Research Progress on the Involvement of PI3K-AKT Signaling Pathway in the Pathogenesis of Osteoporosis

Authors

  • Peng Ling
  • Yanggang Tang
  • Zunian He
  • Dinggui Lu

DOI:

https://doi.org/10.54097/3jpy2584

Keywords:

Osteoporosis, Bone Remodeling, Autophagy, PI3K-AKT Signaling Pathway

Abstract

Osteoporosis is a systemic skeletal disorder characterized by decreased bone mineral density, deterioration of bone microarchitecture, and an elevated susceptibility to fractures. The PI3K-AKT signaling pathway plays a pivotal role in regulating cell survival, proliferation, and differentiation, and is indispensable for normal bone metabolism. Its involvement in the pathogenesis and progression of osteoporosis has not been comprehensively addressed. To elucidate the role of the PI3K-AKT signaling pathway in osteoporosis, particularly its regulation of osteoblast and osteoclast activity and function in autophagy, this review comprehensively summarizes the impact of the PI3K-AKT signaling pathway on bone remodeling processes and recent research advancements, providing valuable references for related disease studies.

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References

[1] Results of the epidemiological survey on osteoporosis in China and the "Healthy Bones" special action have been released. Chinese Journal of Osteoporosis and Metabolic Bone Diseases,2019,12(04):317-318.

[2] Kenkre JS, Bassett J. The bone remodelling cycle. Ann Clin Biochem. 2018 May;55(3):308-327. doi: 10.1177/0004563 218759371. Epub 2018 Mar 4. PMID: 29368538.

[3] Raggatt LJ, Partridge NC. Cellular and molecular mechanisms of bone remodeling. J Biol Chem. 2010 Aug 13; 285 (33): 25103-8. doi: 10.1074/jbc.R109.041087. Epub 2010 May 25. PMID: 20501658; PMCID: PMC2919071.

[4] Hunter DJ, Sambrook PN. Bone loss. Epidemiology of bone loss. Arthritis Res. 2000;2(6):441-5. doi: 10.1186/ar125. Epub 2000 Aug 3. PMID: 11094456; PMCID: PMC128872.

[5] Karsenty G. Transcriptional control of skeletogenesis. Annu Rev Genomics Hum Genet. 2008;9:183-96. doi: 10.1146/ annurev.genom.9.081307.164437. PMID: 18767962.

[6] Chen X, Wang Z, Duan N, Zhu G, Schwarz EM, Xie C. Osteoblast-osteoclast interactions. Connect Tissue Res. 2018 Mar; 59(2):99-107. doi: 10.1080/03008207.2017.1290085. Epub 2017 Mar 21. PMID: 28324674; PMCID: PMC5612831.

[7] Li Xuedong. Leniolisib Alleviates Cranial Bone Resorption Induced by LPS by Inhibiting Osteoclast Differentiation [D]. Guangxi Medical University,2021.

[8] Todd JA, Robinson RJ. Osteoporosis and exercise. Postgrad Med J. 2003 Jun;79(932):320-3. doi: 10.1136/pmj.79.932.320. PMID: 12840119; PMCID: PMC1742726.

[9] Chang L, Graham PH, Ni J, Hao J, Bucci J, Cozzi PJ, Li Y. Targeting PI3K/Akt/mTOR signaling pathway in the treatment of prostate cancer radioresistance. Crit Rev Oncol Hematol. 2015 Dec;96(3):507-17. doi: 10.1016/j.critrevonc.2015.07.005. Epub 2015 Jul 18. PMID: 26253360.

[10] Peltier J, O'Neill A, Schaffer DV. PI3K/Akt and CREB regulate adult neural hippocampal progenitor proliferation and differentiation. Dev Neurobiol. 2007 Sep 1;67(10):1348-61. doi: 10.1002/dneu.20506. PMID: 17638387.

