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Ubiquitin-specific protease 49 attenuates IL-1β-induced rat primary chondrocyte apoptosis by facilitating Axin deubiquitination and subsequent Wnt/β-catenin signaling cascade inhibition

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Abstract

Osteoarthritis (OA) is an age-related chronic joint degenerative disease. Interleukin 1 beta (IL-1β) is considered a marker for the progression of OA. In this study, we found that Ubiquitin-Specific Peptidase 49 (USP49) was significantly less expressed in OA patients compared with healthy individuals. Treating primary rat chondrocytes with different concentrations of IL-1β resulted in decreased Usp49 expression, while Usp49 overexpression could attenuate IL-1β-induced chondrocyte apoptosis by promoting Axin deubiquitination. The deubiquitination of Axin led to the accumulation of the protein, which in turn resulted in β-catenin degradation and Wnt/β-catenin signaling cascade inhibition. Interestingly, we also found that [6]-gingerol, an anti-OA drug, could upregulate the protein level of Usp49 and suppress the Wnt/β-catenin signaling cascade in primary rat chondrocytes. Taken together, our study not only demonstrates that Usp49 can negatively regulate the progression of OA by inhibiting the Wnt/β-catenin signaling cascade, but also elucidates the underlying molecular mechanisms.

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References

  1. Attur M, Krasnokutsky-Samuels S, Samuels J, Abramson SB (2013) Prognostic biomarkers in osteoarthritis. Curr Opin Rheumatol 25(1):136–144. https://doi.org/10.1097/BOR.0b013e32835a9381

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Arden NK, Leyland KM (2013) Osteoarthritis year 2013 in review: clinical. Osteoarthr Cartil 21(10):1409–1413. https://doi.org/10.1016/j.joca.2013.06.021

    Article  CAS  PubMed  Google Scholar 

  3. Racine J (2013) Aaron RK (2013) Pathogenesis and epidemiology of osteoarthritis. R I Med J 96(3):19–22

    Google Scholar 

  4. Global Burden of Disease Study C (2015) Global, regional, and national incidence, prevalence, and years lived with disability for 301 acute and chronic diseases and injuries in 188 countries, 1990–2013: a systematic analysis for the Global Burden of Disease Study 2013. Lancet 386(9995):743–800. https://doi.org/10.1016/S0140-6736(15)60692-4

    Article  Google Scholar 

  5. Mankin HJ (1982) The response of articular cartilage to mechanical injury. J Bone Joint Surg Am 64(3):460–466

    Article  CAS  Google Scholar 

  6. Aigner T, McKenna L (2002) Molecular pathology and pathobiology of osteoarthritic cartilage. Cell Mol Life Sci 59(1):5–18. https://doi.org/10.1007/s00018-002-8400-3

    Article  CAS  PubMed  Google Scholar 

  7. Felson DT, Lawrence RC, Dieppe PA, Hirsch R, Helmick CG, Jordan JM, Kington RS, Lane NE, Nevitt MC, Zhang Y, Sowers M, McAlindon T, Spector TD, Poole AR, Yanovski SZ, Ateshian G, Sharma L, Buckwalter JA, Brandt KD, Fries JF (2000) Osteoarthritis: new insights. Part 1: the disease and its risk factors. Ann Intern Med 133(8):635–646. https://doi.org/10.7326/0003-4819-133-8-200010170-00016

    Article  CAS  PubMed  Google Scholar 

  8. Malfait AM (2016) Osteoarthritis year in review 2015: biology. Osteoarthr Cartil 24(1):21–26. https://doi.org/10.1016/j.joca.2015.09.010

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Moir H, Hughes MG, Potter S, Sims C, Butcher LR, Davies NA, Verheggen K, Jones KP, Thomas AW (1985) Webb R (2010) Exercise-induced immunosuppression: roles of reactive oxygen species and 5'-AMP-activated protein kinase dephosphorylation within immune cells. J Appl Physiol 108(5):1284–1292. https://doi.org/10.1152/japplphysiol.00737.2009

