Journal of Shanghai Jiao Tong University (Medical Science) >

2023 , Vol. 43 >Issue 2: 222 - 229

DOI: https://doi.org/10.3969/j.issn.1674-8115.2023.02.012

Review

Research progress in the roles of Notch signaling pathway during fracture healing

  • Liqiang GUO ,
  • Shitian ZHAO ,
  • Bing SHU
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  • Longhua Hospital, Shanghai University of Traditional Chinese Medicine; Spine Institute, Shanghai Academy of Traditional Chinese Medicine; Key Laboratory of Ministry of Education for Theory and Treatment of Bones and Muscles, Shanghai 200032, China
SHU Bing, E-mail: siren17721101@163.com.

Received date: 2022-03-19

  Accepted date: 2022-06-18

  Online published: 2023-02-28

Supported by

National Key R&D Program of China(2018YFC1704300);National Natural Science Foundation of China(81973876);Ministry of Education Innovation Team Development Program(IRT1270);Innovation Team Project in Key Fields of Ministry of Science and Technology(2015RA4002)

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Abstract

Fracture is the most common large-organ injury in humans. It takes several months or even longer from the onset to the completion of bone reconstruction. In severe cases, delayed healing or even bone discontinuity can occur. The current treatment of fractures mainly pursues the completion of clinical healing and bone healing, and the healing process is divided into three stages: early, intermediate and late. Various factors affect the speed of the healing process, among which signaling pathways and cytokines play an important role in fracture healing, so understanding the important role of signaling pathways and cytokines is important for treating fractures and promoting fracture healing. Recent studies have shown that the Notch signaling pathway can affect cell proliferation and differentiation, inflammatory response, bone reconstruction, angiogenesis and nerve regeneration during fracture healing, and its changes are also closely related to mechanical stimulation and other factors. Therefore, this paper reviews the research progress in the role of Notch signaling pathway in various aspects of fracture healing from the perspectives of cell proliferation and differentiation, inflammatory response, bone reconstruction, angiogenesis, nerve regeneration and mechanical stimulation, and provides new research directions and therapeutic strategies for fracture healing treatment.

Key words： Notch; fracture healing; inflammation; mesenchymal stem cell; bone remodeling; angiogenesis; nerve regeneration

Cite this article

Liqiang GUO , Shitian ZHAO , Bing SHU . Research progress in the roles of Notch signaling pathway during fracture healing[J]. Journal of Shanghai Jiao Tong University (Medical Science), 2023 , 43(2) : 222 -229 . DOI: 10.3969/j.issn.1674-8115.2023.02.012

