Oncostatin M in combination with tumour necrosis factor & [alpha]induces a chondrocyte membrane-associated aggrecanase that is distinct from ADAMTS aggrecanase-1 or -2

Wang Hui ¹, Emma Barksby ¹, David A Young ¹, Tim E Cawston ², Norman Mckie ² and Andrew D Rowan ^3*

¹ Department of Rheumatology, United Kingdom
² University of Newcastle upon Tyne, United Kingdom
³ Newcastle University Medical School, United Kingdom

^* To whom correspondence should be addressed. E-mail: a.d.rowan{at}ncl.ac.uk.

Accepted 6 April 2005

Abstract

Objective: We have previously reported that chondrocyte membranes exhibit an aggrecanase activity. Here we determine whether the combination of oncostatin M (OSM) and tumour necrosis factor (TNF& [alpha]) induces this activity, determine the effects of transforming growth factor 1 (TGF1), interleukin-4 (IL-4) and tissue inhibitor of metalloproteinases (TIMPs) on this activity, and determine whether this activity is due to a known 'A Disintegrin And Metalloproteinase with ThromboSpondin motifs' (ADAMTS) aggrecanase.

Methods: Aggrecanase activity and the ability of agents to prevent the membrane-associated aggrecanase activity were assessed by Western blot using an antibody that recognizes the specific aggrecan neoepitope generated by aggrecanases. The expression of known aggrecanases was measured by real-time polymerase chain reaction in bovine nasal and human articular chondrocytes.

Results: Enhanced chondrocyte membrane-associated aggrecanase activity and increased mRNA expression of ADAMTS-1, -4, -5 and -9, but not ADAMTS-8 or -15, were observed after stimulation by OSM+TNF in bovine chondrocytes. The membrane-associated aggrecanase activity was inhibited by TIMP-3. In human chondrocytes, OSM+TNF also enhanced ADAMTS-1 and -4 expression, but not other ADAMTSs. TNF alone markedly induced ADAMTS-9 expression, whilst OSM addition caused suppression. Both TGF1 and IL-4 markedly blocked the membrane-associated aggrecanase activity and decreased OSM+TNF-induced expression of ADAMTS-9 in bovine and human chondrocytes. IL-4 markedly down-regulated ADAMTS-4 mRNA, whilst TGF& [beta]1 increased this expression in both bovine and human chondrocytes.

Conclusions: We confirm that OSM+TNF up- regulates a membrane-associated aggrecanase activity as well as several ADAMTS aggrecanase mRNAs in chondrocytes. The chondroprotective effects of IL-4 and TIMP-3 suggest they may have therapeutic benefit for aggrecanolysis whilst the differential inhibitory effects of TGF1 may limit its therapeutic potential. Our data indicate that the induced membrane- associated aggrecanase activity is distinct from known soluble ADAMTS aggrecanases and therefore merits further investigation.

Keywords: ADAMTS, TIMP, aggrecanase, chondrocyte, membrane

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