@article{dc1e5d81a190420f803678fae8173d2a,
title = "High molecular weight hyaluronan protects cartilage from degradation by inhibiting aggrecanase expression",
abstract = "Hyaluronan (HA) is an extracellular matrix (ECM) component of articular cartilage and has been used to treat patients with osteoarthritis (OA). A disintegrin and metalloproteinases with thrombospondin motifs (ADAMTSs) play an important role in cartilage degradation in OA. We have previously reported that ADAMTS4 and ADAMTS9 were induced by cytokine stimulation. However, the effect of HA on the cytokine-inducible ADAMTS9 has never been investigated. Moreover, it is unclear whether HA protects cartilage by suppressing aggrecan degradation. Here, we examined the effects of HA on ADAMTS expression in vitro and on cartilage degradation in vivo. ADAMTS9 expression was higher than that of the other aggrecanases (ADAMTS4 and 5) in human chondrocytes, chondrocytic cells, and rat cartilage. ADAMTS4 and 9 mRNA levels were upregulated in cytokine-stimulated chondrocytes and chondrocytic cells. Pre-incubation with HA significantly inhibited ADAMTS9 mRNA expression in cytokine-stimulated cells. In a rat OA model, Adamts5 and 9 mRNA levels were transiently increased after surgery; intra-articular HA injections attenuated the induction of Adamts5 and 9 mRNA. HA also blocked aggrecan cleavage by aggrecanase in OA rats in a molecular size-dependent manner. These results demonstrate that HA attenuates induced aggrecanases expression in OA and thereby protects articular cartilage degradation by this enzyme. Our findings provide insight into the molecular basis for the beneficial effects of HA in OA.",
keywords = "aggrecan, chondrocyte, hyaluronic acid, metalloproteinase",
author = "Takashi Ohtsuki and Keiichi Asano and Junko Inagaki and Akira Shinaoka and Kanae Kumagishi-Shinaoka and Cilek, {Mehmet Z.} and Hatipoglu, {Omer F.} and Toshitaka Oohashi and Keiichiro Nishida and Issei Komatsubara and Satoshi Hirohata",
note = "Funding Information: The authors are grateful to late Dr. Yoshifumi Ninomiya. We dedicate this paper to the memory of him, who greatly contributed to the progress on the research in the matrix biology. We thank Tomoko Yonezawa, Aiji Ohtsuka, Kenji Nohmi, Masamichi Hashimoto, Lauren Wang, Christopher Koch, Dirk Hubmacher, Timothy Mead, Sumeda Nandadasa, and Suneel S. Apte for stimulating discussions and suggestions. The authors also thank Ms. Morishita and Ms. Monobe in the Central Research Laboratory of Okayama University Medical School for technical assistance. This work was supported in part by a Grant-in-Aid for Scientific Research (17K19727 and 17H04313 to S.H., 16K10905 to T.O., and 26350500 to J.I.) from the Japan Society for the Promotion of Science. SH received financial support from Chugai Pharmaceutical Company to conduct this research and Chugai provided all kinds of hyaluronan used in this study. However, Chugai had no role in the study design, collection of data, analysis or interpretation of data, manuscript creation, or in the decision to submit the article for publication. We would like to thank Editage (www. editage.jp) for English language editing. Funding Information: This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. Conflicts of interest disclosure: The authors have no conflicts of interest to disclose concerning this manuscript. Grant sponsor: MEXT/JSPS KAKENHI; Grant numbers: JP17K19727, 17H04313, 16K10905, 26350500. Correspondence to: Satoshi Hirohata (T: +81-86-235-6897; F: +81-86-235-6897; E-mail: hirohas@cc.okayama-u.ac.jp)",
year = "2018",
month = dec,
doi = "10.1002/jor.24126",
language = "English",
volume = "36",
pages = "3247--3255",
journal = "Journal of Orthopaedic Research",
issn = "0736-0266",
publisher = "John Wiley and Sons Inc.",
number = "12",
}