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Kaempferol attenuates the effects of XIST/miR-130a/STAT3 on inflammation and extracellular matrix degradation in osteoarthritis

    Yaosheng Xiao‡

    Medical College of Soochow University, Suzhou, 320505, China

    Department of Orthopaedics, The First Affiliated Hospital of Gannan Medical University, Ganzhou, 341000, China

    Department of Orthopaedics, The Second Affiliated Hospital of Soochow University, Suzhou, 320505, China

    ‡Authors contributed equally

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    ,
    Lulin Liu‡

    Department of Orthopaedics, The First Affiliated Hospital of Gannan Medical University, Ganzhou, 341000, China

    ‡Authors contributed equally

    Search for more papers by this author

    ,
    Yizhou Zheng

    College of Pharmacy, Gannan Medical University, Ganzhou, 341000, China

    ,
    Wuyang Liu

    Department of Orthopaedics, The First Affiliated Hospital of Gannan Medical University, Ganzhou, 341000, China

    &
    Youjia Xu

    *Author for correspondence:

    E-mail Address: xuyoujia@suda.edu.cn

    Medical College of Soochow University, Suzhou, 320505, China

    Department of Orthopaedics, The Second Affiliated Hospital of Soochow University, Suzhou, 320505, China

    Published Online:https://doi.org/10.4155/fmc-2021-0127

    Aim: To investigate whether kaempferol exhibited protective effects on osteoarthritis chondrocytes by modulating the XIST/miR-130a/STAT3 axis. Methods: qRT-PCR and western blot assays were used for gene and protein determination. Dual luciferase reporter and RNA immunoprecipitation assays were employed to study the interaction between miRNA and lncRNA or genes. Results: Kaempferol decreased proinflammatory cytokine production and extracellular matrix degradation in C28/I2 cells. Additionally, kaempferol ameliorated XIST expression and enhanced miR-130a expression. XIST interacted with miR-130a, and STAT3 was identified as a target of miR-130a. Knockdown of XIST expression suppressed proinflammatory cytokine production and extracellular matrix degradation in C28/I2 cells. Overexpression of STAT3 rescued the effects of XIST knockdown. Conclusion: Kaempferol inhibited inflammation and extracellular matrix degradation by modulating the XIST/miR-130a/STAT3 axis in chondrocytes.

    Papers of special note have been highlighted as: • of interest; •• of considerable interest