    Article  CAS  Google Scholar 

  10. Andriacchi TP, Favre J (2014) The nature of in vivo mechanical signals that influence cartilage health and progression to knee osteoarthritis. Curr Rheumatol Rep 16(11):463. https://doi.org/10.1007/s11926-014-0463-2

    Article  PubMed  Google Scholar 

  11. Wojdasiewicz P, Poniatowski LA, Szukiewicz D (2014) The role of inflammatory and anti-inflammatory cytokines in the pathogenesis of osteoarthritis. Mediators Inflamm 2014:561459. https://doi.org/10.1155/2014/561459

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Loeser RF (2013) Aging processes and the development of osteoarthritis. Curr Opin Rheumatol 25(1):108–113. https://doi.org/10.1097/BOR.0b013e32835a9428

    Article  PubMed  PubMed Central  Google Scholar 

  13. Palomo J, Dietrich D, Martin P, Palmer G, Gabay C (2015) The interleukin (IL)-1 cytokine family–Balance between agonists and antagonists in inflammatory diseases. Cytokine 76(1):25–37. https://doi.org/10.1016/j.cyto.2015.06.017

    Article  CAS  PubMed  Google Scholar 

  14. Tsuzaki M, Guyton G, Garrett W, Archambault JM, Herzog W, Almekinders L, Bynum D, Yang X, Banes AJ (2003) IL-1 beta induces COX2, MMP-1, -3 and -13, ADAMTS-4, IL-1 beta and IL-6 in human tendon cells. J Orthop Res 21(2):256–264. https://doi.org/10.1016/S0736-0266(02)00141-9

    Article  CAS  PubMed  Google Scholar 

  15. Yin Y, Wang Y (2017) Association of BMP-14 rs143383 ploymorphism with its susceptibility to osteoarthritis: A meta-analysis and systematic review according to PRISMA guideline. Medicine (Baltimore) 96(42):e7447. https://doi.org/10.1097/MD.0000000000007447

    Article  CAS  Google Scholar 

  16. Lin AC, Seeto BL, Bartoszko JM, Khoury MA, Whetstone H, Ho L, Hsu C, Ali SA, Alman BA (2009) Modulating hedgehog signaling can attenuate the severity of osteoarthritis. Nat Med 15(12):1421–1425. https://doi.org/10.1038/nm.2055

    Article  CAS  PubMed  Google Scholar 

  17. Okura T, Ohkawara B, Takegami Y, Ito M, Masuda A, Seki T, Ishiguro N, Ohno K (2019) Mianserin suppresses R-spondin 2-induced activation of Wnt/beta-catenin signaling in chondrocytes and prevents cartilage degradation in a rat model of osteoarthritis. Sci Rep 9(1):2808. https://doi.org/10.1038/s41598-019-39393-x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Giatromanolaki A, Sivridis E, Maltezos E, Athanassou N, Papazoglou D, Gatter KC, Harris AL, Koukourakis MI (2003) Upregulated hypoxia inducible factor-1alpha and -2alpha pathway in rheumatoid arthritis and osteoarthritis. Arthritis Res Ther 5(4):R193–201. https://doi.org/10.1186/ar756

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Yuasa T, Otani T, Koike T, Iwamoto M, Enomoto-Iwamoto M (2008) Wnt/beta-catenin signaling stimulates matrix catabolic genes and activity in articular chondrocytes: its possible role in joint degeneration. Lab Invest 88(3):264–274. https://doi.org/10.1038/labinvest.3700747

    Article  CAS  PubMed  Google Scholar 

  20. Zhu M, Tang D, Wu Q, Hao S, Chen M, **e C, Rosier RN, O'Keefe RJ, Zuscik M, Chen D (2009) Activation of beta-catenin signaling in articular chondrocytes leads to osteoarthritis-like phenotype in adult beta-catenin conditional activation mice. J Bone Miner Res 24(1):12–21. https://doi.org/10.1359/jbmr.080901

    Article  CAS  PubMed  Google Scholar 

  21. Zhou Q, **ao Z, Zhou R, Zhou Y, Fu P, Li X, Wu Y, Wu H, Qian Q (2019) Ubiquitin-specific protease 3 targets TRAF6 for deubiquitination and suppresses IL-1beta induced chondrocyte apoptosis. Biochem Biophys Res Commun 514(2):482–489. https://doi.org/10.1016/j.bbrc.2019.04.163

