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Kruppel-like factor 4 upregulates matrix metalloproteinase 13 expression in chondrocytes via mRNA stabilization

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Abstract

Matrix metalloproteinase 13 (MMP13) is indispensable for normal skeletal development and is also a principal proteinase responsible for articular joint pathologies. MMP13 mRNA level needs to be tightly regulated in both positive and negative manners to achieve normal development and also to prevent joint destruction. We showed previously that Kruppel-like factor 4 (KLF4) strongly induces the expression of members of the MMP family of genes including that for MMP13 in cultured chondrocytes. Through expression-based screening of approximately 400 compounds, we identified several that efficiently downregulated MMP13 gene expression induced by KLF4. Compounds grouped as topoisomerase inhibitors (transcriptional inhibitors) downregulated MMP13 expression levels, which proved the validity of our screening method. In this screening, trichostatin A (TSA) was identified as one of the most potent repressors. Mechanistically, increased MMP13 mRNA levels induced by KLF4 were not mainly caused by increased rates of RNA polymerase II–mediated MMP13 transcription, but arose from escaping mRNA decay. TSA treatment almost completely blunted the effect of KLF4. Importantly, KLF4 was detected in chondrocytes at the joint destruction sites in a rodent model of osteoarthritis. Our results partially explain how KLF4 regulates numerous proteinase gene expressions simultaneously in chondrocytes. Also, these observations suggest that modulation of KLF4 activity or expression could be a novel therapeutic target for osteoarthritis.

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Acknowledgments

The authors acknowledge Dr. Qingbo Xu, Dr. Jim Darnell, and Dr. Ronald Kahn for sharing the clones used in this study.

Funding

This work was supported by Grants-in-Aid for Scientific Research from MEXT to MA (17K11611), YT (17K17322), JF (17K11960), and the Takeda Science Foundation (SI). Compound screening was supported by the Molecular Profiling Committee, Grants-in-Aid for Scientific Research on Innovative Areas “Platform of Advanced Animal Model Support” from The Ministry of Education, Culture, Sports, Science and Technology, Japan (KAKENHI 16H06276).

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Authors and Affiliations

  1. Department of Oral Anatomy and Developmental Biology, Osaka University Graduate School of Dentistry, 1-8 Yamada-oka, Suita, Osaka, 565-0871, Japan

    Yuto Takeuchi, Sayuri Tatsuta, Akiyoshi Kito, Satoshi Wakisaka & Makoto Abe

  2. Department of Orthodontics and Dentofacial Orthopedics, Osaka University Graduate School of Dentistry, Osaka, Japan

    Yuto Takeuchi & Takashi Yamashiro

  3. Division of Special Care Dentistry, Osaka University Dental Hospital, Osaka, Japan

    Akiyoshi Kito, Junji Fujikawa & Shigehisa Akiyama

  4. Department of Restorative Dentistry and Endodontology, Osaka University Graduate School of Dentistry, Osaka, Japan

    Shousaku Itoh & Yuki Itoh

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  1. Yuto Takeuchi
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Correspondence to Makoto Abe.

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Takeuchi, Y., Tatsuta, S., Kito, A. et al. Kruppel-like factor 4 upregulates matrix metalloproteinase 13 expression in chondrocytes via mRNA stabilization. Cell Tissue Res 382, 307–319 (2020). https://doi.org/10.1007/s00441-020-03228-3

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