GPX7 reduces chondrocyte inflammation and extracellular matrix degradation triggered by IL‑1&beta;, via a mechanism mediated by ferroptosis

Chen,Boyuan; Fu,Weihao; Jie,Chunyang; Zhang,Guoxiu; Li,Zhen; Liu,Yihai; Zhou,Shibo

doi:10.3892/mmr.2024.13242

GPX7 reduces chondrocyte inflammation and extracellular matrix degradation triggered by IL‑1β, via a mechanism mediated by ferroptosis

Authors:
- Boyuan Chen
- Weihao Fu
- Chunyang Jie
- Guoxiu Zhang
- Zhen Li
- Yihai Liu
- Shibo Zhou
View Affiliations

Affiliations: Department of Physical Education, Henan University of Science and Technology, Luoyang, Henan 471023, P.R. China, Integrative Exercise Physiology Laboratory, Department of Physical Education, Jeonbuk National University, Jeonju 54896, Republic of Korea, Department of General Medicine, The First Affiliated Hospital of Henan University of Science and Technology, Luoyang, Henan 471023, P.R. China
Published online on: May 14, 2024 https://doi.org/10.3892/mmr.2024.13242
Article Number: 118
Copyright: © Chen et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

During osteoarthritis (OA), chondrocytes become highly active, with increased matrix synthesis and inflammatory cytokine‑induced catabolic pathways. Early intervention strategies targeting pathological changes may attenuate or halt disease progression. The present study aimed to reveal the role of glutathione peroxidase (GPX)7 in OA. For this purpose, a research model was established by inducing C28/I2 human chondrocytes with interleukin (IL)‑1β, and the expression level of GPX7 was determined. To explore its roles, C28/I2 cells were transfected to gain GPX7 overexpression. The effects of GPX7 overexpression on intracellular inflammation, extracellular matrix (ECM) degradation, apoptosis and ferroptosis were then evaluated. In addition, the cells were treated with the ferroptosis inducer, erastin, and its effects on the aforementioned phenotypes were assessed. The level of GPX7 was decreased in response to IL‑1β treatment, and GPX7 overexpression suppressed cellular inflammation, ECM degradation and apoptosis. Moreover, the reduction of lipid peroxidation, ferrous ions and transferrin indicated that GPX7 overexpression inhibited ferroptosis. Subsequently, inflammation, ECM degradation and apoptosis were found to be promoted in the cells upon treatment with erastin. These findings suggested that the regulatory role of GPX7 may be mediated by a pathway involving ferroptosis. On the whole, the present study revealed that GPX7 reduces IL‑1β‑induced chondrocyte inflammation, apoptosis and ECM degradation partially through a mechanism involving ferroptosis. The results of the present study lay a theoretical foundation for subsequent OA‑related research and may enable the development of translational strategies for the treatment of OA.

