"Mechanisms of synovial joint and articular cartilage formation: Recent advances, but many lingering mysteries","volume":"75","author":"Pacifici","year":"2005","journal-title":"Birth Defects Res. C Embryo Today"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1038\/nrrheum.2011.199","article-title":"Etiology of osteoarthritis: Genetics and synovial joint development","volume":"8","author":"Sandell","year":"2012","journal-title":"Nat. Rev. Rheumatol."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"539","DOI":"10.1007\/s00441-006-0307-0","article-title":"Notch and HES5 are regulated during human cartilage differentiation","volume":"327","author":"Karlsson","year":"2007","journal-title":"Cell Tissue Res."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"397","DOI":"10.1016\/j.acthis.2007.12.005","article-title":"The immunohistochemical localization of notch receptors and ligands in human articular cartilage, chondroprogenitor culture and ultrastructural characteristics of these progenitor cells","volume":"110","author":"Ustunel","year":"2008","journal-title":"Acta Histochem."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"287","DOI":"10.1159\/000121610","article-title":"Notch1, Jagged1, and HES5 are abundantly expressed in osteoarthritis","volume":"188","author":"Karlsson","year":"2008","journal-title":"Cells Tissues Organs."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"ra71","DOI":"10.1126\/scisignal.aaa3792","article-title":"A dual role for NOTCH signaling in joint cartilage maintenance and osteoarthritis","volume":"8","author":"Liu","year":"2015","journal-title":"Sci. Signal"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"1875","DOI":"10.1073\/pnas.1207458110","article-title":"Notch signaling in chondrocytes modulates endochondral ossification and osteoarthritis development","volume":"110","author":"Hosaka","year":"2013","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"2623","DOI":"10.1002\/art.38076","article-title":"RBP-Jkappa-dependent Notch signaling is required for murine articular cartilage and joint maintenance","volume":"65","author":"Mirando","year":"2013","journal-title":"Arthritis Rheum."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"623","DOI":"10.1210\/en.2012-1732","article-title":"Osteoblast lineage-specific effects of notch activation in the skeleton","volume":"154","author":"Canalis","year":"2013","journal-title":"Endocrinology"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"3890","DOI":"10.1210\/en.2008-0140","article-title":"Notch inhibits osteoblast differentiation and causes osteopenia","volume":"149","author":"Zanotti","year":"2008","journal-title":"Endocrinology"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"1320","DOI":"10.1002\/jbmr.3106","article-title":"The Notch Ligand Jagged1 Regulates the Osteoblastic Lineage by Maintaining the Osteoprogenitor Pool","volume":"32","author":"Lawal","year":"2017","journal-title":"J. Bone Miner. Res."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"2569","DOI":"10.1002\/jcp.25647","article-title":"Maintenance of Bone Homeostasis by DLL1-Mediated Notch Signaling","volume":"232","author":"Muguruma","year":"2017","journal-title":"J. Cell Physiol."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"299","DOI":"10.1038\/nm1712","article-title":"Dimorphic effects of Notch signaling in bone homeostasis","volume":"14","author":"Engin","year":"2008","journal-title":"Nat Med"},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"25614","DOI":"10.1074\/jbc.M113.470492","article-title":"Notch signaling in osteocytes differentially regulates cancellous and cortical bone remodeling","volume":"288","author":"Canalis","year":"2013","journal-title":"J. Biol. Chem."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"E171","DOI":"10.1152\/ajpendo.00395.2015","article-title":"Canonical Notch activation in osteocytes causes osteopetrosis","volume":"310","author":"Canalis","year":"2016","journal-title":"Am. J. Physiol. Endocrinol. Metab."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"257","DOI":"10.1111\/j.1749-6632.2009.05307.x","article-title":"Alteration of Notch signaling in skeletal development and disease","volume":"1192","author":"Tao","year":"2010","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"274","DOI":"10.1016\/j.bone.2009.05.027","article-title":"NOTCHing the bone: Insights into multi-functionality","volume":"46","author":"Engin","year":"2010","journal-title":"Bone"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1007\/978-1-4614-0899-4_8","article-title":"The role of Notch signaling in kidney development and disease","volume":"727","author":"Barak","year":"2017","journal-title":"Adv. Exp. Med. Biol."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"68","DOI":"10.1007\/s00223-013-9773-z","article-title":"Notch signaling in skeletal stem cells","volume":"94","author":"Chen","year":"2014","journal-title":"Calcif. Tissue Int."