Hickery Mark S, Bayliss Michael T, Dudhia Jayesh, Lewthwaite Joanne C, Edwards Jo C W, Pitsillides Andrew A
Department of Cell and Molecular Biology, Section for Connective Tissue Research, BMC C12, 221 84, Lund, Sweden.
J Biol Chem. 2003 Dec 26;278(52):53063-71. doi: 10.1074/jbc.M209632200. Epub 2003 Sep 17.
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.
软骨糖胺聚糖（GAG）的合成及组成决定其结构完整性，会随年龄变化，受合成代谢和分解代谢刺激的影响，并受尿苷二磷酸葡萄糖醛酸（UDP - 葡萄糖醛酸）可用性的调节。然而，以转化生长因子 - β1（TGF - β1）和白细胞介素 - 1α（IL - 1α）为典型代表的此类刺激如何在正常人关节软骨老化过程中改变GAG合成尚不清楚。通过外植体实验，我们发现随着软骨成熟，硫酸软骨素（CS）与总GAG的比例下降，而C6S与C4S的比例增加，并且软骨中层区域的软骨细胞（而非表层或深层区域）表现出尿苷5'-二磷酸葡萄糖脱氢酶（UDPGD）活性，该活性在成熟软骨中也会增加。我们还表明，IL - 1α处理会降低总GAG和CS的合成，降低C6S与C4S的比例（C6S减少），但在所有年龄段均未能改变软骨细胞的UDPGD活性。另一方面，TGF - β1可增加未成熟软骨（而非成熟软骨）中的总GAG合成（刺激CS但不刺激非CS），与年龄无关地降低C6S与C4S的比例（C4S增加），并以与年龄呈负相关的方式增加软骨细胞的UDPGD活性。我们的研究结果表明，TGF - β1而非IL - 1α会改变基质合成，使其组成更类似于“不太成熟”的关节软骨。TGF - β1的这些作用似乎仅限于骨骼未成熟时期，与软骨细胞UDPGD活性的增加密切相关，尽管不一定存在机制上的联系。另一方面，IL - 1α的合成代谢抑制作用可能与UDPGD活性的任何直接改变无关，并且在所有年龄段的人体软骨中均有同等表现。
