Skip to main content
SpringerLink
Log in

PMAIP1 regulates autophagy in osteoblasts via the AMPK/mTOR pathway in osteoporosis

  • Research Article
  • Published:
Human Cell Aims and scope Submit manuscript

Abstract

Osteoporosis (OP) is a highly prevalent disorder characterized by low bone mass that severely reduces patient quality of life. Although numerous treatments for OP have been introduced in clinic, many have side effects and high costs. Therefore, there is still an unmet need for optimal solutions. Here, raw signal analysis was used to identify potential high-risk factors for OP, and the biological functions and possible mechanisms of action (MOAs) of these factors were explored via gene set enrichment analysis (GSEA). Subsequently, molecular biological experiments were performed to verify and analyze the discovered risk factors in vitro and in vivo. PMAIP1 was identified as a potential risk factor for OP and significantly suppressed autophagy in osteoblasts via the AMPK/mTOR pathway, thereby inhibiting the proliferation and differentiation of osteoblasts. Furthermore, we constructed an ovariectomy (OVX) model of OP in rats and simultaneously applied si-PMAIP1 for in vivo interference. si-PMAIP1 upregulated the expression of LC3B and p-AMPK and downregulated the expression of p-mTOR, and these effects were reversed by the autophagy inhibitor. Micro-CT revealed that, si-PMAIP1 significantly inhibited the development of osteoporosis in OVX model rats, and this therapeutic effect was attenuated by treatment with an autophagy inhibitor. This study explored the role and mechanism of PMAIP1 in OP and demonstrated that PMAIP1 may serve as a novel target for OP treatment.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

Data availability

The materials and data used and/or analyzed in the present study are available from the corresponding author upon reasonable request.

References

  1. Aibar-Almazán A, et al. Current status of the diagnosis and management of osteoporosis. Int J Mol Sci. 2022;23(16):9465. https://doi.org/10.3390/ijms23169465.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Zhuang HF, et al. Analysis of related factors of brittle hip fracture in postmenopausal women with osteoporosis. Orthop Surg. 2020;12(1):194–8. https://doi.org/10.1111/os.12605.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Salari N, et al. The global prevalence of osteoporosis in the world: a comprehensive systematic review and meta-analysis. J Orthop Surg Res. 2021;16(1):609. https://doi.org/10.1186/s13018-021-02772-0.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Migliorini F, et al. Fragility fractures: risk factors and management in the elderly. Medicina (Kaunas). 2021;57(10):1119. https://doi.org/10.3390/medicina57101119.

    Article  PubMed  Google Scholar 

  5. Tu KN, et al. Osteoporosis: A review of treatment options. P T. 2018;43(2):92–104.

    PubMed  PubMed Central  Google Scholar 

  6. Van Niekerk G, Mitchell M, Engelbrecht AM. Bone resorption: supporting immunometabolism. Biol Lett. 2018;14(2):20170783. https://doi.org/10.1098/rsbl.2017.0783.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Cheng CH, Chen LR, Chen KH. Osteoporosis due to hormone imbalance: An overview of the effects of estrogen deficiency and glucocorticoid overuse on bone turnover. Int J Mol Sci. 2022;23(3):1376. https://doi.org/10.3390/ijms23031376.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. De Martinis M, et al. Vitamin D deficiency, osteoporosis and effect on autoimmune diseases and hematopoiesis: a review. Int J Mol Sci. 2021;22(16):8855. https://doi.org/10.3390/ijms22168855.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Seeman E, Martin TJ. Antiresorptive and anabolic agents in the prevention and reversal of bone fragility. Nat Rev Rheumatol. 2019;15(4):225–36. https://doi.org/10.1038/s41584-019-0172-3.

    Article  PubMed  Google Scholar 

  10. Fink HA, et al. Long-term drug therapy and drug discontinuations and holidays for osteoporosis fracture prevention: a systematic review. Ann Intern Med. 2019;171(1):37–50. https://doi.org/10.7326/M19-0533.

    Article  PubMed  Google Scholar 

  11. Wang H, et al. Mechanistic advances in osteoporosis and anti-osteoporosis therapies. MedComm 2023;4(3):e244. https://doi.org/10.1002/mco2.244

  12. Cao W, et al. An overview of autophagy: Mechanism, regulation and research progress. Bull Cancer. 2021;108(3):304–22. https://doi.org/10.1016/j.bulcan.2020.11.004.