[11] Rafalski VA, Brunet A. Energy metabolism in adult neural stem cell fate. Prog Neurobiol. 2011 Feb;93(2):182-203. doi: 10.1016/j.pneurobio.2010.10.007. Epub 2010 Nov 5. PMID: 21056618.

[12] Katso R, Okkenhaug K, Ahmadi K, White S, Timms J, Waterfield MD. Cellular function of phosphoinositide 3-kinases: implications for development, homeostasis, and cancer. Annu Rev Cell Dev Biol. 2001;17:615-75. doi: 10.1146/annurev.cellbio.17.1.615. PMID: 11687500.

[13] Li H, Prever L, Hirsch E, Gulluni F. Targeting PI3K/AKT/mTOR Signaling Pathway in Breast Cancer. Cancers (Basel). 2021 Jul 14;13(14):3517. doi: 10.3390/ cancers 13143517. PMID: 34298731; PMCID: PMC8304822.

[14] Chen QY, Costa M. PI3K/Akt/mTOR Signaling Pathway and the Biphasic Effect of Arsenic in Carcinogenesis. Mol Pharmacol. 2018 Jul;94(1):784-792. doi: 10.1124/mol. 118. 112268. Epub 2018 May 16. PMID: 29769245; PMCID: PMC 5994485.

[15] Scheid MP, Woodgett JR. Unravelling the activation mechanisms of protein kinase B/Akt. FEBS Lett. 2003 Jul 3;546 (1):108-12. doi: 10.1016/s0014-5793(03)00562-3. PMID: 12829245.

[16] Carpenter RL, Jiang BH. Roles of EGFR, PI3K, AKT, and mTOR in heavy metal-induced cancer. Curr Cancer Drug Targets. 2013 Mar;13(3):252-66. doi: 10.2174/ 15680096113 13030004. PMID: 23297824.

[17] Jin F, Wu Z, Hu X, Zhang J, Gao Z, Han X, Qin J, Li C, Wang Y. The PI3K/Akt/GSK-3β/ROS/eIF2B pathway promotes breast cancer growth and metastasis via suppression of NK cell cytotoxicity and tumor cell susceptibility. Cancer Biol Med. 2019 Feb;16(1):38-54. doi: 10.20892/j.issn.2095-3941.2018. 0253. PMID: 31119045; PMCID: PMC6528454.

[18] Sarbassov DD, Ali SM, Kim DH, Guertin DA, Latek RR, Erdjument-Bromage H, Tempst P, Sabatini DM. Rictor, a novel binding partner of mTOR, defines a rapamycin-insensitive and raptor-independent pathway that regulates the cytoskeleton. Curr Biol. 2004 Jul 27;14(14):1296-302. doi: 10.1016/j.cub.2004.06.054. PMID: 15268862.

[19] Jiang BH, Liu LZ. Role of mTOR in anticancer drug resistance: perspectives for improved drug treatment. Drug Resist Updat. 2008 Jun;11(3):63-76. doi: 10.1016/j.drup.2008.03.001. Epub 2008 Apr 28. PMID: 18440854; PMCID: PMC2519122.

[20] Heitman J, Movva NR, Hall MN. Targets for cell cycle arrest by the immunosuppressant rapamycin in yeast. Science. 1991 Aug 23;253(5022):905-9. doi: 10.1126/science.1715094. PMID: 1715094.

[21] Raut N, Wicks SM, Lawal TO, Mahady GB. Epigenetic regulation of bone remodeling by natural compounds. Pharmacol Res. 2019 Sep;147:104350. doi: 10.1016/j. phrs. 2019.104350. Epub 2019 Jul 14. PMID: 31315065; PMCID: PMC6733678.

[22] Kaloni D, Diepstraten ST, Strasser A, Kelly GL. BCL-2 protein family: attractive targets for cancer therapy. Apoptosis. 2023 Feb; 28(1-2):20-38. doi: 10.1007/s10495-022-01780-7. Epub 2022 Nov 7. PMID: 36342579; PMCID: PMC9950219.

