Progress of research into the role of autophagy related signal transduction pathways in bone metabolism

Update:Jul. 23, 2021Total Views:841Total Downloads:510 DownloadMobile

Author: Zhi-Zhuo LI 1 Li-Jun SHI 2 Fu-Qiang GAO 3 Wei SUN 3

Affiliation: 1. Department of Orthopedics, Peking University China-Japan Friendship School of Clinical Medicine, Beijing 100029, China 2. Department of Orthopedics, Peking Union Medical College, China-Japan Friendship institute of Clinical Medicine, Beijing 100029, China 3. Beijing Key Laboratory of Immune Inflammatory Disease, China-Japan Friendship Hospital, Beijing 100029, China

Keywords: Autophagy Bone Metabolism Signal Transduction Pathway Osteoblast Osteoclast


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Autophagy is an effective protective mechanism against tissue degeneration and plays an important role in cell proliferation, differentiation and maturation. The main cells involved in bone metabolism include osteoblasts and osteoclasts, which play an important role in bone develop-ment and maintenance. It has been found that the level of autophagy is regulated by Sirtuin1 (SIRT1) and mitogen-activated protein kinase 8 (MAPK8)/Forkhead box O3 (FOXO3) in osteoblasts. In osteo-clasts, the level of autophagy is regulated mainly by Bcl-2 interacting coiled-coil protein 1 (Beclin-1), p62/sequestosome 1 (p62/SQSTM1), mammalian target of Rapamycin (mTOR) and hypoxia-inducible factor-1α (HIF-1α). The main focus of this article is a discussion of the autophagy related signal trans-duction pathways in bone metabolism and an analysis of the regulation of autophagy in osteoblasts and osteoclasts.

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1.   Yu L, Chen Y, Tooze SA. Autophagy pathway: cellular and molecular mechanisms[J]. Autophagy, 2018, 14(2): 207-215. DOI: 10.1080/15548627.2017.1378838.

2.   Parzych KR, Klionsky DJ. An overview of autophagy: morphology, mechanism, and regulation[J]. Antioxidants & Redox Signaling, 2014, 20(3): 460-473. DOI: 10.1089/ars. 2013.5371.

3.   Wang S, Deng Z, Ma Y, et al. The role of autophagy and mitophagy in bone metabolic disor-ders[J]. Int J Biol Sci, 2020, 16(14): 2675-2691. DOI: 10.7150/ijbs.46627.

4.   Chen X, Wang Z, Duan N, et al. Osteoblast-osteoclast interactions[J]. Connective Tissue Re-search, 2018, 59(2): 99-107. DOI: 10.1080/03008207.2017.1290085.

5.   Tanaka Y, Nakayamada S, Okada Y. Osteoblasts and osteoclasts in bone remodeling and in-flammation[J]. Curr Drug Targets Inflamm Allergy, 2005, 4(3): 325-328. DOI: 10.2174/1568010054022015.

6.   Mizushima N, Komatsu M. Autophagy: renovation of cells and tissues[J]. Cell, 2011, 147(4): 728-741. DOI: 10.1016/j.cell.2011.10.026.

7.       Ozeki N, Hase N, Hiyama T, et al. MicroRNA-211 and autophagy-related gene 14 signaling regulate osteoblast-like cell differentiation of human induced pluripotent stem cells[J]. Exp Cell Res, 2017, 352(1): 63-74. DOI: 10.1016/j.yexcr.2017.01.018.

8.       Scott RC, Juhász G, Neufeld TP. Direct induction of autophagy by Atg1 inhibits cell growth and induces apoptotic cell death[J]. Curr Biol, 2007, 17(1): 1-11. DOI: 10.1016/j.cub.2006.10.053.

9.   Jung CH, Jun CB, Ro SH, et al. ULK-Atg13-FIP200 complexes mediate mTOR signaling to the autophagy machinery[J]. Mol Biol Cell, 2009, 20(7): 1992-2003. DOI: 10.1091/mbc.e08-12-1249.

10.  Maiese K. Targeting molecules to medicine with mTOR, autophagy and neurodegenerative disorders[J]. Br J Clin Pharmacol, 2016, 82(5): 1245-1266. DOI: 10.1111/bcp. 12804.

11.      Cohen-Kfir E, Artsi H, Levin A, et al. Sirt1 is a regulator of bone mass and a repressor of sost encoding for sclerostin, a bone formation inhibitor[J]. Endocrinology, 2011, 152(12): 4514-4524. DOI: 10.1210/en.2011-1128.

