Current Osteoporosis Reports

, Volume 17, Issue 4, pp 217–225 | Cite as

Contextual Regulation of Skeletal Physiology by Notch Signaling

  • Daniel W. YoungstromEmail author
  • Kurt D. Hankenson
Skeletal Development (R Marcucio and J Feng, Section Editors)
Part of the following topical collections:
  1. Topical Collection on Skeletal Development


Purpose of Review

This article reviews the past 2 years of research on Notch signaling as it relates to bone physiology, with the goal of reconciling seemingly discrepant findings and identifying fruitful areas of potential future research.

Recent Findings

Conditional animal models and high-throughput omics have contributed to a greater understanding of the context-dependent role of Notch signaling in bone. However, significant gaps remain in our understanding of how spatiotemporal context and epigenetic state dictate downstream Notch phenotypes.


Biphasic activation of Notch signaling orchestrates progression of mesenchymal progenitor cells through the osteoblast lineage, but there is a limited understanding of ligand- and receptor-specific functions. Paracrine Notch signaling through non-osteoblastic cell types contributes additional layers of complexity, and we anticipate impactful future work related to the integration of these cell types and signaling mechanisms.


Notch signaling Jagged-1 Bone biology Musculoskeletal metabolism Mesenchymal progenitor cells Osteoblasts 


Funding Information

Daniel Youngstrom reports grants from National Institutes of Health (F32DE026346) during the conduct of the study.

Compliance with Ethical Standards

Conflict of Interest

Kurt Hankenson reports he was co-founder of Skelegen LLC, and has received a research grant from Orthofix. Both are outside the submitted work.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.


Papers of particular interest, published recently, have been highlighted as: • Of importance