    References

    • 1. Wu L, Liu Z. The molecular mechanisms of preventing apoptosis of cartilage chondrocyte to target osteoarthritis. Future Med. Chem. 9(6), 537–540 (2017).
    • 2. Wu L, Huang X, Li L, Huang H, Xu R, Luyten W. Insights on biology and pathology of HIF-1α/-2α, TGFβ/BMP, Wnt/β-catenin, and NF-κB pathways in osteoarthritis. Curr. Pharm. Des. 18(22), 3293–3312 (2012). • Highlights the molecular mechanisms of pathological development of OA.
    • 3. Zhan J, Yan Z, Kong X et al. Lycopene inhibits IL-1β-induced inflammation in mouse chondrocytes and mediates murine osteoarthritis. J. Cell. Mol. Med. 25(7), 3573–3584 (2021).
    • 4. Robinson WH, Lepus CM, Wang Q et al. Low-grade inflammation as a key mediator of the pathogenesis of osteoarthritis. Nat. Rev. Rheumatol. 12(10), 580–592 (2016).
    • 5. Magni A, Agostoni P, Bonezzi C et al. Management of osteoarthritis: expert opinion on NSAIDs. Pain Ther. doi:10.1007/s40122-021-00260-1 (2021) (Epub ahead of print).
    • 6. Andrey G, Duboule D. SnapShot: hox gene regulation. Cell 156(4), 856–856.e851 (2014).
    • 7. He CP, Jiang XC, Chen C et al. The function of lncRNAs in the pathogenesis of osteoarthritis. Bone Joint Res. 10(2), 122–133 (2021). •• Highlights the potential roles of lncRNAs in the pathological development of OA.
    • 8. Yang Y, Sun Z, Liu F, Bai Y, Wu F. FGD5-AS1 inhibits osteoarthritis development by modulating miR-302d-3p/TGFBR2 axis. Cartilage doi:10.1177/19476035211003324 (2021) (Epub ahead of print).
    • 9. Xie L, Feng G, Zhu P, Xie J. The effects of lncRNA PVT1 on clinical characteristics and survival in breast cancer patients: a protocol for systematic review and meta analysis. Medicine (Baltimore) 100(8), e24774 (2021).
    • 10. Lee KA, Cho KC, Kim B et al. Inflammation-modulated metabolic reprogramming is required for DUOX-dependent gut immunity in Drosophila. Cell Host Microbe 23(3), 338–352.e335 (2018).
    • 11. Liu Y, Zhao D, Wang X, Dong Y, Ding F. LncRNA KCNQ1OT1 attenuates osteoarthritic chondrocyte dysfunction via the miR-218-5p/PIK3C2A axis. Cell Tissue Res. doi:10.1007/s00441-021-03441-8 (2021) (Epub ahead of print).
    • 12. Li L, Lv G, Wang B, Kuang L. XIST/miR-376c-5p/OPN axis modulates the influence of proinflammatory M1 macrophages on osteoarthritis chondrocyte apoptosis. J. Cell. Physiol. 235(1), 281–293 (2020).
    • 13. Wang T, Liu Y, Wang Y, Huang X, Zhao W, Zhao Z. Long non-coding RNA XIST promotes extracellular matrix degradation by functioning as a competing endogenous RNA of miR-1277-5p in osteoarthritis. Int. J. Mol. Med. 44(2), 630–642 (2019).
    • 14. Lee H, Zhao X, Son YO, Yang S. Therapeutic single compounds for osteoarthritis treatment. Pharmaceuticals (Basel) 14(2), 131 (2021).
    • 15. Park E, Lee CG, Han SJ et al. Antiosteoarthritic effect of morroniside in chondrocyte inflammation and destabilization of medial meniscus-induced mouse model. Int. J. Mol. Sci. 22(6), 2987 (2021).
    • 16. Chen YL, Yan DY, Wu CY et al. Maslinic acid prevents IL-1β-induced inflammatory response in osteoarthritis via PI3K/AKT/NF-κB pathways. J. Cell. Physiol. 236(3), 1939–1949 (2021).
    • 17. Jiang R, Hao P, Yu G et al. Kaempferol protects chondrogenic ATDC5 cells against inflammatory injury triggered by lipopolysaccharide through down-regulating miR-146a. Int. Immunopharmacol 69, 373–381 (2019). • Highlights the protective activity of kaempferol in OA chondrocytes.
    • 18. Huang X, Pan Q, Mao Z et al. Kaempferol inhibits interleukin-1β stimulated matrix metalloproteinases by suppressing the MAPK-associated ERK and P38 signaling pathways. Mol. Med. Rep. 18(3), 2697–2704 (2018).
    • 19. Au RY, Al-Talib TK, Au AY, Phan PV, Frondoza CG. Avocado soybean unsaponifiables (ASU) suppress TNF-alpha, IL-1beta, COX-2, iNOS gene expression, and prostaglandin E2 and nitric oxide production in articular chondrocytes and monocyte/macrophages. Osteoarthritis Cartilage 15(11), 1249–1255 (2007).
    • 20. Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods 25(4), 402–408 (2001).