[23] Han Junwen. The mechanism of regulating osteoclasts by Du Zhong and Luosifen through the PI3K/Akt pathway to improve osteoporosis [D]. Beijing University of Chinese Medicine,2022.

[24] Li X, Qin L, Bergenstock M, Bevelock LM, Novack DV, Partridge NC. Parathyroid hormone stimulates osteoblastic expression of MCP-1 to recruit and increase the fusion of pre/osteoclasts. J Biol Chem. 2007 Nov 9;282(45):33098-106. doi: 10.1074/jbc.M611781200. Epub 2007 Aug 9. PMID: 17690108.

[25] Qin S, Zhang Q, Zhang L. Effect of OPG gene mutation on protein expression and biological activity in osteoporosis. Exp Ther Med. 2017 Aug;14(2):1475-1480. doi: 10.3892/etm. 2017. 4712. Epub 2017 Jun 28. PMID: 28810612; PMCID: PMC5526059.

[26] Xiong J, Cawley K, Piemontese M, Fujiwara Y, Zhao H, Goellner JJ, O'Brien CA. Soluble RANKL contributes to osteoclast formation in adult mice but not ovariectomy-induced bone loss. Nat Commun. 2018 Jul 25;9(1):2909. doi: 10.1038/s41467-018-05244-y. PMID: 30046091; PMCID: PMC6060116.

[27] Jiang W, Rixiati Y, Huang H, Shi Y, Huang C, Jiao B. Asperolide A prevents bone metastatic breast cancer via the PI3K/AKT/mTOR/c-Fos/NFATc1 signaling pathway. Cancer Med. 2020 Nov;9(21):8173-8185. doi: 10.1002/cam4.3432. Epub 2020 Sep 25. PMID: 32976685; PMCID: PMC7643645.

[28] Liao HJ, Tsai HF, Wu CS, Chyuan IT, Hsu PN. TRAIL inhibits RANK signaling and suppresses osteoclast activation via inhibiting lipid raft assembly and TRAF6 recruitment. Cell Death Dis. 2019 Jan 28;10(2):77. doi: 10.1038/s41419-019-1353-3. PMID: 30692521; PMCID: PMC6349873.

[29] Tong X, Chen M, Song R, Zhao H, Bian J, Gu J, Liu Z. Overexpression of c-Fos reverses osteoprotegerin-mediated suppression of osteoclastogenesis by increasing the Beclin1-induced autophagy. J Cell Mol Med. 2021 Jan;25(2):937-945. doi: 10.1111/jcmm.16152. Epub 2020 Dec 4. PMID: 33277741; PMCID: PMC7812271.

[30] Glick D, Barth S, Macleod KF. Autophagy: cellular and molecular mechanisms. J Pathol. 2010 May;221(1):3-12. doi: 10.1002/path.2697. PMID: 20225336; PMCID: PMC2990190.

[31] Shapiro IM, Layfield R, Lotz M, Settembre C, Whitehouse C. Boning up on autophagy: the role of autophagy in skeletal biology. Autophagy. 2014 Jan;10(1):7-19. doi: 10.4161/ auto. 26679. Epub 2013 Nov 11. PMID: 24225636; PMCID: PMC4028324.

[32] Liu ZZ, Hong CG, Hu WB, Chen ML, Duan R, Li HM, Yue T, Cao J, Wang ZX, Chen CY, Hu XK, Wu B, Liu HM, Tan YJ, Liu JH, Luo ZW, Zhang Y, Rao SS, Luo MJ, Yin H, Wang YY, Xia K, Xu L, Tang SY, Hu RG, Xie H. Autophagy receptor OPTN (optineurin) regulates mesenchymal stem cell fate and bone-fat balance during aging by clearing FABP3. Autophagy. 2021 Oct;17(10):2766-2782. doi: 10.1080/ 15548627. 2020. 1839286. Epub 2020 Nov 4. PMID: 33143524; PMCID: PMC8526045.