  1. 1.
    Mohr OL. Character changes caused by mutation of an entire region of a chromosome in Drosophila. Genetics. 1919;4:275–82.Google Scholar
  2. 2.
    Gridley T. Notch signaling in vertebrate development and disease. Mol Cell Neurosci. 1997;9:103–8.Google Scholar
  3. 3.
    Bray SJ. Notch signalling: a simple pathway becomes complex. Nat Rev Mol Cell Biol. 2006;7:678–89.Google Scholar
  4. 4.
    Canalis E. Notch in skeletal physiology and disease. Osteoporos Int. 2018;29:2611–21.Google Scholar
  5. 5.
    Johnson DS, Li YM, Pettersson M, St George-Hyslop PH. Structural and chemical biology of presenilin complexes. Cold Spring Harb Perspect Med. 2017;7:a024067.Google Scholar
  6. 6.
    Van Tetering G, Vooijs M. Proteolytic cleavage of Notch:“HIT and RUN”. Curr Mol Med. 2011;11:255–69.Google Scholar
  7. 7.
    Schroeter EH, Kisslinger JA, Kopan R. Notch-1 signalling requires ligand-induced proteolytic release of intracellular domain. Nature. 1998;393:382–6.Google Scholar
  8. 8.
    Miele L. Transcription factor RBPJ/CSL: a genome-wide look at transcriptional regulation. Proc Natl Acad Sci U S A. 2011;108:14715–6.Google Scholar
  9. 9.
    Zhou M, Yan J, Ma Z, Zhou Y, NN Abbood J, Liu LS, et al. Comparative and evolutionary analysis of the HES/HEY gene family reveal exon/intron loss and teleost specific duplication events. PLoS One. 2012;7:e40649.Google Scholar
  10. 10.
    Zanotti S, Canalis E. Notch signaling and the skeleton. Endocr Rev. 2016;37:223–53.Google Scholar
  11. 11.
    Kimmel CB, Miller CT, Moens CB. Specification and morphogenesis of the zebrafish larval head skeleton. Dev Biol. 2001;233:239–57.Google Scholar
  12. 12.
    Barske L, Askary A, Zuniga E, Balczerski B, Bump P, Nichols JT, et al. Competition between jagged-notch and endothelin1 signaling selectively restricts cartilage formation in the zebrafish upper face. PLoS Genet. 2016;12:e1005967.Google Scholar
  13. 13.
    Zuniga E, Stellabotte F, Crump JG. Jagged-Notch signaling ensures dorsal skeletal identity in the vertebrate face. Development. 2010;137:1843–52.Google Scholar
  14. 14.
    • Askary A, Xu P, Barske L, Bay M, Bump P, Balczerski B, et al. Genome-wide analysis of facial skeletal regionalization in zebrafish. Development. 2017;144:2994–3005. Jag/Notch signaling is essential for cranial neural crest morphogenesis, particularly in establishing regional boundaries within the developing pharyngeal arches that pattern the craniofacial skeleton. Google Scholar
  15. 15.
    Tavares ALP, Cox TC, Maxson RM, Ford HL, Clouthier DE. Negative regulation of endothelin signaling by SIX1 is required for proper maxillary development. Development. 2017;144:2021–31.Google Scholar
  16. 16.
    Alvarado E, Yousefelahiyeh M, Alvarado G, Shang R, Whitman T, Martinez A, et al. Wdr68 mediates dorsal and ventral patterning events for craniofacial development. PLoS One. 2016;11:e0166984.Google Scholar
  17. 17.
    Bloomquist RF, Fowler TE, Sylvester JB, Miro RJ, Streelman JT. A compendium of developmental gene expression in Lake Malawi cichlid fishes. BMC Dev Biol. 2017;17:3.Google Scholar
  18. 18.
    Xu P, Balczerski B, Ciozda A, Louie K, Oralova V, Huysseune A, et al. Fox proteins are modular competency factors for facial cartilage and tooth specification. Development. 2018;145:dev165498.Google Scholar
  19. 19.
    Tian J, Shao J, Liu C, Hou HY, Chou CW, Shboul M, et al. Deficiency of lrp4 in zebrafish and human LRP4 mutation induce aberrant activation of Jagged-Notch signaling in fin and limb development. Cell Mol Life Sci. 2019;76:163–78.Google Scholar