    Article  CAS  PubMed  Google Scholar 

  22. Zhang X, Bu Y, Zhu B, Zhao Q, Lv Z, Li B, Liu J (2018) Global transcriptome analysis to identify critical genes involved in the pathology of osteoarthritis. Bone Joint Res 7(4):298–307. https://doi.org/10.1302/2046-3758.74.BJR-2017-0245.R1

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Luo XB, ** JC, Liu Z, Long Y, Li LT, Luo ZP, Liu DH (2020) Proinflammatory effects of ubiquitin-specific protease 5 (USP5) in Rheumatoid Arthritis fibroblast-like synoviocytes. Mediators Inflamm 2020:8295149. https://doi.org/10.1155/2020/8295149

    Article  PubMed  PubMed Central  Google Scholar 

  24. Pan T, Song Z, Wu L, Liu G, Ma X, Peng Z, Zhou M, Liang L, Liu B, Liu J, Zhang J, Zhang X, Huang R, Zhao J, Li Y, Ling X, Luo Y, Tang X, Cai W, Deng K, Li L, Zhang H (2019) USP49 potently stabilizes APOBEC3G protein by removing ubiquitin and inhibits HIV-1 replication. Elife. https://doi.org/10.7554/eLife.48318

    Article  PubMed  PubMed Central  Google Scholar 

  25. Zhang Z, Jones A, Joo HY, Zhou D, Cao Y, Chen S, Erdjument-Bromage H, Renfrow M, He H, Tempst P, Townes TM, Giles KE, Ma L, Wang H (2013) USP49 deubiquitinates histone H2B and regulates cotranscriptional pre-mRNA splicing. Genes Dev 27(14):1581–1595. https://doi.org/10.1101/gad.211037.112

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Luo K, Li Y, Yin Y, Li L, Wu C, Chen Y, Nowsheen S, Hu Q, Zhang L, Lou Z, Yuan J (2017) USP49 negatively regulates tumorigenesis and chemoresistance through FKBP51-AKT signaling. EMBO J 36(10):1434–1446. https://doi.org/10.15252/embj.201695669

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Ye L, Zhang Q, Liuyu T, Xu Z, Zhang MX, Luo MH, Zeng WB, Zhu Q, Lin D, Zhong B (2019) USP49 negatively regulates cellular antiviral responses via deconjugating K63-linked ubiquitination of MITA. PLoS Pathog 15(4):e1007680. https://doi.org/10.1371/journal.ppat.1007680

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Tu R, Kang W, Yang X, Zhang Q, **e X, Liu W, Zhang J, Zhang XD, Wang H, Du RL (2018) USP49 participates in the DNA damage response by forming a positive feedback loop with p53. Cell Death Dis 9(5):553. https://doi.org/10.1038/s41419-018-0475-3

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Wang B-W, Jiang Y, Yao Z-L, Chen P-S, Yu B, Wang S-N (2019) Aucubin Protects Chondrocytes Against IL-1β-Induced Apoptosis In Vitro And Inhibits Osteoarthritis In Mice Model. Drug Des Devel Ther 13:3529–3538. https://doi.org/10.2147/DDDT.S210220

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Rao Z, Wang S, Wang J (2017) Peroxiredoxin 4 inhibits IL-1β-induced chondrocyte apoptosis via PI3K/AKT signaling. Biomed Pharmacother 90:414–420. https://doi.org/10.1016/j.biopha.2017.03.075

    Article  CAS  PubMed  Google Scholar 

  31. Li F, Ambrosini G, Chu EY, Plescia J, Tognin S, Marchisio PC, Altieri DC (1998) Control of apoptosis and mitotic spindle checkpoint by survivin. Nature 396(6711):580–584. https://doi.org/10.1038/25141

    Article  CAS  PubMed  Google Scholar 

  32. Guo FJ, **ong Z, Lu X, Ye M, Han X, Jiang R (2014) ATF6 upregulates XBP1S and inhibits ER stress-mediated apoptosis in osteoarthritis cartilage. Cell Signal 26(2):332–342. https://doi.org/10.1016/j.cellsig.2013.11.018

