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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

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. Gold open access

Abstract

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

Type:Article
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 1.1.1.22 (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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