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

J Orthop Res. 2018 Dec;36(12):3247-3255. doi: 10.1002/jor.24126. Epub 2018 Sep 7.


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. © 2018 The Authors. Journal of Orthopaedic Research® Published by Wiley Periodicals, Inc. on behalf of Orthopaedic Research Society. J Orthop Res 36:3247-3255, 2018.

Keywords: aggrecan; chondrocyte; hyaluronic acid; metalloproteinase.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ADAMTS5 Protein / genetics
  • ADAMTS9 Protein / genetics
  • Aggrecans / metabolism
  • Animals
  • Cartilage, Articular / drug effects*
  • Cartilage, Articular / metabolism
  • Cells, Cultured
  • Endopeptidases / genetics*
  • Humans
  • Hyaluronan Receptors / physiology
  • Hyaluronic Acid / pharmacology*
  • Male
  • Molecular Weight
  • Osteoarthritis / metabolism
  • RNA, Messenger / analysis
  • Rats
  • Rats, Sprague-Dawley


  • Aggrecans
  • Hyaluronan Receptors
  • RNA, Messenger
  • Hyaluronic Acid
  • Endopeptidases
  • ADAMTS5 Protein
  • ADAMTS9 Protein
  • aggrecanase