    Article  CAS  PubMed  Google Scholar 

  33. Khan NM, Ahmad I, Haqqi TM (2018) Nrf2/ARE pathway attenuates oxidative and apoptotic response in human osteoarthritis chondrocytes by activating ERK1/2/ELK1-P70S6K-P90RSK signaling axis. Free Radic Biol Med 116:159–171. https://doi.org/10.1016/j.freeradbiomed.2018.01.013

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Wang L, Gai P, Xu R, Zheng Y, Lv S, Li Y, Liu S (2015) Shikonin protects chondrocytes from interleukin-1beta-induced apoptosis by regulating PI3K/Akt signaling pathway. Int J Clin Exp Pathol 8(1):298–308

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Oyagbemi AA, Saba AB, Azeez OI (2010) Molecular targets of [6]-gingerol: Its potential roles in cancer chemoprevention. BioFactors 36(3):169–178. https://doi.org/10.1002/biof.78

    Article  CAS  PubMed  Google Scholar 

  36. Shukla Y, Singh M (2007) Cancer preventive properties of ginger: a brief review. Food Chem Toxicol 45(5):683–690. https://doi.org/10.1016/j.fct.2006.11.002

    Article  CAS  PubMed  Google Scholar 

  37. Kim EC, Min JK, Kim TY, Lee SJ, Yang HO, Han S, Kim YM, Kwon YG (2005) [6]-Gingerol, a pungent ingredient of ginger, inhibits angiogenesis in vitro and in vivo. Biochem Biophys Res Commun 335(2):300–308. https://doi.org/10.1016/j.bbrc.2005.07.076

    Article  CAS  PubMed  Google Scholar 

  38. Oboh G, Akinyemi AJ, Ademiluyi AO (2012) Antioxidant and inhibitory effect of red ginger (Zingiber officinale var. Rubra) and white ginger (Zingiber officinale Roscoe) on Fe(2+) induced lipid peroxidation in rat brain in vitro. Exp Toxicol Pathol 64(1–2):31–36. https://doi.org/10.1016/j.etp.2010.06.002

    Article  CAS  PubMed  Google Scholar 

  39. Kubra IR, Rao LJ (2012) An impression on current developments in the technology, chemistry, and biological activities of ginger (Zingiber officinale Roscoe). Crit Rev Food Sci Nutr 52(8):651–688. https://doi.org/10.1080/10408398.2010.505689

    Article  CAS  PubMed  Google Scholar 

  40. Xu T, Qin G, Jiang W, Zhao Y, Xu Y, Lv X (2018) 6-Gingerol protects heart by suppressing myocardial ischemia/reperfusion induced inflammation via the PI3K/Akt-dependent mechanism in rats. Evid Based Complement Alternat Med 2018:6209679. https://doi.org/10.1155/2018/6209679

    Article  PubMed  PubMed Central  Google Scholar 

  41. Levy AS, Simon O, Shelly J, Gardener M (2006) 6-Shogaol reduced chronic inflammatory response in the knees of rats treated with complete Freund's adjuvant. BMC Pharmacol 6:12–12. https://doi.org/10.1186/1471-2210-6-12

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Villalvilla A, Silva J, Largo R, Gualillo O, Vieira P, Herrero-Beaumont G, Gómez Bahamonde R (2014) 6-Shogaol inhibits chondrocytes’ innate immune responses and cathepsin-K activity. Mol Nutr Food Res 58:256–266. https://doi.org/10.1002/mnfr.201200833

    Article  CAS  PubMed  Google Scholar 

  43. Joddar B, Reen RK, Firstenberg MS, Varadharaj S, McCord JM, Zweier JL, Gooch KJ (2011) Protandim attenuates intimal hyperplasia in human saphenous veins cultured ex vivo via a catalase-dependent pathway. Free Radic Biol Med 50(6):700–709. https://doi.org/10.1016/j.freeradbiomed.2010.12.008

