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Open AccessArticle

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

1
University of Melbourne Department of Paediatrics, Royal Children’s Hospital, Parkville, Victoria 3052, Australia
2
Murdoch Children’s Research Institute, Royal Children’s Hospital, Parkville, Victoria 3052, Australia
3
Royal Melbourne Institute of Technology, 124 La Trobe Street, Melbourne, Victoria 3000, Australia
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2019, 20(3), 573; https://doi.org/10.3390/ijms20030573
Received: 19 December 2018 / Revised: 14 January 2019 / Accepted: 24 January 2019 / Published: 29 January 2019
(This article belongs to the Special Issue Matrix Metalloproteinase)
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. View Full-Text
Keywords: aggrecan; aggrecanase; ADAMTS; cartilage; arthritis aggrecan; aggrecanase; ADAMTS; cartilage; arthritis
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Rogerson, F.M.; Last, K.; Golub, S.B.; Gauci, S.J.; Stanton, H.; Bell, K.M.; Fosang, A.J. ADAMTS-9 in Mouse Cartilage Has Aggrecanase Activity That Is Distinct from ADAMTS-4 and ADAMTS-5. Int. J. Mol. Sci. 2019, 20, 573.

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