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Regulation of osteoarthritis development by ADAM17/Tace in articular cartilage

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Abstract

Introduction

A disintegrin and metalloproteinase 17 (Adam17), also known as TNFα-converting enzyme (Tace), is a membrane-anchored protein involved in shedding of TNF, IL-6 receptor, ligands of epidermal growth factor receptor (EGFR), and Notch receptor. This study aimed to examine the role of Adam17 in adult articular cartilage and osteoarthritis (OA) pathophysiology.

Materials and methods

Adam17 expression was examined in mouse knee joints during OA development. We analyzed OA development in tamoxifen-inducible chondrocyte-specific Adam17 knockout mice of a resection of the medial meniscus and medial collateral ligament (medial) model, destabilization of the medial meniscus (DMM) model, and aging model. We analyzed downstream pathways by in vitro experiments, and further performed intra-articular administration of an Adam17 inhibitor TAPI-0 for surgically induced mouse OA.

Results

Adam17 expression in mouse articular cartilage was increased by OA progression. In all models, Adam17 knockout mice showed ameliorated progression of articular cartilage degradation. Adam17 knockout decreased matrix metallopeptidase 13 (Mmp13) expression in both in vivo and in vitro experiments, whereas Adam17 activation by phorbol-12-myristate-13-acetate (PMA) increased Mmp13 and decreased aggrecan in mouse primary chondrocytes. Adam17 activation enhanced release of soluble TNF and transforming growth factor alpha, a representative EGF ligand, from mouse primary chondrocytes, while it did not change release of soluble IL-6 receptor or nuclear translocation of Notch1 intercellular domain. Intra-articular administration of the Adam17 inhibitor ameliorated OA progression.

Conclusions

This study demonstrates regulation of OA development by Adam17, involvement of EGFR and TNF pathways, and the possibility of Adam17 as a therapeutic target for OA.

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Data availability

All data generated or analyzed during this study are included in this published article.

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Acknowledgements

We thank Dr. Di Chen for generously providing Col2a1-CreERT2 mice. We thank J. Sugita, K. Kaneko, and R. Homma for technical assistance. We also thank Mitchell Arico from Edanz Group (https://jp.edanz.com/ac) for editing a draft of this manuscript.

Funding

This work was supported by JSPS KAKENHI Grant Numbers 20H03799, 19H05654, 19H05565, 19K09641, 18KK0254, 17H04310, and 26462285.

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Authors and Affiliations

  1. Sensory and Motor System Medicine, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan

    Taizo Kaneko, Kosei Nagata, Yasunori Omata, Hiroshi Inui, Toru Moro, Sakae Tanaka & Taku Saito

  2. Bone and Cartilage Regenerative Medicine, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan

    Ryota Chijimatsu, Daisuke Mori, Yasunori Omata & Fumiko Yano

  3. Division of Science for Joint Reconstruction, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan

    Toru Moro

  4. Department of Orthopedic Surgery, National Defense Medical College, Saitama, 359-8513, Japan

    Keisuke Horiuchi

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  1. Taizo Kaneko
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Contributions

All authors have read and approved the final manuscript. TK, KH, and TS conceived and designed the study. TK, RC, DM, and KN performed the experiment. TK, RC, FY, HI, TM, ST, and TS analyzed and interpreted the data. TK and TS wrote the paper.

Corresponding author

Correspondence to Taku Saito.

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Kaneko, T., Horiuchi, K., Chijimatsu, R. et al. Regulation of osteoarthritis development by ADAM17/Tace in articular cartilage. J Bone Miner Metab 40, 196–207 (2022). https://doi.org/10.1007/s00774-021-01278-3

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  • DOI: https://doi.org/10.1007/s00774-021-01278-3

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