Regulation of osteoarthritis development by ADAM17/Tace in articular cartilage
Regulation of osteoarthritis development by ADAM17/Tace in articular cartilage
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DOI：
10.1007/s00774-021-01278-3
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发表时间：
2021-11
影响因子：
3.3
通讯作者：
Taizo Kaneko;K. Horiuchi;Ryota Chijimatsu;Daisuke Mori;Kosei Nagata;Y. Omata;Fumiko Yano;Hiroshi Inui;T. Moro;Sakae Tanaka;Taku Saito
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作者：
Taizo Kaneko;K. Horiuchi;Ryota Chijimatsu;Daisuke Mori;Kosei Nagata;Y. Omata;Fumiko Yano;Hiroshi Inui;T. Moro;Sakae Tanaka;Taku Saito
去整合素和金属蛋白酶17，又称肿瘤坏死因子α转换酶(TACE)，是一种膜锚定蛋白，参与肿瘤坏死因子、白介素6受体、表皮生长因子受体配体和Notch受体的脱落。本研究旨在探讨ADAM17在成人关节软骨和骨性关节炎(OA)病理生理学中的作用。材料和方法检测ADAM17在小鼠膝关节发育过程中的表达。我们分析了他莫昔芬诱导的软骨细胞特异性Adam17基因敲除小鼠在切除内侧半月板和内侧副韧带(内侧)模型、内侧半月板失稳(DMM)模型和衰老模型中骨性关节炎的发展情况。我们通过体外实验分析了ADAM17的下游通路，并进一步对手术诱导的小鼠关节软骨给予ADAM17抑制剂TAPI-0。结果随着OA的进展，Adam17的表达增加。在所有模型中，Adam17基因敲除小鼠的关节软骨降解进展都有所改善。在体内和体外实验中，Adam17基因敲除小鼠的关节软骨细胞中基质金属肽酶13(Mmp13)的表达均降低，而佛波醇-12-肉豆蔻酸酯-13-乙酸酯(PMA)激活的ADAM17则增加了Mmp13的表达，并降低了小鼠原代软骨细胞中的aggrecan。ADAM17激活可促进小鼠原代软骨细胞释放可溶性肿瘤坏死因子和转化生长因子α，而不改变可溶性IL-6受体的释放和Notch1胞间结构域的核移位。关节腔内应用ADAM17抑制剂可改善OA的进展。结论本研究证实了ADAM17对骨性关节炎的发生、EGFR和肿瘤坏死因子途径的参与，以及ADAM17作为骨性关节炎治疗靶点的可能性。
IntroductionA 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 methodsAdam17expression was examined in mouse knee joints during OA development. We analyzed OA development in tamoxifen-inducible chondrocyte-specificAdam17knockout 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.ResultsAdam17expression in mouse articular cartilage was increased by OA progression. In all models,Adam17knockout mice showed ameliorated progression of articular cartilage degradation.Adam17knockout 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.ConclusionsThis 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.