    Article  CAS  PubMed  Google Scholar 

  44. Abusarah J, Benabdoune H, Shi Q, Lussier B, Martel-Pelletier J, Malo M, Fernandes JC, de Souza FP, Fahmi H, Benderdour M (2017) Elucidating the role of protandim and 6-gingerol in protection against osteoarthritis. J Cell Biochem 118(5):1003–1013. https://doi.org/10.1002/jcb.25659

    Article  CAS  PubMed  Google Scholar 

  45. Schulte G, Bryja V (2017) WNT signalling: mechanisms and therapeutic opportunities. Br J Pharmacol 174(24):4543–4546. https://doi.org/10.1111/bph.14065

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Fernandez-Torres J, Zamudio-Cuevas Y, Lopez-Reyes A, Garrido-Rodriguez D, Martinez-Flores K, Lozada CA, Munoz-Valle JF, Oregon-Romero E, Martinez-Nava GA (2018) Gene-gene interactions of the Wnt/beta-catenin signaling pathway in knee osteoarthritis. Mol Biol Rep 45(5):1089–1098. https://doi.org/10.1007/s11033-018-4260-2

    Article  CAS  PubMed  Google Scholar 

  47. Sanchez-Adams J, Leddy HA, McNulty AL, O'Conor CJ, Guilak F (2014) The mechanobiology of articular cartilage: bearing the burden of osteoarthritis. Curr Rheumatol Rep 16(10):451. https://doi.org/10.1007/s11926-014-0451-6

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Enomoto-Iwamoto M, Kitagaki J, Koyama E, Tamamura Y, Wu C, Kanatani N, Koike T, Okada H, Komori T, Yoneda T, Church V, Francis-West PH, Kurisu K, Nohno T, Pacifici M, Iwamoto M (2002) The Wnt antagonist Frzb-1 regulates chondrocyte maturation and long bone development during limb skeletogenesis. Dev Biol 251(1):142–156. https://doi.org/10.1006/dbio.2002.0802

    Article  CAS  PubMed  Google Scholar 

  49. Sassi N, Laadhar L, Allouche M, Achek A, Kallel-Sellami M, Makni S, Sellami S (2014) WNT signaling and chondrocytes: from cell fate determination to osteoarthritis physiopathology. J Recept Signal Transduct Res 34(2):73–80. https://doi.org/10.3109/10799893.2013.863919

    Article  CAS  PubMed  Google Scholar 

  50. **a H, Cao D, Yang F, Yang W, Li W, Liu P, Wang S, Yang F (2020) Jiawei Yanghe decoction ameliorates cartilage degradation in vitro and vivo via Wnt/beta-catenin signaling pathway. Biomed Pharmacother 122:109708. https://doi.org/10.1016/j.biopha.2019.109708

    Article  CAS  PubMed  Google Scholar 

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Funding

This study was funded by The Special Project of Traditional Chinese Medicine Research in Henan Province (2019ZY2080).

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Authors and Affiliations

  1. Department of Orthopedics, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, Henan, China

    Lanbo Yang, Hengtao Tang & Xuejian Wu

  2. Knee Injury Center, Luoyang Orthopedic Hospital of Henan Province (Henan Provincial Orthopaedic Hospital), Luoyang, 471000, Henan, China

    Zhanchao Wang, Chunyu Zou & Yufei Mi

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  1. Lanbo Yang
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  3. Chunyu Zou
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  4. Yufei Mi
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Contributions

XJW conceived and designed the study. LBY, ZCW, CYZ, YFM, and HTT performed the experiments, and collected and analyzed the data. XJW wrote the manuscript. All authors read and approved the final manuscript and agree to be accountable for all aspects of the research in ensuring that the accuracy or integrity of any part of the work are appropriately investigated and resolved.

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Correspondence to Xuejian Wu.

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All experiments conducted in this study were approved by the Ethics Committee of The First Affiliated Hospital of Zhengzhou University and written informed consent was obtained.

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Yang, L., Wang, Z., Zou, C. et al. Ubiquitin-specific protease 49 attenuates IL-1β-induced rat primary chondrocyte apoptosis by facilitating Axin deubiquitination and subsequent Wnt/β-catenin signaling cascade inhibition. Mol Cell Biochem 474, 263–275 (2020). https://doi.org/10.1007/s11010-020-03850-3

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