View Figures

View References

1	Yunus MHM, Nordin A and Kamal H: Pathophysiological perspective of osteoarthritis. Medicina (Kaunas). 56:6142020. View Article : Google Scholar : PubMed/NCBI
2	Yao Q, Wu X, Tao C, Gong W, Chen M, Qu M, Zhong Y, He T, Chen S and Xiao G: Osteoarthritis: Pathogenic signaling pathways and therapeutic targets. Signal Transduct Target Ther. 8:562023. View Article : Google Scholar : PubMed/NCBI
3	Hawker GA and King LK: The burden of osteoarthritis in older adults. Clin Geriatr Med. 38:181–192. 2022. View Article : Google Scholar : PubMed/NCBI
4	Katz JN, Arant KR and Loeser RF: Diagnosis and treatment of hip and knee osteoarthritis: A review. JAMA. 325:568–578. 2021. View Article : Google Scholar : PubMed/NCBI
5	Krause M, Freudenthaler F, Frosch KH, Achtnich A, Petersen W and Akoto R: Operative versus conservative treatment of anterior cruciate ligament rupture. Dtsch Arztebl Int. 115:855–862. 2018.PubMed/NCBI
6	Molnar V, Matišić V, Kodvanj I, Bjelica R, Jeleč Ž, Hudetz D, Rod E, Čukelj F, Vrdoljak T, Vidović D, et al: Cytokines and chemokines involved in osteoarthritis pathogenesis. Int J Mol Sci. 22:92082021. View Article : Google Scholar : PubMed/NCBI
7	Xie Y, Kang R, Klionsky DJ and Tang D: GPX4 in cell death, autophagy, and disease. Autophagy. 19:2621–2638. 2023. View Article : Google Scholar : PubMed/NCBI
8	Kanemura S, Sofia EF, Hirai N, Okumura M, Kadokura H and Inaba K: Characterization of the endoplasmic reticulum-resident peroxidases GPx7 and GPx8 shows the higher oxidative activity of GPx7 and its linkage to oxidative protein folding. J Biol Chem. 295:12772–12785. 2020. View Article : Google Scholar : PubMed/NCBI
9	Wei PC, Hsieh YH, Su MI, Jiang X, Hsu PH, Lo WT, Weng JY, Jeng YM, Wang JM, Chen PL, et al: Loss of the oxidative stress sensor NPGPx compromises GRP78 chaperone activity and induces systemic disease. Mol Cell. 48:747–759. 2012. View Article : Google Scholar : PubMed/NCBI
10	Hu X, Li B, Wu F, Liu X, Liu M, Wang C, Shi Y and Ye L: GPX7 Facilitates BMSCs Osteoblastogenesis via ER Stress and mTOR Pathway. J Cell Mol Med. 25:10454–10465. 2021. View Article : Google Scholar : PubMed/NCBI
11	Kim HJ, Lee Y, Fang S, Kim W, Kim HJ and Kim JW: GPx7 ameliorates non-alcoholic steatohepatitis by regulating oxidative stress. BMB Rep. 53:317–322. 2020. View Article : Google Scholar : PubMed/NCBI
12	Hwang HS and Shim JH: Brazilin and Caesalpinia sappan L. extract protect epidermal keratinocytes from oxidative stress by inducing the expression of GPX7. Chin J Nat Med. 16:203–209. 2018.PubMed/NCBI
13	Zhou X, Zheng Y, Sun W, Zhang Z and Liu J, Yang W, Yuan W, Yi Y, Wang J and Liu J: D-mannose alleviates osteoarthritis progression by inhibiting chondrocyte ferroptosis in a HIF-2α-dependent manner. Cell Prolif. 54:e131342021. View Article : Google Scholar : PubMed/NCBI
14	Zhou Y, Wu H, Wang F, Xu L, Yan Y, Tong X and Yan H: GPX7 Is Targeted by miR-29b and GPX7 knockdown enhances ferroptosis induced by erastin in glioma. Front Oncol. 11:8021242022. View Article : Google Scholar : PubMed/NCBI
15	Wang BW, Jiang Y, Yao ZL, Chen PS, Yu B and Wang SN: Aucubin protects chondrocytes against IL-1β-Induced apoptosis in vitro and inhibits osteoarthritis in mice model. Drug Des Devel Ther. 13:3529–3538. 2019. View Article : Google Scholar : PubMed/NCBI
16	Dixon SJ, Lemberg KM, Lamprecht MR, Skouta R, Zaitsev EM, Gleason CE, Patel DN, Bauer AJ, Cantley AM, Yang WS, et al: Ferroptosis: An iron-dependent form of nonapoptotic cell death. Cell. 149:1060–1072. 2012. View Article : Google Scholar : PubMed/NCBI
17	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(−Delta Delta C(T)) Method. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI
18	Guilak F, Nims RJ, Dicks A, Wu CL and Meulenbelt I: Osteoarthritis as a disease of the cartilage pericellular matrix. Matrix Biol. 71–72. 40–50. 2018.