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"2611","DOI":"10.1007\/s00198-018-4694-3","article-title":"Notch in skeletal physiology and disease","volume":"29","author":"Canalis","year":"2018","journal-title":"Osteoporos. Int"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"5573","DOI":"10.1172\/JCI96221","article-title":"Notch signaling suppresses glucose metabolism in mesenchymal progenitors to restrict osteoblast differentiation","volume":"128","author":"Lee","year":"2018","journal-title":"J. Clin. Invest."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"5150634","DOI":"10.1155\/2019\/5150634","article-title":"NOTCH Signaling Is Activated through Mechanical Strain in Human Bone Marrow-Derived Mesenchymal Stromal Cells","volume":"2019","author":"Ziouti","year":"2019","journal-title":"Stem. Cells Int."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"309","DOI":"10.1016\/S0092-8674(00)80209-3","article-title":"Osteoprotegerin: A novel secreted protein involved in the regulation of bone density","volume":"89","author":"Simonet","year":"1997","journal-title":"Cell"},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"R45","DOI":"10.1186\/ar3758","article-title":"Differential regulation of osteoclastogenesis by Notch2\/Delta-like 1 and Notch1\/Jagged1 axes","volume":"14","author":"Sekine","year":"2012","journal-title":"Arthritis Res. Ther."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"2227","DOI":"10.1182\/blood-2002-06-1740","article-title":"Regulation of osteoclast development by Notch signaling directed to osteoclast precursors and through stromal cells","volume":"101","author":"Yamada","year":"2003","journal-title":"Blood"},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"6402","DOI":"10.1128\/MCB.00299-08","article-title":"The association of Notch2 and NF-kappaB accelerates RANKL-induced osteoclastogenesis","volume":"28","author":"Fukushima","year":"2008","journal-title":"Mol. Cell Biol."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"6509","DOI":"10.1074\/jbc.M707000200","article-title":"NOTCH1 regulates osteoclastogenesis directly in osteoclast precursors and indirectly via osteoblast lineage cells","volume":"283","author":"Bai","year":"2008","journal-title":"J. Biol. Chem."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"2598","DOI":"10.1002\/jcb.25205","article-title":"Notch signaling promotes osteoclast maturation and resorptive activity","volume":"116","author":"Ashley","year":"2015","journal-title":"J. Cell Biochem."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"319","DOI":"10.1084\/jem.20111566","article-title":"TNF-induced osteoclastogenesis and inflammatory bone resorption are inhibited by transcription factor RBP-J","volume":"209","author":"Zhao","year":"2012","journal-title":"J. Exp. Med."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"2648","DOI":"10.1074\/jbc.M110.183038","article-title":"HES1 (hairy and enhancer of split 1) is a determinant of bone mass","volume":"286","author":"Zanotti","year":"2010","journal-title":"J. Biol. Chem."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"12232","DOI":"10.1074\/jbc.M117.786129","article-title":"Sustained Notch2 signaling in osteoblasts, but not in osteoclasts, is linked to osteopenia in a mouse model of Hajdu-Cheney syndrome","volume":"292","author":"Zanotti","year":"2017","journal-title":"J. Biol. Chem."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"296","DOI":"10.1002\/jor.21518","article-title":"Notch signaling components are upregulated during both endochondral and intramembranous bone regeneration","volume":"30","author":"Dishowitz","year":"2013","journal-title":"J. Orthop. Res."},{"key":"ref_90","doi-asserted-by":"crossref","unstructured":"Dishowitz, M.I., Mutyaba, P.L., Takacs, J.D., Barr, A.M., Engiles, J.B., Ahn, J., and Hankenson, K.D. (2013). Systemic inhibition of canonical Notch signaling results in sustained callus inflammation and alters multiple phases of fracture healing. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0068726"},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"1471","DOI":"10.1172\/JCI80672","article-title":"NOTCH signaling in skeletal progenitors is critical for fracture repair","volume":"126","author":"Wang","year":"2016","journal-title":"J. Clin. Invest."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"1283","DOI":"10.1002\/jbmr.2140","article-title":"Analysis of alphaSMA-labeled progenitor cell commitment identifies notch signaling as an important pathway in fracture healing","volume":"29","author":"Matthews","year":"2014","journal-title":"J. Bone Miner. Res."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"e2595","DOI":"10.1038\/cddis.2017.2","article-title":"Notch activation enhances mesenchymal stem cell sheet osteogenic potential by inhibition of cellular senescence","volume":"8","author":"Tian","year":"2017","journal-title":"Cell Death Dis."