  20. 20.
    Dong Y, Jesse AM, Kohn A, Gunnell LM, Honjo T, Zuscik MJ, et al. RBPjkappa-dependent Notch signaling regulates mesenchymal progenitor cell proliferation and differentiation during skeletal development. Development. 2010;137:1461–71.Google Scholar
  21. 21.
    Hilton MJ, Tu X, Wu X, Bai S, Zhao H, Kobayashi T, et al. Notch signaling maintains bone marrow mesenchymal progenitors by suppressing osteoblast differentiation. Nat Med. 2008;14:306–14.Google Scholar
  22. 22.
    Wopat S, Bagwell J, Sumigray KD, Dickson AL, Huitema LFA, Poss KD, et al. Spine patterning is guided by segmentation of the notochord sheath. Cell Rep. 2018;22:2026–38.Google Scholar
  23. 23.
    Lough DM, Chambers C, Germann G, Bueno R, Reichensperger J, Swanson E, et al. Regulation of ADSC Osteoinductive potential using notch pathway inhibition and gene rescue: a potential on/off switch for clinical applications in bone formation and reconstructive efforts. Plast Reconstr Surg. 2016;138:642e–52e.Google Scholar
  24. 24.
    Liu X, Zhang C, Jing J, Peng W, Zhu S, Zou S. Role of Notch signaling in the physiological patterning of posterofrontal and sagittal cranial sutures. J Craniofac Surg. 2017;28:1620–5.Google Scholar
  25. 25.
    Liu Y, Jing H, Kou X, Chen C, Liu D, Jin Y, et al. PD-1 is required to maintain stem cell properties in human dental pulp stem cells. Cell Death Differ. 2018;25:1350–60.Google Scholar
  26. 26.
    Long Q, Luo Q, Wang K, Bates A, Shetty AK. Mash1-dependent Notch signaling pathway regulates GABAergic neuron-like differentiation from bone marrow-derived mesenchymal stem cells. Aging Dis. 2017;8:301–13.Google Scholar
  27. 27.
    Shu Q, Zhuang H, Fan J, Wang X, G X. Wogonin induces retinal neuron-like differentiation of bone marrow stem cells by inhibiting Notch-1 signaling. Oncotarget. 2017;8:28431–41.Google Scholar
  28. 28.
    Yu Z, Zou Y, Fan J, Li C, Ma L. Notch1 is associated with the differentiation of human bone marrowderived mesenchymal stem cells to cardiomyocytes. Mol Med Rep. 2016;14:5065–71.Google Scholar
  29. 29.
    Cheng Y, Gu W, Zhang G, Li X, Guo X. Activation of Notch1 signaling alleviates dysfunction of bone marrow-derived mesenchymal stem cells induced by cigarette smoke extract. Int J Chron Obstruct Pulmon Dis. 2017;12:3133–47.Google Scholar
  30. 30.
    Liao J, Yu X, Hu X, Fan J, Wang J, Zhang Z, et al. lncRNA H19 mediates BMP9-induced osteogenic differentiation of mesenchymal stem cells (MSCs) through Notch signaling. Oncotarget. 2017;8:53581–601.Google Scholar
  31. 31.
    Zanotti S, Canalis E. Parathyroid hormone inhibits Notch signaling in osteoblasts and osteocytes. Bone. 2017;103:159–67.Google Scholar
  32. 32.
    • Lawal RA, Zhou X, Batey K, Hoffman CM, Georger MA, Radtke F, et al. The notch ligand Jagged1 regulates the osteoblastic lineage by maintaining the osteoprogenitor pool. J Bone Miner Res. 2017;32:1320–31. Prx1-Cre;Jag1 f/f mice experience depletion of the MPC pool and develop osteosclerosis due to premature differentiation of osteoblasts. Google Scholar
  33. 33.
    Lee SY, Long F. Notch signaling suppresses glucose metabolism in mesenchymal progenitors to restrict osteoblast differentiation. J Clin Invest. 2018;128:5573–86.Google Scholar
  34. 34.
    Li H, He Y, Hao P, Liu P. Identification of characteristic gene modules of osteosarcoma using bioinformatics analysis indicates the possible molecular pathogenesis. Mol Med Rep. 2017;15:2113–9.Google Scholar
  35. 35.
    Lu J, Song G, Tang Q, Yin J, Zou C, Zhao Z, et al. MiR-26a inhibits stem cell-like phenotype and tumor growth of osteosarcoma by targeting Jagged1. Oncogene. 2017;36:231–41.Google Scholar