    • 21. Du Z, Sun T, Hacisuleyman E et al. Integrative analyses reveal a long noncoding RNA-mediated sponge regulatory network in prostate cancer. Nat. Commun. 7, 10982 (2016).
    • 22. Chen L, Wang Y, Sun L, Yan J, Mao HQ. Nanomedicine strategies for anti-inflammatory treatment of noninfectious arthritis. Adv. Healthc. Mater. 10(11), e2001732 (2021).
    • 23. Sokolove J, Lepus CM. Role of inflammation in the pathogenesis of osteoarthritis: latest findings and interpretations. Ther. Adv. Musculoskelet. Dis. 5(2), 77–94 (2013).
    • 24. Ma X, Zhang Z, Shen M et al. Changes of type II collagenase biomarkers on IL-1β-induced rat articular chondrocytes. Exp. Ther. Med. 21(6), 582 (2021).
    • 25. Daheshia M, Yao JQ. The interleukin 1beta pathway in the pathogenesis of osteoarthritis. J. Rheumatol. 35(12), 2306–2312 (2008).
    • 26. Kumavat R, Kumar V, Malhotra R et al. Biomarkers of joint damage in osteoarthritis: current status and future directions. Mediators Inflamm. 2021, 5574582 (2021). •• Highlights the potential biomarkers and therapeutic targets of OA.
    • 27. Goldring MB. The role of the chondrocyte in osteoarthritis. Arthritis Rheum. 43(9), 1916–1926 (2000).
    • 28. Li X, Liao Z, Deng Z, Chen N, Zhao L. Combining bulk and single-cell RNA-sequencing data to reveal gene expression pattern of chondrocytes in the osteoarthritic knee. Bioengineered 12(1), 997–1007 (2021).
    • 29. Minashima T, Campbell KA, Hadley SR, Zhang Y, Kirsch T. The role of ANK interactions with MYBBP1a and SPHK1 in catabolic events of articular chondrocytes. Osteoarthritis Cartilage 22(6), 852–861 (2014).
    • 30. Chen Y, Ni H, Zhao Y et al. Potential role of lncRNAs in contributing to pathogenesis of intervertebral disc degeneration based on microarray data. Med. Sci. Monit. 21, 3449–3458 (2015).
    • 31. Ji Q, Qiao X, Liu Y, Wang D. Expression of long-chain noncoding RNA GAS5 in osteoarthritis and its effect on apoptosis and autophagy of osteoarthritis chondrocytes. Histol. Histopathol. 36(4), 18312 (.2021).
    • 32. Wang YZ, Yao L, Liang SK et al. LncPVT1 promotes cartilage degradation in diabetic OA mice by downregulating miR-146a and activating TGF-β/SMAD4 signaling. J. Bone Miner. Metab. 39(4), 534–546 (2021).
    • 33. Shvedova M, Kobayashi T. MicroRNAs in cartilage development and dysplasia. Bone 140, 115564 (2020). • Highlights the potential roles of microRNAs in OA development.
    • 34. Swingler TE, Niu L, Smith P et al. The function of microRNAs in cartilage and osteoarthritis. Clin. Exp. Rheumatol. 37(120 Suppl. 5), 40–47 (2019).
    • 35. Le LT, Swingler TE, Crowe N et al. The microRNA-29 family in cartilage homeostasis and osteoarthritis. J. Mol. Med. 94(5), 583–596 (2016).
    • 36. Huang X, Chen Z, Shi W et al. TMF inhibits miR-29a/Wnt/β-catenin signaling through upregulating Foxo3a activity in osteoarthritis chondrocytes. Drug Des. Devel. Ther. 13, 2009–2019 (2019).
    • 37. Hillmer EJ, Zhang H, Li HS, Watowich SS. STAT3 signaling in immunity. Cytokine Growth Factor Rev. 31, 1–15 (2016).
    • 38. Lee H, Herrmann A, Deng JH et al. Persistently activated Stat3 maintains constitutive NF-kappaB activity in tumors. Cancer Cell 15(4), 283–293 (2009).
    • 39. Hahn YI, Saeidi S, Kim SJ et al. STAT3 stabilizes IKKα protein through direct interaction in transformed and cancerous human breast epithelial cells. Cancers (Basel) 13(1), 82 (2020).
    • 40. Piipponen M, Nissinen L, Riihilä P et al. p53-regulated long noncoding RNA PRECSIT promotes progression of cutaneous squamous cell carcinoma via STAT3 signaling. Am. J. Pathol. 190(2), 503–517 (2020).
    • 41. Zhang S, Yang Y, Huang S et al. SIRT1 inhibits gastric cancer proliferation and metastasis via STAT3/MMP-13 signaling. J. Cell. Physiol. 234(9), 15395–15406 (2019).
    • 42. Zeng R, Lu X, Lin J et al. FOXM1 activates JAK1/STAT3 pathway in human osteoarthritis cartilage cell inflammatory reaction. Exp. Biol. Med. 246(6), 644–653 (2021).
    • 43. Teng Y, Ni G, Zhang W et al. TRIM59 attenuates IL-1β-driven cartilage matrix degradation in osteoarthritis via direct suppression of NF-κB and JAK2/STAT3 signaling pathway. Biochem. Biophys. Res. Commun. 529(1), 28–34 (2020).