[33] Wang Z, Liu N, Liu K, Zhou G, Gan J, Wang Z, Shi T, He W, Wang L, Guo T, Bao N, Wang R, Huang Z, Chen J, Dong L, Zhao J, Zhang J. Autophagy mediated CoCrMo particle-induced peri-implant osteolysis by promoting osteoblast apoptosis. Autophagy. 2015;11(12):2358-69. doi: 10.1080/ 15548627. 2015.1106779. PMID: 26566231; PMCID: PMC4835204.

[34] Zhang L, Guo YF, Liu YZ, Liu YJ, Xiong DH, Liu XG, Wang L, Yang TL, Lei SF, Guo Y, Yan H, Pei YF, Zhang F, Papasian CJ, Recker RR, Deng HW. Pathway-based genome-wide association analysis identified the importance of regulation-of-autophagy pathway for ultradistal radius BMD. J Bone Miner Res. 2010 Jul;25(7):1572-80. doi: 10.1002/jbmr.36. PMID: 20200951; PMCID: PMC3153999.

[35] Dallas SL, Xie Y, Shiflett LA, Ueki Y. Mouse Cre Models for the Study of Bone Diseases. Curr Osteoporos Rep. 2018 Aug;16(4):466-477. doi: 10.1007/s11914-018-0455-7. PMID: 29934753; PMCID: PMC6397767.

[36] Murtaza G, Khan AK, Rashid R, Muneer S, Hasan SMF, Chen J. FOXO Transcriptional Factors and Long-Term Living. Oxid Med Cell Longev. 2017;2017:3494289. doi: 10.1155/ 2017/ 3494289. Epub 2017 Aug 15. PMID: 28894507; PMCID: PMC5574317.

[37] Almeida M. Unraveling the role of FoxOs in bone--insights from mouse models. Bone. 2011 Sep;49(3):319-27. doi: 10.1016/ j.bone.2011.05.023. Epub 2011 Jun 1. PMID: 2166 4311; PMCID: PMC3143252.

[38] Tower J. Hsps and aging. Trends Endocrinol Metab. 2009 Jul;20(5):216-22. doi: 10.1016/j.tem.2008.12.005. Epub 2009 Apr 24. PMID: 19394247; PMCID: PMC3835556.

[39] Demontis F, Perrimon N. FOXO/4E-BP signaling in Drosophila muscles regulates organism-wide proteostasis during aging. Cell. 2010 Nov 24;143(5):813-25. doi: 10.1016/j. cell. 2010.10.007. PMID: 21111239; PMCID: PMC3066043.

[40] Wang L, Liu S, Zhao Y, Liu D, Liu Y, Chen C, Karray S, Shi S, Jin Y. Osteoblast-induced osteoclast apoptosis by fas ligand/FAS pathway is required for maintenance of bone mass. Cell Death Differ. 2015 Oct;22(10):1654-64. doi: 10.1038/ cdd.2015.14. Epub 2015 Mar 6. PMID: 25744024; PMCID: PMC4563780.

[41] Cabezudo S, Sanz-Flores M, Caballero A, Tasset I, Rebollo E, Diaz A, Aragay AM, Cuervo AM, Mayor F Jr, Ribas C. Gαq activation modulates autophagy by promoting mTORC1 signaling. Nat Commun. 2021 Jul 27;12(1):4540. doi: 10.1038/ s41467-021-24811-4. PMID: 34315875; PMCID: PMC8316 552.

[42] Spangle JM, Roberts TM, Zhao JJ. The emerging role of PI3K/AKT-mediated epigenetic regulation in cancer. Biochim Biophys Acta Rev Cancer. 2017 Aug;1868(1):123-131. doi: 10.1016/j.bbcan.2017.03.002. Epub 2017 Mar 14. PMID: 28315368; PMCID: PMC5548615.