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1038\/s41536-017-0037-9","article-title":"Intraoperative delivery of the Notch ligand Jagged-1 regenerates appendicular and craniofacial bone defects","volume":"2","author":"Youngstrom","year":"2017","journal-title":"NPJ Regen. Med."},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"376","DOI":"10.1038\/nature13146","article-title":"Endothelial Notch activity promotes angiogenesis and osteogenesis in bone","volume":"507","author":"Ramasamy","year":"2014","journal-title":"Nature"},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"1281","DOI":"10.1016\/j.yexcr.2013.01.010","article-title":"Notch as a hub for signaling in angiogenesis","volume":"319","author":"Benedito","year":"2013","journal-title":"Exp Cell Res."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"560","DOI":"10.1016\/S8756-3282(01)00608-1","article-title":"Prevention of fracture healing in rats by an inhibitor of angiogenesis","volume":"29","author":"Hausman","year":"2001","journal-title":"Bone"},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"1464","DOI":"10.1093\/hmg\/ddp057","article-title":"Notch signaling contributes to the pathogenesis of human osteosarcomas","volume":"18","author":"Engin","year":"2009","journal-title":"Hum. Mol. Genet."},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"390","DOI":"10.1016\/j.ccr.2014.07.023","article-title":"Notch activation as a driver of osteogenic sarcoma","volume":"26","author":"Tao","year":"2014","journal-title":"Cancer Cell"},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"479","DOI":"10.1007\/978-1-4419-0284-9_28","article-title":"How the NOTCH pathway contributes to the ability of osteosarcoma cells to metastasize","volume":"152","author":"Hughes","year":"2009","journal-title":"Cancer Treat. Res."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"1957","DOI":"10.1038\/sj.bjc.6605060","article-title":"Inhibition of Notch pathway prevents osteosarcoma growth by cell cycle regulation","volume":"100","author":"Tanaka","year":"2009","journal-title":"Br. J. Cancer"},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"417","DOI":"10.1038\/nsmb.3013","article-title":"Notch is a direct negative regulator of the DNA-damage response","volume":"22","author":"Vermezovic","year":"2015","journal-title":"Nat. Struct. Mol. Biol."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"2068","DOI":"10.1016\/j.celrep.2016.07.038","article-title":"NOTCH1 Inhibits Activation of ATM by Impairing the Formation of an ATM-FOXO3a-KAT5\/Tip60 Complex","volume":"6","author":"Adamowicz","year":"2016","journal-title":"Cell Rep."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1016\/j.ccell.2014.11.017","article-title":"The osteogenic niche promotes early-stage bone colonization of disseminated breast cancer cells","volume":"27","author":"Wang","year":"2018","journal-title":"Cancer Cell"},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"517","DOI":"10.1002\/jbmr.3332","article-title":"Osteoblast-Derived Extracellular Vesicles Are Biological Tools for the Delivery of Active Molecules to Bone","volume":"33","author":"Cappariello","year":"2018","journal-title":"J. Bone Miner. Res."},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"511","DOI":"10.1007\/s10555-014-9494-4","article-title":"Integrating new discoveries into the \u201cvicious cycle\u201d paradigm of prostate to bone metastases","volume":"33","author":"Cook","year":"2015","journal-title":"Cancer Metastasis Rev."},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"6854","DOI":"10.1158\/0008-5472.CAN-04-2500","article-title":"JAGGED1 expression is associated with prostate cancer metastasis and recurrence","volume":"64","author":"Santagata","year":"2004","journal-title":"Cancer Res."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"3662","DOI":"10.1074\/jbc.M308158200","article-title":"Notch signaling and ERK activation are important for the osteomimetic properties of prostate cancer bone metastatic cell lines","volume":"279","author":"Zayzafoon","year":"2004","journal-title":"J. Biol. Chem."},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"731","DOI":"10.1016\/j.ccell.2017.11.002","article-title":"Therapeutic Antibody Targeting Tumor- and Osteoblastic Niche-Derived Jagged1 Sensitizes Bone Metastasis to Chemotherapy","volume":"32","author":"Zheng","year":"2017","journal-title":"Cancer Cell"}],"container-title":["Biomolecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2218-273X\/10\/2\/332\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T08:59:01Z","timestamp":1760173141000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2218-273X\/10\/2\/332"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,2,19]]},"references-count":109,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2020,2]]}},"alternative-id":["biom10020332"],"URL":"https:\/\/doi.org\/10.3390\/biom10020332","relation":{},"ISSN":["2218-273X"],"issn-type":[{"value":"2218-273X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,2,19]]}}}