References

1 FORTINI M E. Introduction: Notch in development and disease[J]. Semin Cell Dev Biol, 2012, 23(4): 419-420.
2 SIEBEL C, LENDAHL U. Notch signaling in development, tissue homeostasis, and disease[J]. Physiol Rev, 2017, 97(4): 1235-1294.
3 YU J, CANALIS E. Notch and the regulation of osteoclast differentiation and function[J]. Bone, 2020, 138: 115474.
4 SHAYA O, BINSHTOK U, HERSCH M, et al. Cell-cell contact area affects Notch signaling and Notch-dependent patterning[J]. Dev Cell, 2017, 40(5): 505-511.e6.
5 KOPAN R, ILAGAN M X G. The canonical Notch signaling pathway: unfolding the activation mechanism[J]. Cell, 2009, 137(2): 216-233.
6 LI L, TANG P, LI S, et al. Notch signaling pathway networks in cancer metastasis: a new target for cancer therapy[J]. Med Oncol, 2017, 34(10): 180.
7 FAYYAZ S, ATTAR R, XU B J, et al. Realizing the potential of blueberry as natural inhibitor of metastasis and powerful apoptosis inducer: tapping the treasure trove for effective regulation of cell signaling pathways[J]. Anticancer Agents Med Chem, 2020, 20(15): 1780-1786.
8 EINHORN T A, GERSTENFELD L C. Fracture healing: mechanisms and interventions[J]. Nat Rev Rheumatol, 2015, 11(1): 45-54.
9 ONO T, TAKAYANAGI H. Osteoimmunology in bone fracture healing[J]. Curr Osteoporos Rep, 2017, 15(4): 367-375.
10 DISHOWITZ M I, MUTYABA P L, TAKACS J D, et al. Systemic inhibition of canonical Notch signaling results in sustained callus inflammation and alters multiple phases of fracture healing[J]. PLoS One, 2013, 8(7): e68726.
11 NOVAK S, ROEDER E, SINDER B P, et al. Modulation of Notch1 signaling regulates bone fracture healing[J]. J Orthop Res, 2020, 38(11): 2350-2361.
12 WU A C, RAGGATT L J, ALEXANDER K A, et al. Unraveling macrophage contributions to bone repair[J]. Bonekey Rep, 2013, 2: 373.
13 LOI F, CóRDOVA L A, PAJARINEN J, et al. Inflammation, fracture and bone repair[J]. Bone, 2016, 86: 119-130.
14 KEEWAN E, NASER S A. The role of Notch signaling in macrophages during inflammation and infection: implication in rheumatoid arthritis?[J]. Cells, 2020, 9(1): 111.
15 HILTON M J, TU X L, WU X M, et al. Notch signaling maintains bone marrow mesenchymal progenitors by suppressing osteoblast differentiation[J]. Nat Med, 2008, 14(3): 306-314.
16 ZHANG Q H, WANG C M, LIU Z L, et al. Notch signal suppresses toll-like receptor-triggered inflammatory responses in macrophages by inhibiting extracellular signal-regulated kinase 1/2-mediated nuclear factor κB activation[J]. J Biol Chem, 2012, 287(9): 6208-6217.
17 HALL S R R, JIANG Y J, LEARY E, et al. Identification and isolation of small CD44-negative mesenchymal stem/progenitor cells from human bone marrow using elutriation and polychromatic flow cytometry[J]. Stem Cells Transl Med, 2013, 2(8): 567-578.
18 SONG K, HUANG M Q, SHI Q, et al. Cultivation and identification of rat bone marrow-derived mesenchymal stem cells[J]. Mol Med Rep, 2014, 10(2): 755-760.
19 GU Q L, CAI Y, HUANG C, et al. Curcumin increases rat mesenchymal stem cell osteoblast differentiation but inhibits adipocyte differentiation[J]. Pharmacogn Mag, 2012, 8(31): 202-208.
20 SHAO J, ZHANG W W, YANG T Y. Using mesenchymal stem cells as a therapy for bone regeneration and repairing[J]. Biol Res, 2015, 48(1): 62.
21 DISHOWITZ M I, TERKHORN S P, BOSTIC S A, et al. Notch signaling components are upregulated during both endochondral and intramembranous bone regeneration[J]. J Orthop Res, 2012, 30(2): 296-303.
22 MATTHEWS B G, GRCEVIC D, WANG L P, et al. Analysis of αSMA-labeled progenitor cell commitment identifies Notch signaling as an important pathway in fracture healing[J]. J Bone Miner Res, 2014, 29(5): 1283-1294.
23 WANG C, INZANA J A, MIRANDO A J, et al. NOTCH signaling in skeletal progenitors is critical for fracture repair[J]. J Clin Invest, 2016, 126(4): 1471-1481.
24 MUGURUMA Y, HOZUMI K, WARITA H, et al. Maintenance of bone homeostasis by DLL1-mediated Notch signaling[J]. J Cell Physiol, 2017, 232(9): 2569-2580.
25 SEMENOVA D, BOGDANOVA M, KOSTINA A, et al. Dose-dependent mechanism of Notch action in promoting osteogenic differentiation of mesenchymal stem cells[J]. Cell Tissue Res, 2020, 379(1): 169-179.
26 ZANOTTI S, CANALIS E. Notch1 and Notch2 expression in osteoblast precursors regulates femoral microarchitecture[J]. Bone, 2014, 62: 22-28.
