Zinc finger protein-440 promotes cartilage degenerative mechanisms in human facet and knee osteoarthritis chondrocytes

  • A. Nakamura
    Affiliations
    Schroeder Arthritis Institute, Krembil Research Institute, University Health Network, Toronto, Ontario, Canada

    Institute of Medical Science, Department of Medicine, University of Toronto, Ontario, Canada

    Department of Rheumatology, University of Toronto, Ontario, Canada
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  • Y.R. Rampersaud
    Affiliations
    Schroeder Arthritis Institute, Krembil Research Institute, University Health Network, Toronto, Ontario, Canada

    Department of Surgery, University of Toronto, Ontario, Canada
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  • K. Sundararajan
    Affiliations
    Schroeder Arthritis Institute, Krembil Research Institute, University Health Network, Toronto, Ontario, Canada
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  • S. Nakamura
    Affiliations
    Schroeder Arthritis Institute, Krembil Research Institute, University Health Network, Toronto, Ontario, Canada
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  • B. Wu
    Affiliations
    Schroeder Arthritis Institute, Krembil Research Institute, University Health Network, Toronto, Ontario, Canada
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  • E. Matip
    Affiliations
    Schroeder Arthritis Institute, Krembil Research Institute, University Health Network, Toronto, Ontario, Canada
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  • N. Haroon
    Affiliations
    Schroeder Arthritis Institute, Krembil Research Institute, University Health Network, Toronto, Ontario, Canada

    Institute of Medical Science, Department of Medicine, University of Toronto, Ontario, Canada

    Department of Rheumatology, University of Toronto, Ontario, Canada
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  • R.J. Krawetz
    Affiliations
    McCaig Institute for Bone &Joint Health, University of Calgary, Calgary, AB, Canada
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  • E. Rossomacha
    Affiliations
    Schroeder Arthritis Institute, Krembil Research Institute, University Health Network, Toronto, Ontario, Canada
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  • R. Gandhi
    Affiliations
    Schroeder Arthritis Institute, Krembil Research Institute, University Health Network, Toronto, Ontario, Canada

    Department of Surgery, University of Toronto, Ontario, Canada
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  • M. Kotlyar
    Affiliations
    Schroeder Arthritis Institute, Krembil Research Institute, University Health Network, Toronto, Ontario, Canada
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  • J.S. Rockel
    Affiliations
    Schroeder Arthritis Institute, Krembil Research Institute, University Health Network, Toronto, Ontario, Canada
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  • I. Jurisica
    Affiliations
    Schroeder Arthritis Institute, Krembil Research Institute, University Health Network, Toronto, Ontario, Canada

    Departments of Medical Biophysics and Computer Science, University of Toronto, Toronto, ON, Canada

    Institute of Neuroimmunology, Slovak Academy of Sciences, Bratislava, Slovakia
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  • M. Kapoor
    Correspondence
    Address correspondence and reprint requests to: M. Kapoor, Schroeder Arthritis Institute, University Health Network, Department of Surgery and Department of Laboratory Medicine and Pathobiology, University of Toronto; Krembil Research Institute, 60 Leonard Avenue, Toronto, Ontario, M5T 2S8, Canada. Tel.: 1-416-603-5800 ext. 4796.
    Affiliations
    Schroeder Arthritis Institute, Krembil Research Institute, University Health Network, Toronto, Ontario, Canada

    Department of Surgery, University of Toronto, Ontario, Canada

    Department of Laboratory Medicine and Pathobiology, University of Toronto, Ontario, Canada
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Published:December 17, 2020DOI:https://doi.org/10.1016/j.joca.2020.12.004

      Summary

      Objectives

      To investigate the role of zinc finger protein 440 (ZNF440) in the pathophysiology of cartilage degeneration during facet joint (FJ) and knee osteoarthritis (OA).

      Methods

      Expression of ZNF440 in FJ and knee cartilage was determined by immunohistochemistry, quantitative (q)PCR, and Western blotting (WB). Human chondrocytes isolated from FJ and knee OA cartilage were cultured and transduced with ZNF440 or control plasmid, or transfected with ZNF440 or control small interfering RNA (siRNA), with/without interleukin (IL)-1β. Gene and protein levels of catabolic, anabolic and apoptosis markers were determined by qPCR or WB, respectively. In silico analyses were performed to determine compounds with potential to inhibit expression of ZNF440.

      Results

      ZNF440 expression was increased in both FJ and knee OA cartilage compared to control cartilage. In vitro, overexpression of ZNF440 significantly increased expression of MMP13 and PARP p85, and decreased expression of COL2A1. Knockdown of ZNF440 with siRNA partially reversed the catabolic and cell death phenotype of human knee and FJ OA chondrocytes stimulated with IL-1β. In silico analysis followed by validation assays identified scriptaid as a compound with potential to downregulate the expression of ZNF440. Validation experiments showed that scriptaid reduced the expression of ZNF440 in OA chondrocytes and concomitantly reduced the expression of MMP13 and PARP p85 in human knee OA chondrocytes overexpressing ZNF440.

      Conclusions

      The expression of ZNF440 is significantly increased in human FJ and knee OA cartilage and may regulate cartilage degenerative mechanisms. Furthermore, scriptaid reduces the expression of ZNF440 and inhibits its destructive effects in OA chondrocytes.

