Skip to main content
JDRS · Open access journal
Joint Diseases and
Related Surgery
Online manuscript submissionSubmit a manuscript e-ISSN 2687-4792

Original Article · Open access

Estrogen receptor is involved in the osteoarthritis mediated by ATG16L1-NLRP3 activation

PDF Cite this article

Fa-Xue Liao

Department of Orthopedics, the First Affiliated Hospital, Anhui Medical University, Hefei, China Anhui Public Health Clinical Center, Hefei, China

ORCID: 0009-0006-9667-895X

Shuo Yang

Department of Orthopedics, the First Affiliated Hospital, Anhui Medical University, Hefei, China Anhui Public Health Clinical Center, Hefei, China

ORCID: 0009-0007-1268-1594

Zhi-Hong Liu

Department of Orthopedics, the First Affiliated Hospital, Anhui Medical University, Hefei, China Anhui Public Health Clinical Center, Hefei, China

ORCID: 0009-0003-6720-4112

Kai-Da Bo

Department of Orthopedics, the First Affiliated Hospital, Anhui Medical University, Hefei, China Anhui Public Health Clinical Center, Hefei, China

ORCID: 0009-0000-5784-0236

Peng-Fei Xu

Department of Orthopedics, the First Affiliated Hospital, Anhui Medical University, Hefei, China Anhui Public Health Clinical Center, Hefei, China

ORCID: 0009-0007-8114-0636

Jun Chang

Department of Orthopedics, the First Affiliated Hospital, Anhui Medical University, Hefei, China Anhui Public Health Clinical Center, Hefei, China

ORCID: 0009-0002-6254-7872

Abstract

Objectives: This study aims to explore the mechanisms of dual regulation of osteoarthritis (OA) progression by the involvement of estrogen receptor (ER) in autophagy and inflammation.

Materials and methods: Bioinformatics methods were used to explore the relationship among associated genes. Western blot assays were used to detect related protein expression of OA in C28I2 and induced OA cellular model. Real-time quantitative polymerase chain reaction (RT-qPCR) analysis were used to detect OA related gene expression in C28I2 and induced OA cellular model. Co-immunoprecipitation (CO-IP) analysis were used to verify the direct interaction between ER and NOD-like receptor thermal protein domain associated protein 3 (NLRP3).

Results: The C28I2 cellular model of OA was induced by interleukin-1β (IL-1β). The small interfering ribonucleic acid (SiRNA)-mediated knockdown of autophagy-related 16 like 1 (ATG16L1) in C28I2 decreased the expression of MAP1LC3B (LC3B) and NLRP3. Besides, ER-beta (ERβ) agonist changed the gene expression of NLRP3 and ATG16L1. Moreover, CO-IP analysis indicated the direct interaction between ER and NLRP3.

Conclusion: Our study results revealed that ATG16L1, NLRP3, and IL-1β interacted closely and ERβ was involved in OA process by affecting autophagy and inflammatory activation.

* The two authors contributed equally to this study.

Declarations

Ethics Committee Approval

This project was approved by the ethics committee of Anhui Public Health Clinical Center (North District of The First Affiliated Hospital of Anhui Medical University) in accordance with the principles of the Declaration of Helsinki and Guide for the Care and Use of Laboratory Ani-mals (date: 02.29.2024, no: PJ-YX2024-014). The study was conducted in accordance with the principles of the Declaration of Helsinki.

Author Contributions

Writing-original draft, conceptualization, investigation, methodology, validation: F.X.L.; Investigation, methodology, formal analysis, resources, data curation: S.Y.; Software, formal analysis, visualization: Z.H.L.; Methodology, Investigation: K.D.B.; Formal analysis, validation, conceptualization: P.F.X.; Writing-review & editing, supervision, funding acquisition, conceptualization, project administration: J.C.

Conflict of Interest

The authors declared no conflicts of interest with respect to the authorship and/or publication of this article.

Financial Disclosure

This research was funded by the scientific research project of Anhui Province Health Commission (No. AHWJ2021b112), the research fund of Anhui Institute of Translational Medicine (NO. 2022zhyx-C91) and the scientific research fund of Anhui Medical University (No.2022xkj201) for supporting the research of this project.

Acknowledgments

We would like to thank the scientific research project of Anhui Province Health Commission (No.AHWJ2021b112), the research fund of Anhui Institute of Translational Medicine (NO. 2022zhyx-C91) and the scientific research fund of Anhui Medical University (No.2022xkj201) for supporting the research of this project.

Data Sharing Statement

The data that support the findings of this study are available from the corresponding author upon reasonable request.