  36. 36.
    Pan BL, L W, Pan L, Yang YX, Li HH, Dai YJ, et al. Up-regulation of microRNA-340 promotes osteosarcoma cell apoptosis while suppressing proliferation, migration, and invasion by inactivating the CTNNB1-mediated Notch signaling pathway. Biosci Rep. 2018;38:BSR20171615.Google Scholar
  37. 37.
    Kong D, Wang Y. Knockdown of lncRNA HULC inhibits proliferation, migration, invasion, and promotes apoptosis by sponging miR-122 in osteosarcoma. J Cell Biochem. 2018;119:1050–61.Google Scholar
  38. 38.
    Zhang SZ, Cai L, Li B. MEG3 long non-coding RNA prevents cell growth and metastasis of osteosarcoma. Bratisl Lek Listy. 2017;118:632–6.Google Scholar
  39. 39.
    Zhou S, Yu L, Xiong M, Dai G. LncRNA SNHG12 promotes tumorigenesis and metastasis in osteosarcoma by upregulating Notch2 by sponging miR-195-5p. Biochem Biophys Res Commun. 2018;495:1822–32.Google Scholar
  40. 40.
    Zheng H, Bae Y, Kasimir-Bauer S, Tang R, Chen J, Ren G, et al. Therapeutic antibody targeting tumor- and osteoblastic niche-derived Jagged1 sensitizes bone metastasis to chemotherapy. Cancer Cell. 2017;32:731–747 e6.Google Scholar
  41. 41.
    Ongaro A, Pellati A, Bagheri L, Rizzo P, Caliceti C, Massari L, et al. Characterization of notch signaling during osteogenic differentiation in human osteosarcoma cell line MG63. J Cell Physiol. 2016;231:2652–63.Google Scholar
  42. 42.
    Youngstrom DW, Dishowitz MI, Bales CB, Carr E, Mutyaba PL, Kozloff KM, et al. Jagged1 expression by osteoblast-lineage cells regulates trabecular bone mass and periosteal expansion in mice. Bone. 2016;91:64–74.Google Scholar
  43. 43.
    Uribe-Etxebarria V, Luzuriaga J, Garcia-Gallastegui P, Agliano A, Unda F, Ibarretxe G. Notch/Wnt cross-signalling regulates stemness of dental pulp stem cells through expression of neural crest and core pluripotency factors. Eur Cell Mater. 2017;34:249–70.Google Scholar
  44. 44.
    Muruganandan S, Govindarajan R, McMullen NM, Sinal CJ. Chemokine-like receptor 1 is a novel Wnt target gene that regulates mesenchymal stem cell differentiation. Stem Cells. 2017;35:711–24.Google Scholar
  45. 45.
    • Shao J, Zhou Y, Xiao Y. The regulatory roles of Notch in osteocyte differentiation via the crosstalk with canonical Wnt pathways during the transition of osteoblasts to osteocytes. Bone. 2018;108:165–78. Hes1 is a context-dependent ostocytic differentiation factor that downregulates Wnt and upregulates E11: coordinating progression of osteoblasts into osteocytes. Google Scholar
  46. 46.
    Urbanek K, Lesiak M, Krakowian D, Koryciak-Komarska H, Likus W, Czekaj P, et al. Notch signaling pathway and gene expression profiles during early in vitro differentiation of liver-derived mesenchymal stromal cells to osteoblasts. Lab Investig. 2017;97:1225–34.Google Scholar
  47. 47.
    Ji Y, Ke Y, Gao S. Intermittent activation of notch signaling promotes bone formation. Am J Transl Res. 2017;9:2933–44.Google Scholar
  48. 48.
    Xu Y, Shu B, Tian Y, Chelly M, Morandi MM, Barton S, et al. Notch activation promotes osteoblast mineralization by inhibition of apoptosis. J Cell Physiol. 2018;233:6921–8.Google Scholar
  49. 49.
    Yin X, Zeng Z, Xing J, Zhang A, Jiang W, Wang W, et al. Hey1 functions as a positive regulator of odontogenic differentiation in odontoblastlineage cells. Int J Mol Med. 2018;41:331–9.Google Scholar
  50. 50.
    Ndong JC, Stephenson Y, Davis ME, Garcia AJ, Goudy S. Controlled JAGGED1 delivery induces human embryonic palate mesenchymal cells to form osteoblasts. J Biomed Mater Res A. 2018;106:552–60.Google Scholar