12.  Sun W, Qiao W, Zhou B, et al. Overexpression of Sirt1 in mesenchymal stem cells protects against bone loss in mice by FOXO3a deacetylation and oxidative stress inhibition[J]. Metabo-lism, 2018, 88: 61-71. DOI: 10.1016/j.metabol.2018.06.006.

13.      Gómez-Puerto MC, Verhagen LP, Braat AK, et al. Activation of autophagy by FOXO3 regulates redox homeostasis during osteogenic differentiation[J]. Autophagy, 2016, 12(10): 1804-1816. DOI: 10.1080/ 15548627.2016.1203484.

14.      Wei M, Duan D, Liu Y, et al. Autophagy may protect MC3T3-E1 cells from fluoride-induced apoptosis[J]. Molecular Medicine Reports, 2014, 9(6): 2309-2315. DOI: 10.3892/mmr.2014.2079.

15.  Wang Z, Liu N, Liu K, et al. Autophagy mediated CoCrMo particle-induced peri-implant oste-olysis by promoting osteoblast apoptosis[J]. Autophagy, 2015, 11(12): 2358-2369. DOI: 10.1080/15548627.2015.1106779.

16.  Goodman SB, Gallo J. Periprosthetic osteolysis: mechanisms, prevention and treatment[J]. J Clin Med, 2019, 8(12): 2091. DOI: 10.3390/jcm8122091.

17.  Su B, Li D, Xu J, et al. Wear particles enhance autophagy through up-regulation of CD147 to promote osteoclastogenesis[J]. Iranian Journal of Basic Medical ences, 2018, 21(8): 806-812. DOI: 10.22038/ijbms. 2018.29347.7093.

18.  Xue Y, Liang Z, Fu X, et al. IL-17A modulates osteoclast precursors' apoptosis through au-tophagy-TRAF3 signaling during osteoclastogenesis[J]. Biochem Biophys Res Commun, 2019, 508(4): 1088-1092. DOI: 10.1016/j.bbrc. 2018.12.029.

19.      Arai A, Kim S, Goldshteyn V, et al. Beclin1 modulates bone homeostasis by regulating os-teoclast and chondrocyte differentiation[J]. J Bone Miner Res, 2019, 34(9): 1753-1766. DOI: 10.1002/jbmr.3756.

20.  Kim CJ, Shin SH, Kim BJ, et al. The effects of kaempferol-inhibited autophagy on osteoclast formation[J]. Int J Mol Sci, 2018, 19(1): 125. DOI: 10.3390/ijms19010125.

21.  Rea SL, Walsh JP, Layfield R, et al. New insights into the role of sequestosome 1/p62 mutant proteins in the pathogenesis of Paget's disease of bone[J]. Endocr Rev, 2013, 34(4): 501-524. DOI: 10.1210/er.2012-1034.

22.  Tong X, Zhang C, Wang D, et al. Suppression of AMP-activated protein kinase reverses oste-oprotegerin-induced inhibition of osteoclast differentiation by reducing autophagy[J]. Cell Prolif, 2020, 53(1): e12714. DOI: 10. 1111/cpr.12714.

23.  Tong X, Gu J, Song R, et al. Osteoprotegerin inhibit osteoclast differentiation and bone re-sorption by enhancing autophagy via AMPK/mTOR/p70S6K signaling pathway in vitro[J]. J Cell Biochem, 2018. DOI: 10.1002/jcb.27468.

24.  Egan D, Kim J, Shaw RJ, et al. The autophagy initiating kinase ULK1 is regulated via opposing phosphorylation by AMPK and mTOR[J]. Autophagy, 2011, 7(6): 643-644. DOI: 10.4161/auto.7.6.15123.

25.  Zhao Y, Chen G, Zhang W, et al. Autophagy regulates hypoxia-induced osteoclastogenesis through the HIF-1α/BNIP3 signaling pathway[J]. Journal of Cellular Physiology, 2011, 227(2): 639-648. DOI: 10.1002/jcp.22768.

26.  Sun KT, Chen MY, Tu MG, et al. MicroRNA-20a regulates autophagy related protein-ATG16L1 in hypoxia-induced osteoclast differentiation[J]. Bone, 2015, 73: 145-153. DOI: 10.1016/j.bone.2014.11.026.

27.  Horvai AE, Boyce BF. Metabolic bone diseases[J]. Seminars in Diagnostic Pathology, 2011, 28(1): 13-25. DOI: 10.1053/j.semdp.2011.02.004.

28.  Veronesi F, Tschon M, Fini M. Gene expression in osteolysis: review on the identification of al-tered molecular pathways in preclinical and clinical studies[J]. Int J Mol Sci, 2017, 18(3): 499. DOI: 10.3390/ijms18030499.

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