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. 2005 May 5;64(11):1624–1632. doi: 10.1136/ard.2004.028191

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

W Hui 1, H Barksby 1, D Young 1, T Cawston 1, N McKie 1, A Rowan 1
PMCID: PMC1755260  PMID: 15883123

Abstract

Objective: To determine whether oncostatin M (OSM) + tumour necrosis factor α (TNFα) induces aggrecanase activity in chondrocyte membranes, to determine the effects of transforming growth factor ß1 (TGFß1), interleukin 4 (IL4), and tissue inhibitor of metalloproteinases (TIMPs) on this activity, and to determine whether this activity is due to a known ADAMTS aggrecanase.

Methods: Aggrecanase activity and ability of agents to prevent membrane associated aggrecanase activity were assessed by Western blotting. Expression of known aggrecanases was measured by real time polymerase chain reaction in bovine nasal and human articular chondrocytes.

Results: Chondrocyte membrane associated aggrecanase activity and increased mRNA expression of ADAMTS-1, -4, -5, and -9, but not ADAMTS-4 or -15, were enhanced after stimulation by OSM+TNFα in bovine chondrocytes. This activity was inhibited by TIMP-3. In human chondrocytes, OSM+TNFα also enhanced ADAMTS-1 and -4 expression, but not that of other ADAMTSs. TNFα alone induced ADAMTS-9 expression, whereas OSM addition caused suppression. Both TGFß1 and IL4 blocked membrane associated aggrecanase activity and decreased OSM+TNFα-induced expression of ADAMTS-9 in bovine and human chondrocytes. IL4 down regulated ADAMTS-4 mRNA, whereas TGFß1 increased this expression in both bovine and human chondrocytes.

Conclusions: OSM+TNFα up regulates membrane associated aggrecanase activity and several ADAMTS aggrecanase mRNAs in chondrocytes. The chondroprotective effects of IL4 and TIMP-3 suggest that they may have therapeutic benefit for aggrecanolysis, whereas the differential inhibitory effects of TGFß1 may limit its therapeutic potential. Induced membrane associated aggrecanase activity is distinct from known soluble ADAMTS aggrecanases and merits further investigation.

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Figure 1.

Figure 1

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 Effect of cytokines and TIMPs on chondrocyte membrane associated aggrecanase activity. Bovine nasal chondrocytes were cultured until 80–90% confluence, serum starved overnight, and then stimulated with various cytokines individually or in combination for 24 hours. Harvested cells were lysed and the plasma membrane fraction enriched by density centrifugation. Membranes (50–100 µg) were incubated with deglycosylated aggrecan (100 µg) at 37°C for 16 hours. Aggrecanase activity was examined by Western blot using an antibody (R663) that recognises the neoepitope generated after cleavage of aggrecan at the Glu373–Ala374 bond. (A) Effect of cytokine dose on the membrane activity; (B) effect of TGFß1 (15 ng/ml) or IL4 (25 ng/ml) inclusion in the 24 hour chondrocyte stimulation; (C) the effect of TIMP-1, -2, and -3 (0.1, 0.5, or 1.5 µg), added for 30 minutes at room temperature before the addition of substrate. The data shown are representative of three separate chondrocyte preparations.

Figure 2.

Figure 2

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 Effects of OSM and TNFα on the expression of ADAMTS aggrecanases in chondrocytes. Bovine nasal or human articular chondrocytes were cultured until 80–90% confluence and then serum starved overnight. Cells were stimulated with OSM, TNFα alone or in combination for 24 hours. Total RNA was isolated, reverse transcribed, and the resulting cDNA used in a separate real time PCR with specific primers for ADAMTS-1, -4, -5, -8, -9, or -15. No signal was detected for ADAMTS-8 in human chondrocytes with any treatment. Results were normalised to either 18S (for bovine) or GAPDH (for human) and are presented graphically as relative mRNA levels.48 The data shown are representative of two separate chondrocyte preparations.

Figure 3.

Figure 3

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 Effects of TGFß1 on OSM+TNFα-induced ADAMTS aggrecanases. Bovine nasal or human articular chondrocytes were stimulated with OSM+TNFα (both at 10 ng/ml)±TGFß1 for 24 hours. Real time PCR was performed on isolated RNA, and the normalised results presented graphically as described in fig 2. No signal was detected for ADAMTS-8 in human chondrocytes with any treatment. The data shown are representative of two separate chondrocyte preparations.

Figure 4.

Figure 4

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 Effects of IL4 on OSM+TNFα-induced ADAMTS aggrecanases. Bovine nasal or human articular chondrocytes were stimulated with OSM+TNFα (both at 10 ng/ml) ± IL4 for 24 hours. Real time PCR was performed on isolated RNA, and the normalised results presented graphically as described in fig 2. No signal was detected for ADAMTS-8 in human chondrocytes with any treatment. The data shown are representative of two separate chondrocyte preparations.

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