  51. 51.
    An SY, Heo JS. Low oxygen tension modulates the osteogenic differentiation of mouse embryonic stem cells. Tissue Cell. 2018;52:9–16.Google Scholar
  52. 52.
    Lu W, Chen X, Si Y, Hong S, Shi Z, W F. Transplantation of rat mesenchymal stem cells overexpressing hypoxia-inducible factor 2alpha improves blood perfusion and arteriogenesis in a rat hindlimb ischemia model. Stem Cells Int. 2017;2017:3794817.Google Scholar
  53. 53.
    Liang D, Wang KJ, Tang ZQ, Liu RH, Zeng F, Cheng MY, et al. Effects of nicotine on the metabolism and gene expression profile of Sprague Dawley rat primary osteoblasts. Mol Med Rep. 2018;17:8269–81.Google Scholar
  54. 54.
    Wang H, Jiang Z, Zhang J, Xie Z, Wang Y, Yang G. Enhanced osteogenic differentiation of rat bone marrow mesenchymal stem cells on titanium substrates by inhibiting Notch3. Arch Oral Biol. 2017;80:34–40.Google Scholar
  55. 55.
    Liao J, Wei Q, Zou Y, Fan J, Song D, Cui J, et al. Notch signaling augments BMP9-induced bone formation by promoting the osteogenesis-angiogenesis coupling process in mesenchymal stem cells (MSCs). Cell Physiol Biochem. 2017;41:1905–23.Google Scholar
  56. 56.
    • Cui J, Zhang W, Huang E, Wang J, Liao J, Li R, et al. BMP9-induced osteoblastic differentiation requires functional Notch signaling in mesenchymal stem cells. Lab Investig. 2019;99:58–71. Hey1 is a downstream target of Bmp signaling; Notch signaling is necessary for the osteoblastogenic and anabolic activity of Bmp9. Google Scholar
  57. 57.
    Cao J, Wei Y, Lian J, Yang L, Zhang X, Xie J, et al. Notch signaling pathway promotes osteogenic differentiation of mesenchymal stem cells by enhancing BMP9/Smad signaling. Int J Mol Med. 2017;40:378–88.Google Scholar
  58. 58.
    Irshad S, Bansal M, Guarnieri P, Davis H, Al Haj Zen A, Baran B, et al. Bone morphogenetic protein and Notch signalling crosstalk in poor-prognosis, mesenchymal-subtype colorectal cancer. J Pathol. 2017;242:178–92.Google Scholar
  59. 59.
    Wang N, Liu W, Tan T, Dong CQ, Lin DY, Zhao J, et al. Notch signaling negatively regulates BMP9-induced osteogenic differentiation of mesenchymal progenitor cells by inhibiting JunB expression. Oncotarget. 2017;8:109661–74.Google Scholar
  60. 60.
    Benedito R, Roca C, Sorensen I, Adams S, Gossler A, Fruttiger M, et al. The notch ligands Dll4 and Jagged1 have opposing effects on angiogenesis. Cell. 2009;137:1124–35.Google Scholar
  61. 61.
    Graziani I, Eliasz S, De Marco MA, Chen Y, Pass HI, De May RM, et al. Opposite effects of Notch-1 and Notch-2 on mesothelioma cell survival under hypoxia are exerted through the Akt pathway. Cancer Res. 2008;68:9678–85.Google Scholar
  62. 62.
    Muguruma Y, Hozumi K, Warita H, Yahata T, Uno T, Ito M, et al. Maintenance of bone homeostasis by DLL1-mediated Notch signaling. J Cell Physiol. 2017;232:2569–80.Google Scholar
  63. 63.
    Dishowitz MI, Terkhorn SP, Bostic SA, Hankenson KD. Notch signaling components are upregulated during both endochondral and intramembranous bone regeneration. J Orthop Res. 2012;30:296–303.Google Scholar
  64. 64.
    Wagley Y, Mitchell T, Ashley J, Loomes KM, Hankenson K. Skeletal involvement in Alagille syndrome. Journal; 2018, pp 121–135 .Google Scholar
  65. 65.
    Giannakopoulos A, Fryssira H, Tzetis M, Xaidara A, Kanaka-Gantenbein C. Central precocious puberty in a boy with 22q13 deletion syndrome and NOTCH-1 gene duplication. J Pediatr Endocrinol Metab. 2016;29:1307–11.Google Scholar
  66. 66.
