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J. Biol. Chem., Vol. 278, Issue 52, 53063-53071, December 26, 2003

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Age-related Changes in the Response of Human Articular Cartilage to IL-1 and Transforming Growth Factor- (TGF-)

CHONDROCYTES EXHIBIT A DIMINISHED SENSITIVITY TO TGF-^*

Mark S. Hickery, Michael T. Bayliss¶, Jayesh Dudhia¶, Joanne C. Lewthwaite¶, Jo C. W. Edwards||, and Andrew A. Pitsillides^**¶

From the Department of Cell and Molecular Biology, Section for Connective Tissue Research, BMC C12, 221 84, Lund, Sweden, the ^¶Department of Veterinary Basic Sciences, The Royal Veterinary College, University of London, London NW1 0TU, and the ^||Department of Rheumatology, University College London School of Medicine, London W1P 9PG, United Kingdom

Cartilage glycosaminoglycan (GAG) synthesis and composition, upon which its structural integrity depends, varies with age, is modified by anabolic and catabolic stimuli, and is regulated by UDP-glucuronate availability. However, how such stimuli, prototypically represented by transforming growth factor-1 (TGF-1) and IL-1, modify GAG synthesis during aging of normal human articular cartilage is not known. Using explants, we show that chondroitin sulfate (CS):total GAG ratios decrease, whereas C6S:C4S ratios increase with cartilage maturation, and that chondrocytes in the cartilage mid-zone, but not the superficial or deep zones, exhibit uridine 5'-diphosphoglucose dehydrogenase (UDPGD) activity, which is also increased in mature cartilage. We also show that IL-1 treatment reduces both total GAG and CS synthesis, decreases C6S:C4S ratios (less C6S), but fails to modify chondrocyte UDPGD activity at all ages. On the other hand, TGF-1 increases total GAG synthesis in immature, but not mature, cartilage (stimulates CS but not non-CS), age-independently decreases C6S:C4S (more C4S), and increases chondrocyte UDPGD activity in a manner inversely correlated with age. Our findings show that TGF-1, but not IL-1, modifies matrix synthesis such that its composition more closely resembles "less mature" articular cartilage. These effects of TGF-1, which appear to be restricted to periods of skeletal immaturity, are closely associated although not necessarily mechanistically linked with increases in chondrocyte UDPGD activity. The antianabolic effects of IL-1 are, on the other hand, likely to be independent of any direct modification in UDPGD activity and manifest equally in human cartilage of all ages.

Received for publication, September 19, 2002 , and in revised form, September 15, 2003.

^* This work was supported by grants from the Arthritis Research Campaign and The Wellcome Trust. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Present address: Cartela AB, Biomedical Centre, I12, 221 84, Lund, Sweden.

^¶ To whom correspondence should be addressed. Tel.: 44-20-7468-5000; Fax: 44-20-7388-1027; E-mail: apitsill{at}rvc.ac.uk.

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