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

doi:10.3969/j.issn.1674-8115.2023.02.012

Abstract

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

CLC Number:

GUO Liqiang, ZHAO Shitian, SHU Bing. 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.

Figures/Tables 1

TrendMD

References 53

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, SÖRENSEN 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 CD31^hiEmcn^hi 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	KAMIŃSKA 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.

[1]	WU Zhenkai, DENG Bo, PAN Yu, DING Feng. Research progress in the role and mechanism of acyloxyacyl hydrolase in diseases [J]. Journal of Shanghai Jiao Tong University (Medical Science), 2023, 43(1): 101-107.
[2]	LI Yuehua, LI Qingfeng, XIE Yun. Advances in application of adipose-derived mesenchymal stem cells in autoimmune diseases [J]. Journal of Shanghai Jiao Tong University (Medical Science), 2022, 42(8): 1131-1138.
[3]	A Tingxi, SHAO Chunyi, FU Yao. Research progress on the role of regulatory T cells in ocular surface diseases [J]. Journal of Shanghai Jiao Tong University (Medical Science), 2022, 42(8): 1145-1150.
[4]	LIU Hongqiang, LU Yanqing, GAO Yuxuan, WANG Yiyun, WANG Chuandong, ZHANG Xiaoling. Construction of OPEI vector for silencing TRAF6 to promote cartilage regeneration in inflammatory environment [J]. Journal of Shanghai Jiao Tong University (Medical Science), 2022, 42(7): 846-857.
[5]	ZHANG Lincheng, ZHONG Hua. Progress in pathogenesis and clinical treatment of sarcoidosis [J]. Journal of Shanghai Jiao Tong University (Medical Science), 2022, 42(7): 931-938.
[6]	LEI Haitao, TIAN Xuemei, JIN Fangquan. Advances in the correlation between cytokine signal transduction inhibitors and rheumatoid arthritis [J]. Journal of Shanghai Jiao Tong University (Medical Science), 2022, 42(7): 945-951.
[7]	WANG Xinpeng, WANG Junying, CAI Jiayi, FU Wanbing, ZHONG Hua. Effect of low-dose decitabine on the biological behavior of bone marrow mesenchymal stem cells derived from patients with immune thrombocytopenia [J]. Journal of Shanghai Jiao Tong University (Medical Science), 2022, 42(6): 758-767.
[8]	ZHANG Huanyu, JIANG Yiting, ZHU Xiaochen, HE Zhiyan, ZHOU Wei, SONG Zhongchen. Effects of gingipain extracts on brain neuroinflammation in mice [J]. Journal of Shanghai Jiao Tong University (Medical Science), 2022, 42(5): 570-577.
[9]	KANG Wenhui, CHEN Yiting, ZHAO Anda, LI Rong, LI Shenghui. Research progress of the mechanism of melatonin in the pathogenesis and course of asthma [J]. Journal of Shanghai Jiao Tong University (Medical Science), 2022, 42(5): 667-672.
[10]	WU Yue, ZHANG Jiaying, WANG Wei, LI Jin. Classification and research progress of corneal neurotization [J]. Journal of Shanghai Jiao Tong University (Medical Science), 2022, 42(4): 528-534.
[11]	HAO Lei, JIN Ge, YANG Yongtao, WANG Junwei, SUN Yang, QIN Cuiling, ZHAN Qunling. Effect of miR-124-1 mediated by exosomes of bone marrow-derived mesenchymal stem cells on the regulation of transformation of M2 microglia [J]. Journal of Shanghai Jiao Tong University (Medical Science), 2022, 42(3): 323-330.
[12]	LIU Ziwei, CAO Wenwen, WANG Yunrui, FENG Xiaoling. Potential role of SIRT1 in unexplained recurrent spontaneous abortion [J]. Journal of Shanghai Jiao Tong University (Medical Science), 2022, 42(10): 1466-1473.
[13]	JIANG Yi, JIANG Ping, ZHANG Mingming, FANG Jingyuan. Research progress in the role of Akkermansia muciniphila in gut-related diseases [J]. Journal of Shanghai Jiao Tong University (Medical Science), 2022, 42(10): 1490-1497.
[14]	Yi-feng SHI, Ying-ru HUANG, Yun-xiao LIU, Song ZHANG, Hua XIAN. Effects of heat shock protein 70 on cytoactive of sciatic nerve cryopreservation and nerve regeneration after allograft [J]. JOURNAL OF SHANGHAI JIAOTONG UNIVERSITY (MEDICAL SCIENCE), 2021, 41(9): 1190-1196.
[15]	Chi-hsiang CHUANG, Jia-chen DONG, Rong SHU. Biological and angiogenic effects of enamel matrix derivative on periodontal regeneration-related cells [J]. JOURNAL OF SHANGHAI JIAOTONG UNIVERSITY (MEDICAL SCIENCE), 2021, 41(8): 1099-1102.