[43] Tian LY, Smit DJ, Jücker M. The Role of PI3K/AKT/mTOR Signaling in Hepatocellular Carcinoma Metabolism. Int J Mol Sci. 2023 Jan 31;24(3):2652. doi: 10.3390/ijms24032652. PMID: 36768977; PMCID: PMC9916527.

[44] Karar J, Maity A. PI3K/AKT/mTOR Pathway in Angiogenesis. Front Mol Neurosci. 2011 Dec 2;4:51. doi: 10.3389/ fnmol. 2011.00051. PMID: 22144946; PMCID: PMC3228996.

[45] Huang WC, Hung MC. Induction of Akt activity by chemotherapy confers acquired resistance. J Formos Med Assoc. 2009 Mar;108(3):180-94. doi: 10.1016/S0929-6646(09) 60051-6. PMID: 19293033.

[46] Liu J, Gu X, Guan Z, Huang D, Xing H, Zheng L. Role of m6A modification in regulating the PI3K/AKT signaling pathway in cancer. J Transl Med. 2023 Nov 1;21(1):774. doi: 10.1186/s 12967-023-04651-0. PMID: 37915034; PMCID: PMC1061 9263.

[47] Agani F, Jiang BH. Oxygen-independent regulation of HIF-1: novel involvement of PI3K/AKT/mTOR pathway in cancer. Curr Cancer Drug Targets. 2013 Mar;13(3):245-51. doi: 10. 2174/ 1568009611313030003. PMID: 23297826.

[48] Coffer PJ, Jin J, Woodgett JR. Protein kinase B (c-Akt): a multifunctional mediator of phosphatidylinositol 3-kinase activation. Biochem J. 1998 Oct 1;335 (Pt 1)(Pt 1):1-13. doi: 10.1042/bj3350001. PMID: 9742206; PMCID: PMC1219745.

[49] Huang S, Czech MP. The GLUT4 glucose transporter. Cell Metab. 2007 Apr;5(4):237-52. doi: 10.1016/j.cmet. 2007. 03. 006. PMID: 17403369.

[50] Xie Y, Shi X, Sheng K, Han G, Li W, Zhao Q, Jiang B, Feng J, Li J, Gu Y. PI3K/Akt signaling transduction pathway, erythropoiesis and glycolysis in hypoxia (Review). Mol Med Rep. 2019 Feb;19(2):783-791. doi: 10.3892/mmr.2018.9713. Epub 2018 Dec 3. PMID: 30535469; PMCID: PMC6323245.

[51] Amarasekara DS, Yun H, Kim S, Lee N, Kim H, Rho J. Regulation of Osteoclast Differentiation by Cytokine Networks. Immune Netw. 2018 Feb 7;18(1):e8. doi: 10.4110/in. 2018.18. e8. PMID: 29503739; PMCID: PMC5833125.

[52] Yao Z, Lei W, Duan R, Li Y, Luo L, Boyce BF. RANKL cytokine enhances TNF-induced osteoclastogenesis independently of TNF receptor associated factor (TRAF) 6 by degrading TRAF3 in osteoclast precursors. J Biol Chem. 2017 Jun 16;292(24):10169-10179. doi: 10.1074/jbc.M116.771816. Epub 2017 Apr 24. PMID: 28438834; PMCID: PMC5473222.

[53] Boyce BF. Advances in osteoclast biology reveal potential new drug targets and new roles for osteoclasts. J Bone Miner Res. 2013 Apr;28(4):711-22. doi: 10.1002/jbmr.1885. PMID: 23436579; PMCID: PMC3613781.

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29-08-2024

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How to Cite

Ling, P., Tang, Y., He, Z., & Lu, D. (2024). Research Progress on the Involvement of PI3K-AKT Signaling Pathway in the Pathogenesis of Osteoporosis. International Journal of Biology and Life Sciences, 7(1), 38-42. https://doi.org/10.54097/3jpy2584