    Article  PubMed  Google Scholar 

  13. Trojani MC, et al. Autophagy and bone diseases. Joint Bone Spine. 2022;89(3): 105301. https://doi.org/10.1016/j.jbspin.2021.105301.

    Article  CAS  PubMed  Google Scholar 

  14. Zhang L, et al. Pathway-based genome-wide association analysis identified the importance of regulation-of-autophagypathway for ultradistal radius BMD. J Bone Miner Res. 2010;25(7):1572–80. https://doi.org/10.1002/jbmr.36.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Sun Y, et al. Recent advances in osteoclast biological behavior. Front Cell Dev Biol. 2021;9: 788680. https://doi.org/10.3389/fcell.2021.788680.

    Article  PubMed  PubMed Central  Google Scholar 

  16. Domazetovic V, et al. Oxidative stress in bone remodeling: role of antioxidants. Clin Cases Miner Bone Metab. 2017;14(2):209–16. https://doi.org/10.11138/ccmbm/2017.14.1.209.

    Article  PubMed  PubMed Central  Google Scholar 

  17. Wang T, Liu X, He C. Glucocorticoid-induced autophagy and apoptosis in bone. Apoptosis. 2020;25(3–4):157–68. https://doi.org/10.1007/s10495-020-01599-0.

    Article  CAS  PubMed  Google Scholar 

  18. Liang X, et al. Icariin promotes osteogenic differentiation of bone marrow stromal cells and prevents bone loss in OVX mice via activating autophagy. J Cell Biochem. 2019;120(8):13121–32. https://doi.org/10.1002/jcb.28585.

    Article  CAS  PubMed  Google Scholar 

  19. Gavali S, et al. Estrogen enhances human osteoblast survival and function via promotion of autophagy. Biochim Biophys Acta Mol Cell Res. 2019;1866(9):1498–507. https://doi.org/10.1016/j.bbamcr.2019.06.014.

    Article  CAS  PubMed  Google Scholar 

  20. Yuan Y, et al. The effect of QiangGuYin on osteoporosis through the AKT/mTOR/autophagy signaling pathway mediated by CKIP-1. Aging (Albany NY). 2022;14(2):892–906. https://doi.org/10.18632/aging.203848.

    Article  CAS  PubMed  Google Scholar 

  21. Cai L, Gao Z, Gu Z. Lin28A alleviates ovariectomy-induced osteoporosis through activation of the AMP-activated protein kinase pathway in rats. Int J Rheum Dis. 2022;25(12):1416–23. https://doi.org/10.1111/1756-185X.14436.

    Article  CAS  PubMed  Google Scholar 

  22. Hadji P, Coleman R, Gnant M. Bone effects of mammalian target of rapamycin (mTOR) inhibition with everolimus. Crit Rev Oncol Hematol. 2013;87(2):101–11. https://doi.org/10.1016/j.critrevonc.2013.05.015.

    Article  PubMed  Google Scholar 

  23. Park SA, et al. Role of the SIRT1/p53 regulatory axis in oxidative stress-mediated granulosa cell apoptosis. Mol Med Rep. 2021;23(1):20. https://doi.org/10.3892/mmr.2020.11658.

    Article  CAS  PubMed  Google Scholar 

  24. Weller S, et al. The BCL-2 inhibitor ABT-199/venetoclax synergizes with proteasome inhibition via transactivation of the MCL-1 antagonist NOXA. Cell Death Discov. 2022;8(1):215. https://doi.org/10.1038/s41420-022-01009-1.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Idrus E, et al. The role of the BH3-only protein Noxa in bone homeostasis. Biochem Biophys Res Commun. 2011;410(3):620–5. https://doi.org/10.1016/j.bbrc.2011.06.040.

    Article  CAS  PubMed  Google Scholar 

  26. Masuda H, et al. Anti-apoptotic Bcl-2 family member Mcl-1 regulates cell viability and bone-resorbing activity of osteoclasts. Bone. 2014;58:1–10. https://doi.org/10.1016/j.bone.2013.09.020.

    Article  CAS  PubMed  Google Scholar 

  27. Pang T, et al. Relationship between osteoporosis and expression of Bcl-2 and CXCL12. Exp Ther Med. 2018;15(2):1293–7. https://doi.org/10.3892/etm.2017.5513.

    Article  CAS  PubMed  Google Scholar 

  28. Al-Bari AA, Al MA. Current advances in regulation of bone homeostasis. FASEB Bioadv. 2020;2(11):668–79. https://doi.org/10.1096/fba.2020-00058.