    Zanotti S, Yu J, Adhikari S, Canalis E. Glucocorticoids inhibit notch target gene expression in osteoblasts. J Cell Biochem. 2018;119:6016–23.Google Scholar
  67. 67.
    Sato AY, Richardson D, Cregor M, Davis HM, Au ED, McAndrews K, et al. Glucocorticoids induce bone and muscle atrophy by tissue-specific mechanisms upstream of E3 ubiquitin ligases. Endocrinology. 2017;158:664–77.Google Scholar
  68. 68.
    Chen X, Jiao J, He X, Zhang J, Wang H, Xu Y, et al. CHI3L1 regulation of inflammation and the effects on osteogenesis in a Staphylococcus aureus-induced murine model of osteomyelitis. FEBS J. 2017;284:1738–47.Google Scholar
  69. 69.
    Paic F, Igwe JC, Nori R, Kronenberg MS, Franceschetti T, Harrington P, et al. Identification of differentially expressed genes between osteoblasts and osteocytes. Bone. 2009;45:682–92.Google Scholar
  70. 70.
    Canalis E, Parker K, Feng JQ, Zanotti S. Osteoblast lineage-specific effects of notch activation in the skeleton. Endocrinology. 2013;154:623–34.Google Scholar
  71. 71.
    Canalis E, Schilling L, Zanotti S. Effects of sex and Notch signaling on the osteocyte cell Pool. J Cell Physiol. 2017;232:363–70.Google Scholar
  72. 72.
    Canalis E, Bridgewater D, Schilling L, Zanotti S. Canonical Notch activation in osteocytes causes osteopetrosis. Am J Physiol Endocrinol Metab. 2016;310:E171–82.Google Scholar
  73. 73.
    Lim J, Burclaff J, He G, Mills JC, Long F. Unintended targeting of Dmp1-Cre reveals a critical role for Bmpr1a signaling in the gastrointestinal mesenchyme of adult mice. Bone Res. 2017;5:16049.Google Scholar
  74. 74.
    Manokawinchoke J, Pavasant P, Osathanon T. Intermittent compressive stress regulates Notch target gene expression via transforming growth factor-beta signaling in murine pre-osteoblast cell line. Arch Oral Biol. 2017;82:47–54.Google Scholar
  75. 75.
    Canalis E. Clinical and experimental aspects of notch receptor signaling: Hajdu-Cheney syndrome and related disorders. Metabolism. 2018;80:48–56.Google Scholar
  76. 76.
    Fukushima H, Shimizu K, Watahiki A, Hoshikawa S, Kosho T, Oba D, et al. NOTCH2 Hajdu-Cheney mutations escape SCF(FBW7)-dependent proteolysis to promote osteoporosis. Mol Cell. 2017;68:645–658 e5.Google Scholar
  77. 77.
    • Vollersen N, Hermans-Borgmeyer I, Cornils K, Fehse B, Rolvien T, Triviai I, et al. High bone turnover in mice carrying a pathogenic Notch2 mutation causing Hajdu-Cheney syndrome. J Bone Miner Res. 2018;33:70–83. Notch2-activating HCS mice develop widespread osteopenia and bone porosity due to increased osteoclastogenic signaling by osteoblast-lineage cells. Google Scholar
  78. 78.
    Zanotti S, Yu J, Sanjay A, Schilling L, Schoenherr C, Economides AN, et al. Sustained Notch2 signaling in osteoblasts, but not in osteoclasts, is linked to osteopenia in a mouse model of Hajdu-Cheney syndrome. J Biol Chem. 2017;292:12232–44.Google Scholar
  79. 79.
    Canalis E, Sanjay A, Yu J, Zanotti S. An antibody to Notch2 reverses the osteopenic phenotype of Hajdu-Cheney mutant male mice. Endocrinology. 2017;158:730–42.Google Scholar
  80. 80.
    Wang Y, Luo TB, Liu L, Cui ZQ. LncRNA LINC00311 promotes the proliferation and differentiation of osteoclasts in osteoporotic rats through the Notch signaling pathway by targeting DLL3. Cell Physiol Biochem. 2018;47:2291–306.Google Scholar
  81. 81.
    Ashley JW, Ahn J, Hankenson KD. Notch signaling promotes osteoclast maturation and resorptive activity. J Cell Biochem. 2015;116:2598–609.Google Scholar
  82. 82.