27 ZANOTTI S, SMERDEL-RAMOYA A, STADMEYER L, et al. Notch inhibits osteoblast differentiation and causes osteopenia[J]. Endocrinology, 2008, 149(8): 3890-3899.
28 UGARTE F, RYSER M, THIEME S, et al. Notch signaling enhances osteogenic differentiation while inhibiting adipogenesis in primary human bone marrow stromal cells[J]. Exp Hematol, 2009, 37(7): 867-875.e1.
29 JI Y T, KE Y X, GAO S. Intermittent activation of Notch signaling promotes bone formation[J]. Am J Transl Res, 2017, 9(6): 2933-2944.
30 ZHAO B H, GRIMES S N, LI S S, et al. TNF-induced osteoclastogenesis and inflammatory bone resorption are inhibited by transcription factor RBP-J[J]. J Exp Med, 2012, 209(2): 319-334.
31 CANALIS E, SCHILLING L, YEE S P, et al. Hajdu Cheney mouse mutants exhibit osteopenia, increased osteoclastogenesis, and bone resorption[J]. J Biol Chem, 2016, 291(4): 1538-1551.
32 GOEL P N, MOHARRER Y, HEBB J H, et al. Suppression of Notch signaling in osteoclasts improves bone regeneration and healing[J]. J Orthop Res, 2019, 37(10): 2089-2103.
33 BENEDITO R, ROCA C, S?RENSEN I, et al. The Notch ligands Dll4 and Jagged1 have opposing effects on angiogenesis[J]. Cell, 2009, 137(6): 1124-1135.
34 SAHARA M, HANSSON E M, WERNET O, et al. Manipulation of a VEGF-Notch signaling circuit drives formation of functional vascular endothelial progenitors from human pluripotent stem cells[J]. Cell Res, 2015, 25(1): 148.
35 ZHANG B, PU W T. Notching up vascular regeneration[J]. Cell Res, 2014, 24(7): 777-778.
36 KUSUMBE A P, RAMASAMY S K, ADAMS R H. Coupling of angiogenesis and osteogenesis by a specific vessel subtype in bone[J]. Nature, 2014, 507(7492): 323-328.
37 RAMASAMY S K, KUSUMBE A P, WANG L, et al. Endothelial Notch activity promotes angiogenesis and osteogenesis in bone[J]. Nature, 2014, 507(7492): 376-380.
38 YANG M, LI C J, SUN X, et al. MiR-497~195 cluster regulates angiogenesis during coupling with osteogenesis by maintaining endothelial Notch and HIF-1α activity[J]. Nat Commun, 2017, 8: 16003.
39 ZANOTTI S, CANALIS E. Notch signaling and the skeleton[J]. Endocr Rev, 2016, 37(3): 223-253.
40 XU R, YALLOWITZ A, QIN A, et al. Targeting skeletal endothelium to ameliorate bone loss[J]. Nat Med, 2018, 24(6): 823-833.
41 ZHU Y, RUAN Z, LIN Z Y, et al. The association between CD31hiEmcnhi endothelial cells and bone mineral density in Chinese women[J]. J Bone Miner Metab, 2019, 37(6): 987-995.
42 WANG L, ZHOU F, ZHANG P, et al. Human type H vessels are a sensitive biomarker of bone mass[J]. Cell Death Dis, 2017, 8(5): e2760.
43 SHAO J, ZHOU Y H, LIN J Y, et al. Notch expressed by osteocytes plays a critical role in mineralisation[J]. J Mol Med, 2018, 96(3): 333-347.
44 PFLANZ D, BIRKHOLD A I, ALBIOL L, et al. Sost deficiency led to a greater cortical bone formation response to mechanical loading and altered gene expression[J]. Sci Rep, 2017, 7(1): 9435.
45 ZIOUTI F, EBERT R, RUMMLER M, et al. NOTCH signaling is activated through mechanical strain in human bone marrow-derived mesenchymal stromal cells[J]. Stem Cells Int, 2019, 2019: 5150634.
46 MANOKAWINCHOKE J, PAVASANT P, OSATHANON T. Intermittent compressive stress regulates Notch target gene expression via transforming growth factor-β signaling in murine pre-osteoblast cell line[J]. Arch Oral Biol, 2017, 82: 47-54.
47 NIEDERMAIR T, STRAUB R H, BROCHHAUSEN C, et al. Impact of the sensory and sympathetic nervous system on fracture healing in ovariectomized mice[J]. Int J Mol Sci, 2020, 21(2): 405.
48 MIYATA S. Cytoskeletal signal-regulated oligodendrocyte myelination and remyelination[J]. Adv Exp Med Biol, 2019, 1190: 33-42.
49 ARTHUR-FARRAJ P, WANEK K, HANTKE J, et al. Mouse schwann cells need both NRG1 and cyclic AMP to myelinate[J]. Glia, 2011, 59(5): 720-733.
50 WANG J, REN K Y, WANG Y H, et al. Effect of active Notch signaling system on the early repair of rat sciatic nerve injury[J]. Artif Cells Nanomed Biotechnol, 2015, 43(6): 383-389.
51 ZANOTTI S, CANALIS E. Parathyroid hormone inhibits Notch signaling in osteoblasts and osteocytes[J]. Bone, 2017, 103: 159-167.
52 ZANOTTI S, YU J, ADHIKARI S, et al. Glucocorticoids inhibit Notch target gene expression in osteoblasts[J]. J Cell Biochem, 2018, 119(7): 6016-6023.
53 KAMI?SKA A, MAREK S, PARDYAK L, et al. Crosstalk between androgen-ZIP9 signaling and Notch pathway in rodent Sertoli cells[J]. Int J Mol Sci, 2020, 21(21): 8275.
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