19	Wilkinson JM and Zeggini E: The genetic epidemiology of joint shape and the development of osteoarthritis. Calcif Tissue Int. 109:257–276. 2021. View Article : Google Scholar : PubMed/NCBI
20	Cui N, Hu M and Khalil RA: Biochemical and biological attributes of matrix metalloproteinases. Prog Mol Biol Transl Sci. 147:1–73. 2017. View Article : Google Scholar : PubMed/NCBI
21	Huang J, Zhao L and Chen D: Growth factor signalling in osteoarthritis. Growth Factors. 36:187–195. 2018. View Article : Google Scholar : PubMed/NCBI
22	Wang T and He C: Pro-inflammatory cytokines: The link between obesity and osteoarthritis. Cytokine Growth Factor Rev. 44:38–50. 2018. View Article : Google Scholar : PubMed/NCBI
23	Wang J, Chen J, Zhang B and Jia X: IL-6 regulates the bone metabolism and inflammatory microenvironment in aging mice by inhibiting Setd7. Acta Histochem. 123:1517182021. View Article : Google Scholar : PubMed/NCBI
24	Ashruf OS and Ansari MY: Natural compounds: Potential therapeutics for the inhibition of cartilage matrix degradation in osteoarthritis. Life (Basel). 13:1022022.PubMed/NCBI
25	Zhu R, Wang Y, Ouyang Z, Hao W, Zhou F, Lin Y, Cheng Y, Zhou R and Hu W: Targeting regulated chondrocyte death in osteoarthritis therapy. Biochem Pharmacol. 215:1157072023. View Article : Google Scholar : PubMed/NCBI
26	Zhang T and Li J: Experimental study on the ratios of chondrocytes apoptosis in OA. Chin Modern Doctor. 46:35–36. 2008.(In Chinese).
27	Mou Y, Wang J, Wu J, He D, Zhang C, Duan C and Li B: Ferroptosis, a new form of cell death: Opportunities and challenges in cancer. J Hematol Oncol. 12:342019. View Article : Google Scholar : PubMed/NCBI
28	Mo Z, Xu P and Li H: Stigmasterol alleviates interleukin-1beta-induced chondrocyte injury by down-regulatingsterol regulatory element binding transcription factor 2 to regulateferroptosis. Bioengineered. 12:9332–9340. 2021. View Article : Google Scholar : PubMed/NCBI
29	Sun K, Hou L, Guo Z, Wang G, Guo J, Xu J, Zhang X and Guo F: JNK-JUN-NCOA4 axis contributes to chondrocyte ferroptosis and aggravates osteoarthritis via ferritinophagy. Free Radic Biol Med. 200:87–101. 2023. View Article : Google Scholar : PubMed/NCBI
30	Yang J, Hu S, Bian Y, Yao J, Wang D, Liu X, Guo Z, Zhang S and Peng L: Targeting cell death: Pyroptosis, ferroptosis, apoptosis and necroptosis in osteoarthritis. Front Cell Dev Biol. 9:7899482022. View Article : Google Scholar : PubMed/NCBI
31	Zhang X, Hou L, Guo Z, Wang G, Xu J, Zheng Z, Sun K and Guo F: Lipid peroxidation in osteoarthritis: Focusing on 4-hydroxynonenal, malondialdehyde, and ferroptosis. Cell Death Discov. 9:3202023. View Article : Google Scholar : PubMed/NCBI
32	An F, Zhang J, Gao P, Xiao Z, Chang W, Song J, Wang Y, Ma H, Zhang R, Chen Z and Yan C: New insight of the pathogenesis in osteoarthritis: The intricate interplay of ferroptosis and autophagy mediated by mitophagy/chaperone-mediated autophagy. Front Cell Dev Biol. 11:12970242023. View Article : Google Scholar : PubMed/NCBI
33	Rochette L, Dogon G, Rigal E, Zeller M, Cottin Y and Vergely C: Lipid peroxidation and iron metabolism: Two corner stones in the homeostasis control of ferroptosis. Int J Mol Sci. 24:4492022. View Article : Google Scholar : PubMed/NCBI
34	Hou Y, Wang S, Jiang L, Sun X, Li J, Wang N, Liu X, Yao X, Zhang C, Deng H and Yang G: Patulin induces acute kidney injury in mice through autophagy-ferroptosis pathway. J Agric Food Chem. 70:6213–6223. 2022. View Article : Google Scholar : PubMed/NCBI
35	Cotticelli MG, Xia S, Lin D, Lee T, Terrab L, Wipf P, Huryn DM and Wilson RB: Ferroptosis as a novel therapeutic target for friedreich's Ataxia. J Pharmacol Exp Ther. 369:47–54. 2019. View Article : Google Scholar : PubMed/NCBI
36	Weaver K and Skouta R: The selenoprotein glutathione peroxidase 4: From molecular mechanisms to novel therapeutic opportunities. Biomedicines. 10:8912022. View Article : Google Scholar : PubMed/NCBI