      Keywords

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      References

        • Martel-Pelletier J.
        • Barr A.J.
        • Cicuttini F.M.
        • Conaghan P.G.
        • Cooper C.
        • Goldring M.B.
        • et al.
        Osteoarthritis.
        Nat Rev Dis Prim. 2016; 2: 16072https://doi.org/10.1038/nrdp.2016.72
        • Kapoor M.
        • Martel-Pelletier J.
        • Lajeunesse D.
        • Pelletier J.-P.
        • Fahmi H.
        Role of proinflammatory cytokines in the pathophysiology of osteoarthritis.
        Nat Rev Rheumatol. 2011; 7: 33-42https://doi.org/10.1038/nrrheum.2010.196
        • Klug A.
        The discovery of zinc fingers and their development for practical applications in gene regulation and genome manipulation.
        Q Rev Biophys. 2010; 43: 1-21https://doi.org/10.1017/S0033583510000089
        • Mesuraca M.
        • Galasso O.
        • Guido L.
        • Chiarella E.
        • Scicchitano S.
        • Vatrinet R.
        • et al.
        Expression profiling and functional implications of a set of zinc finger proteins, ZNF423, ZNF470, ZNF521, and ZNF780B, in primary osteoarthritic articular chondrocytes.
        Mediators Inflamm. 2014; 2014: 318793https://doi.org/10.1155/2014/318793
        • Nakamura A.
        • Rampersaud Y.R.
        • Sharma A.
        • Lewis S.J.
        • Wu B.
        • Datta P.
        • et al.
        Identification of microRNA-181a-5p and microRNA-4454 as mediators of facet cartilage degeneration.
        JCI Insight. 2016; https://doi.org/10.1172/jci.insight.86820
        • Nakamura A.
        • Rampersaud Y.R.
        • Nakamura S.
        • Sharma A.
        • Zeng F.
        • Rossomacha E.
        • et al.
        MicroRNA-181a-5p antisense oligonucleotides attenuate osteoarthritis in facet and knee joints.
        Ann Rheum Dis. 2018; https://doi.org/10.1136/annrheumdis-2018-213629
        • Weishaupt D.
        • Zanetti M.
        • Boos N.
        • Hodler J.
        MR imaging and CT in osteoarthritis of the lumbar facet joints.
        Skeletal Radiol. 1999; 28: 215-219https://doi.org/10.1007/s002560050503
        • Kellgren J.H.
        • Lawrence J.S.
        Radiological assessment of osteo-arthrosis.
        Ann Rheum Dis. 1957; 16: 494-502https://doi.org/10.1136/ard.16.4.494
        • Pritzker K.P.H.
        • Gay S.
        • Jimenez S.A.
        • Ostergaard K.
        • Pelletier J.-P.
        • Revell P.A.
        • et al.
        Osteoarthritis cartilage histopathology: grading and staging.
        Osteoarthr Cartil. 2006; 14: 13-29https://doi.org/10.1016/j.joca.2005.07.014
        • Lamb J.
        • Crawford E.D.
        • Peck D.
        • Modell J.W.
        • Blat I.C.
        • Wrobel M.J.
        • et al.
        The Connectivity Map: using gene-expression signatures to connect small molecules, genes, and disease.
        Science. 2006; 313: 1929-1935https://doi.org/10.1126/science.1132939
        • Blanco F.J.
        • Guitian R.
        • Vazquez-Martul E.
        • de Toro F.J.
        • Galdo F.
        Osteoarthritis chondrocytes die by apoptosis. A possible pathway for osteoarthritis pathology.
        Arthritis Rheum. 1998; 41: 284-289https://doi.org/10.1002/1529-0131(199802)41:2<284::AID-ART12>3.0.CO;2-T
        • Nakamoto T.
        • Izu Y.
        • Kawasaki M.
        • Notomi T.
        • Hayata T.
        • Noda M.
        • et al.
        Mice deficient in CIZ/NMP4 develop an attenuated form of K/BxN-Serum induced arthritis.
        J Cell Biochem. 2016; 117: 970-977https://doi.org/10.1002/jcb.25382
        • Liu T.M.
        • Guo X.M.
        • Tan H.S.
        • Hui J.H.
        • Lim B.
        • Lee E.H.
        Zinc-finger protein 145, acting as an upstream regulator of SOX9, improves the differentiation potential of human mesenchymal stem cells for cartilage regeneration and repair.
        Arthritis Rheum. 2011; 63: 2711-2720https://doi.org/10.1002/art.30430
        • Monneret C.
        Histone deacetylase inhibitors.
        Eur J Med Chem. 2005; 40: 1-13https://doi.org/10.1016/j.ejmech.2004.10.001
        • Culley K.L.
        • Hui W.
        • Barter M.J.
        • Davidson R.K.
        • Swingler T.E.
        • Destrument A.P.M.
        • et al.
        Class I histone deacetylase inhibition modulates metalloproteinase expression and blocks cytokine-induced cartilage degradation.
        Arthritis Rheum. 2013; 65: 1822-1830https://doi.org/10.1002/art.37965
        • Ji B.
        • Guo W.
        • Ma H.
        • Xu B.
        • Mu W.
        • Zhang Z.
        • et al.
        Isoliquiritigenin suppresses IL-1β induced apoptosis and inflammation in chondrocyte-like ATDC5 cells by inhibiting NF-κB and exerts chondroprotective effects on a mouse model of anterior cruciate ligament transection.
        Int J Mol Med. 2017; 40: 1709-1718https://doi.org/10.3892/ijmm.2017.3177