References

  1. Xiong A, Li G, Liu S, Chen Y, Xu C, Weng J, et al. Anterolateral approach may be superior to posterolateral approach in controlling postoperative lower limb discrepancy in primary total hip arthroplasty: A singlecenter, retrospective cohort study. Jt Dis Relat Surg 2023;34:32-41. DOI: 10.52312/jdrs.2022.763.
  2. Wu L, Zhao X, Lu ZD, Yang Y, Ma L, Li P. Accuracy analysis of artificial intelligence-assisted three-dimensional preoperative planning in total hip replacement. Jt Dis Relat Surg 2023;34:537-47. DOI: 10.52312/jdrs.2023.1059.
  3. Wu D, Wong P, Guo C, Tam LS, Gu J. Pattern and trend of five major musculoskeletal disorders in China from 1990 to 2017: Findings from the Global Burden of Disease Study 2017. BMC Med 2021;19:34. DOI: 10.1186/s12916-021-01905-w.
  4. Yoon DS, Lee KM, Choi Y, Ko EA, Lee NH, Cho S, et al. TLR4 downregulation by the RNA-binding protein PUM1 alleviates cellular aging and osteoarthritis. Cell Death Differ 2022;29:1364-78. DOI: 10.1038/s41418-021-00925-6.
  5. Calvo J, Santiago L, Arias M, Pardo J, Albareda J, MartínezLostao L, et al. Granzyme-A deficiency attenuates experimental osteoarthritis in mice, but perforin deficiency does not. Jt Dis Relat Surg 2023;34:271-8. DOI: 10.52312/jdrs.2023.892.
  6. Rellmann Y, Eidhof E, Dreier R. Review: ER stressinduced cell death in osteoarthritic cartilage. Cell Signal 2021;78:109880. DOI: 10.1016/j.cellsig.2020.109880.
  7. Dubey NK, Wei HJ, Yu SH, Williams DF, Wang JR, Deng YH, et al. Adipose-derived Stem Cells Attenuates Diabetic Osteoarthritis via Inhibition of Glycation-mediated Inflammatory Cascade. Aging Dis 2019;10:483-96. DOI: 10.14336/AD.2018.0616.
  8. Qiu WJ, Xu MZ, Zhu XD, Ji YH. MicroRNA-27a alleviates IL-1β-induced inflammatory response and articular cartilage degradation via TLR4/NF-κB signaling pathway in articular chondrocytes. Int Immunopharmacol 2019;76:105839. DOI: 10.1016/j.intimp.2019.105839.
  9. Wang BW, Jiang Y, Yao ZL, Chen PS, Yu B, Wang SN. Aucubin protects chondrocytes against IL-1β-induced apoptosis in vitro and inhibits osteoarthritis in mice model. Drug Des Devel Ther 2019;13:3529-38. DOI: 10.2147/DDDT.S210220.
  10. Ni B, Pei W, Qu Y, Zhang R, Chu X, Wang Y, et al. MCC950, the NLRP3 Inhibitor, protects against cartilage degradation in a mouse model of osteoarthritis. Oxid Med Cell Longev 2021;2021:4139048. DOI: 10.1155/2021/4139048.
  11. Sharma M, de Alba E. Structure, activation and regulation of NLRP3 and AIM2 inflammasomes. Int J Mol Sci 2021;22:872. DOI: 10.3390/ijms22020872.
  12. Shao BZ, Xu ZQ, Han BZ, Su DF, Liu C. NLRP3 inflammasome and its inhibitors: A review. Front Pharmacol 2015;6:262. DOI: 10.3389/fphar.2015.00262.
  13. Moss JJ, Wirth M, Tooze SA, Lane JD, Hammond CL. Autophagy coordinates chondrocyte development and early joint formation in zebrafish. FASEB J 2021;35:e22002. DOI: 10.1096/fj.202101167R.
  14. Feng X, Zhang H, Meng L, Song H, Zhou Q, Qu C, et al. Hypoxia-induced acetylation of PAK1 enhances autophagy and promotes brain tumorigenesis via phosphorylating ATG5. Autophagy 2021;17:723-42. DOI: 10.1080/15548627.2020.1731266.
  15. Jin LY, Guo C, Xu S, Liu HY, Li XF. The role of estrogen receptor α in response to longitudinal bone growth in ob/ ob mice. Front Endocrinol (Lausanne) 2021;12:749449. DOI: 10.3389/fendo.2021.749449.
  16. Shi J, Zhao W, Ying H, Zhang Y, Du J, Chen S, et al. Estradiol inhibits NLRP3 inflammasome in fibroblastlike synoviocytes activated by lipopolysaccharide and adenosine triphosphate. Int J Rheum Dis 2018;21:2002-10. DOI: 10.1111/1756-185X.13198.