    Article  PubMed  PubMed Central  Google Scholar 

  29. Chen X, et al. Osteoblast-osteoclast interactions. Connect Tissue Res. 2018;59(2):99–107. https://doi.org/10.1080/03008207.2017.1290085.

    Article  CAS  PubMed  Google Scholar 

  30. Hahn M, et al. Aberrant splicing of the tumor suppressor CYLD promotes the development of chronic lymphocytic leukemia via sustained NF-κB signaling. Leukemia. 2018;32(1):72–82. https://doi.org/10.1038/leu.2017.168.

    Article  CAS  PubMed  Google Scholar 

  31. Kim JM, et al. Osteoblast-Osteoclast Communication and Bone Homeostasis Cells. 2020;9(9):2073. https://doi.org/10.3390/cells9092073.

    Article  CAS  PubMed  Google Scholar 

  32. Kanis JA, et al. Scientific Advisory Board of the European Society for Clinical and Economic Aspects of Osteoporosis (ESCEO) and the Committees of Scientific Advisors and National Societies of the International Osteoporosis Foundation (IOF). Correction to: European guidance for the diagnosis and management of osteoporosis in postmenopausal women. Osteoporos Int. 2020;31(4):801. https://doi.org/10.1007/s00198-020-05303-5

  33. Hattersley G, et al. Binding selectivity of abaloparatide for PTH-Type-1-receptor conformations and effects on downstream signaling. Endocrinology. 2016;157(1):141–9. https://doi.org/10.1210/en.2015-1726.

    Article  CAS  PubMed  Google Scholar 

  34. Chen T, et al. The therapeutic potential of mesenchymal stem cells in treating osteoporosis. Biol Res. 2021;54(1):42. https://doi.org/10.1186/s40659-021-00366-y.

    Article  PubMed  PubMed Central  Google Scholar 

  35. Rizzoli R. Postmenopausal osteoporosis: Assessment and management. Best Pract Res Clin Endocrinol Metab. 2018;32(5):739–57. https://doi.org/10.1016/j.beem.2018.09.005.

    Article  PubMed  Google Scholar 

  36. Guo YF, et al. The role of autophagy in bone homeostasis. J Cell Physiol. 2021;236(6):4152–73. https://doi.org/10.1002/jcp.30111.

    Article  CAS  PubMed  Google Scholar 

  37. Yan X, Zhou R, Ma Z. Autophagy-cell survival and death. Adv Exp Med Biol. 2019;1206:667–96. https://doi.org/10.1007/978-981-15-0602-4_29.

    Article  CAS  PubMed  Google Scholar 

  38. Li DY, et al. Autophagy attenuates the oxidative stress-induced apoptosis of Mc3T3-E1 osteoblasts. Eur Rev Med Pharmacol Sci. 2017;21(24):5548–56. https://doi.org/10.26355/eurrev_201712_13991.

    Article  PubMed  Google Scholar 

  39. Wang G, et al. AMPK/mTOR pathway is involved in autophagy induced by magnesium-incorporated TiO2 surface to promote BMSC osteogenic differentiation. J Funct Biomater. 2022;13(4):221. https://doi.org/10.3390/jfb13040221.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Yin P, et al. Cell-based therapies for degenerative musculoskeletal diseases. Adv Sci (Weinh). 2023;10(21): e2207050. https://doi.org/10.1002/advs.202207050.

    Article  CAS  PubMed  Google Scholar 

  41. Li Y, et al. AMP-activated protein kinase stimulates osteoblast differentiation and mineralization through autophagy induction. Int J Mol Med. 2018;41(5):2535–44. https://doi.org/10.3892/ijmm.2018.3498.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Cheng Y, et al. Strontium promotes osteogenic differentiation by activating autophagy via the the AMPK/mTOR signaling pathway in MC3T3-E1 cells. Int J Mol Med. 2019;44(2):652–60. https://doi.org/10.3892/ijmm.2019.4216.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Sun J, et al. Quercetin attenuates osteoporosis in orchiectomy mice by regulating glucose and lipid metabolism via the GPRC6A/AMPK/mTOR signaling pathway. Front Endocrinol (Lausanne). 2022;13: 849544. https://doi.org/10.3389/fendo.2022.849544.

