Hickery, MS; Bayliss, MT; Dudhia, J; Lewthwaite, JC; Edwards, JC; Pitsillides, AA; (2003) Age-related changes in the response of human articular cartilage to IL-1alpha and transforming growth factor-beta (TGF-beta): chondrocytes exhibit a diminished sensitivity to TGF-beta. Journal of Biological Chemistry , 278 (52) 53063 - 53071.
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-beta1 (TGF-beta1) and IL-1alpha, 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-1alpha 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-beta1 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-beta1, but not IL-1alpha, modifies matrix synthesis such that its composition more closely resembles "less mature" articular cartilage. These effects of TGF-beta1, 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-1alpha 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
|Title:||Age-related changes in the response of human articular cartilage to IL-1alpha and transforming growth factor-beta (TGF-beta): chondrocytes exhibit a diminished sensitivity to TGF-beta|
|Open access status:||An open access publication|
|Additional information:||DA - 20031222 IS - 0021-9258 LA - eng PT - Journal Article RN - 0 (Glycosaminoglycans) RN - 0 (Interleukin-1) RN - 0 (Proteoglycans) RN - 0 (Recombinant Proteins) RN - 0 (Sulfates) RN - 0 (Transforming Growth Factor beta) RN - 0 (transforming growth factor beta1) RN - 58-98-0 (Uridine Diphosphate) RN - 9007-28-7 (Chondroitin Sulfates) RN - EC 188.8.131.52 (Uridine Diphosphate Glucose Dehydrogenase) SB - IM|
|Keywords:||activity, adolescent, adult, age, Aged, Aging, beta, Cartilage, Cartilage, Articular, Cells, Cultured, chemistry, chondrocytes, CHONDROITIN SULFATE, Chondroitin Sulfates, COMPOSITION, effects, FACTOR-BETA, Gene Expression Regulation, Glucose, Glycosaminoglycans, growth, GROWTH FACTOR, GROWTH FACTOR BETA, GROWTH-FACTOR, GROWTH-FACTOR-BETA, Hand, IM, INCREASE, INCREASES, Interleukin-1, LA, LESS, MATRIX, maturation, metabolism, Middle Aged, Other, PROTEIN, Proteins, PROTEOGLYCAN, Proteoglycans, RATIO, recombinant, Recombinant Proteins, response, Sensitivity, Skeletal, structural, structural integrity, Sulfates, Support, Non-U.S.Gov't, synthesis, TGF BETA, TGF-BETA, Time Factors, transforming growth factor, Transforming Growth Factor beta, transforming growth factor-beta, treatment, Uridine Diphosphate, Uridine Diphosphate Glucose Dehydrogenase|
|UCL classification:||UCL > School of Life and Medical Sciences > Faculty of Medical Sciences > Medicine (Division of)|
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