3 years ago

High molecular weight hyaluronan protects cartilage from degradation by inhibiting aggrecanase expression

Toshitaka Oohashi, Takashi Ohtsuki, Akira Shinaoka, Junko Inagaki, Mehmet Zeynel Cilek, Issei Komatsubara, Omer Faruk Hatipoglu, Satoshi Hirohata, Kanae Kumagishi‐Shinaoka, Keiichiro Nishida, Keiichi Asano


Hyaluronan is an extracellular matrix component of articular cartilage and has been used to treat patients with osteoarthritis. A disintegrin and metalloproteinases with thrombospondin motifs (ADAMTSs) play an important role in cartilage degradation in osteoarthritis. We have previously reported that ADAMTS4 and ADAMTS9 were induced by cytokine stimulation. However, the effect of hyaluronan on the cytokine‐inducible ADAMTS9 has never been investigated. Moreover, it is unclear whether hyaluronan protects cartilage by suppressing aggrecan degradation. Here, we examined the effects of hyaluronan 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 hyaluronan significantly inhibited ADAMTS9 mRNA expression in cytokine‐stimulated cells. In a rat osteoarthritis model, Adamts5 and 9 mRNA levels were transiently increased after surgery; intra‐articular hyaluronan injections attenuated the induction of Adamts5 and 9 mRNA. Hyaluronan also blocked aggrecan cleavage by aggrecanase in osteoarthritis rats in a molecular size‐dependent manner. These results demonstrate that hyaluronan attenuates induced aggrecanases expression in osteoarthritis and thereby protects articular cartilage degradation by this enzyme. Our findings provide insight into the molecular basis for the beneficial effects of hyaluronan in osteoarthritis. This article is protected by copyright. All rights reserved

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