    Manokawinchoke J, Sumrejkanchanakij P, Subbalekha K, Pavasant P, Osathanon T. Jagged1 inhibits osteoprotegerin expression by human periodontal ligament cells. J Periodontal Res. 2016;51:789–99.Google Scholar
  83. 83.
    Jeong SY, Kim JA, Oh IH. The adaptive remodeling of stem cell niche in stimulated bone marrow counteracts the leukemic niche. Stem Cells. 2018;36:1617–29.Google Scholar
  84. 84.
    Kim A, Shim S, Kim MJ, Myung JK, Park S. Mesenchymal stem cell-mediated Notch2 activation overcomes radiation-induced injury of the hematopoietic system. Sci Rep. 2018;8:9277.Google Scholar
  85. 85.
    Mantelmacher FD, Fishman S, Cohen K, Pasmanik Chor M, Yamada Y, Zvibel I, et al. Glucose-dependent insulinotropic polypeptide receptor deficiency leads to impaired bone marrow hematopoiesis. J Immunol. 2017;198:3089–98.Google Scholar
  86. 86.
    He Q, Scott Swindle C, Wan C, Flynn RJ, Oster RA, Chen D, et al. Enhanced hematopoietic stem cell self-renewal-promoting ability of clonal primary mesenchymal stromal/stem cells versus their osteogenic progeny. Stem Cells. 2017;35:473–84.Google Scholar
  87. 87.
    Michalicka M, Boisjoli G, Jahan S, Hovey O, Doxtator E, Abu-Khader A, et al. Human bone marrow mesenchymal stromal cell-derived osteoblasts promote the expansion of hematopoietic progenitors through beta-catenin and Notch signaling pathways. Stem Cells Dev. 2017;26:1735–48.Google Scholar
  88. 88.
    Gao S, Wang H, Jiang H, R F, H Y, Liu C, et al. Abnormal changes in the quantity and function of osteoblasts cultured in vitro in patients with myelodysplastic syndrome. Oncol Lett. 2018;16:4384–90.Google Scholar
  89. 89.
    Berenstein R, Nogai A, Waechter M, Blau O, Kuehnel A, Schmidt-Hieber M, et al. Multiple myeloma cells modify VEGF/IL-6 levels and osteogenic potential of bone marrow stromal cells via notch/miR-223. Mol Carcinog. 2016;55:1927–39.Google Scholar
  90. 90.
    Guo P, Poulos MG, Palikuqi B, Badwe CR, Lis R, Kunar B, et al. Endothelial jagged-2 sustains hematopoietic stem and progenitor reconstitution after myelosuppression. J Clin Invest. 2017;127:4242–56.Google Scholar
  91. 91.
    Guo J, Fei C, Zhao Y, Zhao S, Zheng Q, J S, et al. Lenalidomide restores the osteogenic differentiation of bone marrow mesenchymal stem cells from multiple myeloma patients via deactivating notch signaling pathway. Oncotarget. 2017;8:55405–21.Google Scholar
  92. 92.
    Liu X, Ren S, Ge C, Cheng K, Li X, Zhao RC. Sca1(+)Lin(−)CD117(−) mouse bone marrow-derived mesenchymal stem cells regulate immature dendritic cell maturation by inhibiting TLR4-IRF8 signaling via the notch-RBP-J pathway. Stem Cells Dev. 2018;27:556–65.Google Scholar
  93. 93.
    Xu LL, Fu HX, Zhang JM, Feng FE, Wang QM, Zhu XL, et al. Impaired function of bone marrow mesenchymal stem cells from immune thrombocytopenia patients in inducing regulatory dendritic cell differentiation through the Notch-1/Jagged-1 signaling pathway. Stem Cells Dev. 2017;26:1648–61.Google Scholar
  94. 94.
    Kusumbe AP, Ramasamy SK, Adams RH. Coupling of angiogenesis and osteogenesis by a specific vessel subtype in bone. Nature. 2014;507:323–8.Google Scholar
  95. 95.
    Ramasamy SK, Kusumbe AP, Schiller M, Zeuschner D, Bixel MG, Milia C, et al. Blood flow controls bone vascular function and osteogenesis. Nat Commun. 2016;7:13601.Google Scholar
  96. 96.
    Deng S, Zeng Y, Wu L, Hu Z, Shen J, Shen Y, et al. The regulatory roles of VEGF-Notch signaling pathway on aplastic anemia with kidney deficiency and blood stasis. J Cell Biochem. 2018.Google Scholar
  97. 97.
