NOTCH signaling in skeletal progenitors is critical for fracture repair

Wang, Cuicui; Inzana, Jason A.; Mirando, Anthony J.; Ren, Yinshi; Liu, Zhaoyang; Shen, Jie; O’Keefe, Regis J.; Awad, Hani A.; Hilton, Matthew J.

doi:10.1172/jci80672

Cited by 101 publications

(81 citation statements)

References 56 publications

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“…Whereas these results suggest a negative role of Notch in fracture healing, it is important to note that γ-secretase inhibitors are not specific inhibitors of Notch activation. Interestingly, the downregulation of Rbpjκ , a main component of canonical Notch signaling, in chondrogenic-/osteogenic-expressing cells results in non-union fractures [83]. This suggests that a degree of Notch signaling is necessary for fracture repair.…”

Section: Notch and Acquired Skeletal Diseasesmentioning

confidence: 99%

Notch in skeletal physiology and disease

Canalis

2018

Osteoporos Int

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Notch (Notch1 through 4) are transmembrane receptors that play a fundamental role in cell differentiation and function. Notch receptors are activated following interactions with their ligands in neighboring cells. There are five classic ligands termed Jagged (Jag)1 and Jag2 and Delta-like (Dll)1, Dll3, and Dll4. Recent work has established Notch as a signaling pathway that plays a critical role in the differentiation and function of cells of the osteoblast and osteoclast lineages and in skeletal development and bone remodeling. The effects of Notch are cell-context dependent, and the four Notch receptors carry out specific functions in the skeleton. Gain- and loss-of-function mutations of components of the Notch signaling pathway result in a variety of congenital disorders with significant craniofacial and skeletal manifestations. The Notch ligand Jag1 is a determinant of bone mineral density, and Notch plays a role in the early phases of fracture healing. Alterations in Notch signaling are associated with osteosarcoma and with the metastatic potential of carcinoma of the breast and of the prostate. Controlling Notch signaling could prove useful in diseases of Notch gain-of-function and in selected skeletal disorders. However, clinical data on agents that modify Notch signaling are not available. In conclusion, Notch signaling is a novel pathway that regulates skeletal homeostasis in health and disease.

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Section: Notch and Acquired Skeletal Diseasesmentioning

confidence: 99%

Notch in skeletal physiology and disease

Canalis

2018

Osteoporos Int

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“…Wnt, Notch, BMP and other signaling pathways have all been implicated in influencing the periosteal response to fracture [45–47] and PI3K forms a major node downstream of these signaling pathway. Understanding how PI3K-AKT activity regulates periosteal expansion may provide valuable insights into developing new/improved therapeutics to treat fractures.…”

Section: Discussionmentioning

confidence: 99%

Loss of Cbl-PI3K interaction modulates the periosteal response to fracture by enhancing osteogenic commitment and differentiation

Scanlon¹,

Walia

Yu³

et al. 2017

Bone

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The periosteum contains multipotent skeletal progenitors that contribute to bone repair. The signaling pathways regulating the response of periosteal cells to fracture are largely unknown. Phosphatidylinositol-3 Kinase (PI3K), a prominent lipid kinase, is a major signaling protein downstream of several factors that regulate osteoblast differentiation. Cbl is an E3 ubiquitin ligase and a major adaptor protein that binds to the p85 regulatory subunit and modulates PI3K activity. Substitution of tyrosine 737 to phenylalanine (Y737F) in Cbl abolishes the interaction between Cbl and the p85 subunit without affecting the Cbl’s ubiquitin ligase function. Here, we investigated the role of PI3K signaling during the very early stages of fracture healing using OsterixRFP reporter mice. We found that the absence of PI3K regulation by Cbl resulted in robust periosteal thickening, with increased proliferation of periosteal cells. While the multipotent properties of periosteal progenitors to differentiate into chondrocytes and adipocytes did not change, osteogenic differentiation in the absence of Cbl-PI3K interaction was highly augmented. The increased stability and nuclear localization of Osterix observed in periosteal cells lacking Cbl-PI3K interaction may explain this enhanced osteogenic differentiation since the expression of Osterix transcriptional target genes including osteocalcin and BSP are increased in YF cells. Overall, our findings highlight a hitherto unexplored and novel role for Cbl and PI3K in modulating the osteogenic response of periosteal cells during the early stages of fracture repair.

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“…Mice with complete disruption of canonical Notch signaling by Prx1 ‐Cre mediated disruption of the Notch transcription factor CSL have non‐unions. Notch signaling appears to be required for the proliferation and/or migration of mesenchymal progenitor cells …”

Section: Fibrovascular Phase—endothelial and Mesenchymal Progenitorsmentioning

confidence: 99%

Cellular biology of fracture healing

Bahney

Zondervan²,

Allison³

et al. 2018

Journal Orthopaedic Research

318

326

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The biology of bone healing is a rapidly developing science. Advances in transgenic and gene-targeted mice have enabled tissue and cell-specific investigations of skeletal regeneration. As an example, only recently has it been recognized that chondrocytes convert to osteoblasts during healing bone, and only several years prior, seminal publications reported definitively that the primary tissues contributing bone forming cells during regeneration were the periosteum and endosteum. While genetically modified animals offer incredible insights into the temporal and spatial importance of various gene products, the complexity and rapidity of healing— coupled with the heterogeneity of animal models—renders studies of regenerative biology challenging. Herein, cells that play a key role in bone healing will be reviewed and extracellular mediators regulating their behavior discussed. We will focus on recent studies that explore novel roles of inflammation in bone healing, and the origins and fates of various cells in the fracture environment.

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NOTCH signaling in skeletal progenitors is critical for fracture repair

Cited by 101 publications

References 56 publications

Notch in skeletal physiology and disease

Notch in skeletal physiology and disease

Loss of Cbl-PI3K interaction modulates the periosteal response to fracture by enhancing osteogenic commitment and differentiation

Cellular biology of fracture healing

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