    Article  PubMed  Google Scholar 

  44. Zhang X, et al. Ginsenoside Rg3 attenuates ovariectomy-induced osteoporosis via AMPK/mTOR signaling pathway. Drug Dev Res. 2020;81(7):875–84. https://doi.org/10.1002/ddr.21705.

    Article  CAS  PubMed  Google Scholar 

  45. Wang M, Liu Y, Gui H, et al. ED-71 ameliorates bone regeneration in type 2 diabetes by reducing ferroptosis in osteoblasts via the HIF1α pathway. Eur J Pharmacol. 2024;969: 176303. https://doi.org/10.1016/j.ejphar.2023.176303.

    Article  CAS  PubMed  Google Scholar 

  46. Wang Y, Chen Y, Xiao H, et al. METTL3-mediated m6A modification increases Hspa1a stability to inhibit osteoblast aging. Cell Death Discov. 2024;10(1):155. https://doi.org/10.1038/s41420-024-01925-4

  47. Du YX, Zhao YT, Sun YX, Xu AH. Acid sphingomyelinase mediates ferroptosis induced by high glucose via autophagic degradation of GPX4 in type 2 diabetic osteoporosis. Mol Med. 2023;29(1):125. https://doi.org/10.1186/s10020-023-00724-4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Rea SL, Walsh JP, Layfield R, Ratajczak T, Xu J. New insights into the role of sequestosome 1/p62 mutant proteins in the pathogenesis of Paget’s disease of bone. Endocr Rev. 2013;34(4):501–24. https://doi.org/10.1210/er.2012-1034.

    Article  CAS  PubMed  Google Scholar 

  49. Xu S, Zhang Y, Wang J, et al. TSC1 regulates osteoclast podosome organization and bone resorption through mTORC1 and Rac1/Cdc42. Cell Death Differ. 2018;25(9):1549–66. https://doi.org/10.1038/s41418-017-0049-4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Xu C, Wang Z, Liu YJ, Duan K, Guan J. Harnessing GMNP-loaded BMSC-derived EVs to target miR-3064-5p via MEG3 overexpression: Implications for diabetic osteoporosis therapy in rats. Cell Signal. 2024;118: 111055. https://doi.org/10.1016/j.cellsig.2024.111055.

    Article  CAS  PubMed  Google Scholar 

  51. Niu Z, Zhou Y, Liang M, et al. Crosstalk between ALK3(BMPR1A) deficiency and autophagy signaling mitigates pathological bone loss in osteoporosis. Bone. 2024;182: 117052. https://doi.org/10.1016/j.bone.2024.117052.

    Article  CAS  PubMed  Google Scholar 

Download references

Funding

This study was funded by the cultivating scientific research project of the Second Hospital of Dalian Medical University (XJ2023000701) and the Dalian Medical Science Research Program Project (2211004).

Author information

Authors and Affiliations

  1. Department of Rehabilitation Medicine, The Second Hospital of Dalian Medical University, Dalian, Liaoning, People’s Republic of China

    Yijie Gao & Yunxia Du

  2. Department of Joint Surgery, Dalian Municipal Central Hospital, Dalian, Liaoning, People’s Republic of China

    Anquan Huang & Yantao Zhao

  3. Dalian Medical University, Dalian, Liaoning, People’s Republic of China

    Yijie Gao

Authors
  1. Yijie Gao
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Anquan Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yantao Zhao
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yunxia Du
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

YD and YZ conceived and designed the study. YG and AH performed the study and acquired the data. YG analyzed the data and wrote the manuscript. All authors have read and agreed to the published version of the manuscript.

Corresponding authors

Correspondence to Yantao Zhao or Yunxia Du.

Ethics declarations

Conflict of interest

The authors declare that they have no competing interests.

Ethical approval and consent to publish

The ethical principles established by the National Institutes of Health Guide for the Care and Use of Laboratory Animals (NIH Publications No. 8523, revised 2011) were followed. All animal experiments were approved by the Institutional Ethics Review Board of Dalian Municipal Central Hospital (Ethical number: YN2021-087-01), and the use of animals in our experiments was consistent with ethical requirements.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (DOCX 1165 kb)

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Gao, Y., Huang, A., Zhao, Y. et al. PMAIP1 regulates autophagy in osteoblasts via the AMPK/mTOR pathway in osteoporosis. Human Cell (2024). https://doi.org/10.1007/s13577-024-01067-w

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s13577-024-01067-w

Keywords

Search

Navigation