  17. Prieto-Alhambra D, Judge A, Javaid MK, Cooper C, Diez-Perez A, Arden NK. Incidence and risk factors for clinically diagnosed knee, hip and hand osteoarthritis: Influences of age, gender and osteoarthritis affecting other joints. Ann Rheum Dis 2014;73:1659-64. DOI: 10.1136/annrheumdis-2013-203355.
  18. Xu F, Hu QF, Li J, Shi CJ, Luo JW, Tian WC, et al. SOX4- activated lncRNA MCM3AP-AS1 aggravates osteoarthritis progression by modulating miR-149-5p/Notch1 signaling. Cytokine 2022;152:155805. DOI: 10.1016/j.cyto.2022.155805.
  19. Huang L, Su W, Wu Z, Zheng L, Lv C. Glucosamine suppresses oxidative stress and induces protective autophagy in osteoblasts by blocking the ROS/Akt/mTOR signaling pathway. Cell Biol Int 2022;46:829-39. DOI: 10.1002/cbin.11783.
  20. Zhu X, Dai S, Xia B, Gong J, Ma B. Activation of the alpha 7 nicotinic acetylcholine receptor mitigates osteoarthritis progression by inhibiting NF-κB/NLRP3 inflammasome activation and enhancing autophagy. PLoS One 2021;16:e0256507. DOI: 10.1371/journal.pone.0256507.
  21. Kuwahara M, Akasaki Y, Kurakazu I, Sueishi T, Toya M, Uchida T, et al. C10orf10/DEPP activates mitochondrial autophagy and maintains chondrocyte viability in the pathogenesis of osteoarthritis. FASEB J 2022;36:e22145. DOI: 10.1096/fj.202100896R.
  22. Vinatier C, Domínguez E, Guicheux J, Caramés B. Role of the inflammation-autophagy-senescence integrative network in osteoarthritis. Front Physiol 2018;9:706. DOI: 10.3389/fphys.2018.00706.
  23. Chen W, Zheng H, Zhang X, Xu Y, Fu Z, Ji X, et al. Columbianetin alleviates lipopolysaccharides (LPS)- induced inflammation and apoptosis in chondrocyte through activation of autophagy by inhibiting serum and glucocorticoid-induced protein kinase 1 (SGK1) expression. Bioengineered 2022;13:4051-62. DOI: 10.1080/21655979.2022.2032970.
  24. Zuo R, Wang Y, Li J, Wu J, Wang W, Li B, et al. Rapamycin induced autophagy inhibits inflammation-mediated endplate degeneration by enhancing Nrf2/Keap1 signaling of cartilage endplate stem cells. Stem Cells 2019;37:828-40. DOI: 10.1002/stem.2999.
  25. Cai C, Min S, Yan B, Liu W, Yang X, Li L, et al. MiR-27a promotes the autophagy and apoptosis of IL-1β treatedarticular chondrocytes in osteoarthritis through PI3K/ AKT/mTOR signaling. Aging (Albany NY) 2019;11:6371-84. DOI: 10.18632/aging.102194.
  26. Zhong J, Wang B, Wu B, Shang J, Jiang N, Cui A, et al. Clock knockdown attenuated reactive oxygen speciesmediated senescence of chondrocytes through restoring autophagic flux. Life Sci 2021;269:119036. DOI: 10.1016/j.lfs.2021.119036.
  27. Zheng G, Zhan Y, Li X, Pan Z, Zheng F, Zhang Z, et al. TFEB, a potential therapeutic target for osteoarthritis via autophagy regulation. Cell Death Dis 2018;9:858. DOI: 10.1038/s41419-018-0909-y.
  28. Hughbanks ML, Rodriguez-Fontan F, Kleck CJ, BurgerVan der Walt E. Estrogen receptor Alpha in human knee articular cartilage of healthy and osteoarthritic females. J Orthop 2021;27:1-8. DOI: 10.1016/j.jor.2021.08.005.
  29. Son YO, Chun JS. Estrogen-related receptor γ is a novel catabolic regulator of osteoarthritis pathogenesis. BMB Rep 2018;51:165-6. DOI: 10.5483/bmbrep.2018.51.4.019.
  30. Xu X, Li X, Liang Y, Ou Y, Huang J, Xiong J, et al. Estrogen modulates cartilage and subchondral bone remodeling in an ovariectomized rat model of postmenopausal osteoarthritis. Med Sci Monit 2019;25:3146-53. DOI: 10.12659/MSM.916254.