    Ishige-Wada M, Kwon SM, Eguchi M, Hozumi K, Iwaguro H, Matsumoto T, et al. Jagged-1 signaling in the bone marrow microenvironment promotes endothelial progenitor cell expansion and commitment of CD133+ human cord blood cells for postnatal vasculogenesis. PLoS One. 2016;11:e0166660.Google Scholar
  98. 98.
    Ko FC, Martins JS, Reddy P, Bragdon B, Hussein AI, Gerstenfeld LC, et al. Acute phosphate restriction impairs bone formation and increases marrow adipose tissue in growing mice. J Bone Miner Res. 2016;31:2204–14.Google Scholar
  99. 99.
    Liang T, Zhu L, Gao W, Gong M, Ren J, Yao H, et al. Coculture of endothelial progenitor cells and mesenchymal stem cells enhanced their proliferation and angiogenesis through PDGF and Notch signaling. FEBS Open Bio. 2017;7:1722–36.Google Scholar
  100. 100.
    Hebb JH, Ashley JW, McDaniel L, Lopas LA, Tobias J, Hankenson KD, et al. Bone healing in an aged murine fracture model is characterized by sustained callus inflammation and decreased cell proliferation. J Orthop Res. 2018;36:149–58.Google Scholar
  101. 101.
    Matthews BG, Grcevic D, Wang L, Hagiwara Y, Roguljic H, Joshi P, et al. Analysis of alphaSMA-labeled progenitor cell commitment identifies notch signaling as an important pathway in fracture healing. J Bone Miner Res. 2014;29:1283–94.Google Scholar
  102. 102.
    Wang H, Wang Y, He J, Diao C, Sun J, Wang J. Identification of key gene networks associated with fracture healing using alphaSMA-labeled progenitor cells. Mol Med Rep. 2018;18:834–40.Google Scholar
  103. 103.
    Dishowitz MI, PL Mutyaba, JD Takacs, AM Barr, JB Engiles, J Ahn and KD Hankenson. (2013). Systemic inhibition of canonical Notch signaling results in sustained callus inflammation and alters multiple phases of fracture healing. PLoS One 8:e68726.Google Scholar
  104. 104.
    • Youngstrom DW, Senos R, Zondervan RL, Brodeur JD, Lints AR, Young DR, et al. Intraoperative delivery of the Notch ligand Jagged-1 regenerates appendicular and craniofacial bone defects. NPJ Regen Med. 2017;2:32. Recombinant Jag1 protein promotes intramembranous bone healing in surgical mouse/rat models. Google Scholar
  105. 105.
    Bragdon BC, Bahney CS. Origin of reparative stem cells in fracture healing. Curr Osteoporos Rep. 2018;16:490–503.Google Scholar
  106. 106.
    Hu DP, Ferro F, Yang F, Taylor AJ, Chang W, Miclau T, et al. Cartilage to bone transformation during fracture healing is coordinated by the invading vasculature and induction of the core pluripotency genes. Development. 2017;144:221–34.Google Scholar
  107. 107.
    Lin NY, Distler A, Beyer C, Philipi-Schobinger A, Breda S, Dees C, et al. Inhibition of Notch1 promotes hedgehog signalling in a HES1-dependent manner in chondrocytes and exacerbates experimental osteoarthritis. Ann Rheum Dis. 2016;75:2037–44.Google Scholar
  108. 108.
    Wang C, Shen J, Yukata K, Inzana JA, O'Keefe RJ, Awad HA, et al. Transient gamma-secretase inhibition accelerates and enhances fracture repair likely via Notch signaling modulation. Bone. 2015;73:77–89.Google Scholar
  109. 109.
    Wang C, Inzana JA, Mirando AJ, Ren Y, Liu Z, Shen J, et al. NOTCH signaling in skeletal progenitors is critical for fracture repair. J Clin Invest. 2016;126:1471–81.Google Scholar
  110. 110.
    Tang Q, Jin H, Tong M, Zheng G, Xie Z, Tang S, et al. Inhibition of Dll4/Notch1 pathway promotes angiogenesis of Masquelet's induced membrane in rats. Exp Mol Med. 2018;50:41.Google Scholar

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© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of Orthopaedic SurgeryUniversity of Michigan Medical SchoolAnn ArborUSA

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