ADAMTS-9 in Mouse Cartilage Has Aggrecanase Activity That Is Distinct From ADAMTS-4 and ADAMTS-5

Int J Mol Sci. 2019 Jan 29;20(3):573. doi: 10.3390/ijms20030573.


A disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS)-4 and ADAMTS-5 are the principal aggrecanases in mice and humans; however, mice lacking the catalytic domain of both enzymes (TS-4/5∆cat) have no skeletal phenotype, suggesting there is an alternative aggrecanase for modulating normal growth and development in these mice. We previously identified aggrecanase activity that (a) cleaved at E↓G rather than E↓A bonds in the aggrecan core protein, and (b) was upregulated by retinoic acid but not IL-1α. The present study aimed to identify the alternative aggrecanase. Femoral head cartilage explants from TS-4/5∆cat mice were stimulated with IL-1α or retinoic acid and total RNA was analysed by microarray. In addition to ADAMTS-5 and matrix metalloproteinase (MMP)-13, which are not candidates for the novel aggrecanase, the microarray analyses identified MMP-11, calpain-5 and ADAMTS-9 as candidate aggrecanases upregulated by retinoic acid. When calpain-5 and MMP-11 failed to meet subsequent criteria, ADAMTS-9 emerged as the most likely candidate for the novel aggrecanase. Immunohistochemistry revealed ADAMTS-9 expression throughout the mouse growth plate and strong expression, particularly in the proliferative zone of the TS-4/5-∆cat mice. In conclusion, ADAMTS-9 has a novel specificity for aggrecan, cleaving primarily at E↓G rather than E↓A bonds in mouse cartilage. ADAMTS-9 might have more important roles in normal skeletal development compared with ADAMTS-4 and ADAMTS-5, which have key roles in joint pathology.

Keywords: ADAMTS; aggrecan; aggrecanase; arthritis; cartilage.

MeSH terms

  • ADAMTS4 Protein / metabolism*
  • ADAMTS5 Protein / metabolism*
  • ADAMTS9 Protein / genetics
  • ADAMTS9 Protein / metabolism*
  • Aggrecans / metabolism
  • Animals
  • Arthritis / genetics
  • Arthritis / metabolism
  • Cartilage / metabolism*
  • Cells, Cultured
  • Endopeptidases / metabolism*
  • Immunohistochemistry
  • Matrix Metalloproteinase 13 / genetics
  • Matrix Metalloproteinase 13 / metabolism
  • Mice
  • RNA, Messenger / metabolism


  • Aggrecans
  • RNA, Messenger
  • Endopeptidases
  • ADAMTS5 Protein
  • ADAMTS9 Protein
  • Matrix Metalloproteinase 13
  • ADAMTS4 Protein
  • aggrecanase