Age-related changes in human bone proteoglycan structure - Impact of osteogenesis imperfecta
Age-related changes in human bone proteoglycan structure - Impact of osteogenesis imperfecta
复制标题
DOI：
10.1074/jbc.m202124200
复制
发表时间：
2002-11-15
影响因子：
4.8
通讯作者：
Fedarko, NS
中科院分区：
文献类型：
--
作者：
Grzesik, WJ;Frazier, CR;Fedarko, NS
蛋白聚糖（PG）是经历广泛的翻译后修饰的分子家族，所述修饰包括向蛋白质核心添加糖胺聚糖（GAG）链以及N-和0-连接的寡糖。据报道，PG的组成和结构随年龄而改变。为了测试PG的翻译后修饰是否可以作为实际年龄的体外替代终点标志物，测定了14名供体（年龄范围，胎儿至60岁）正常人骨细胞衍生的PG的GAG修饰程度。用（SO42-）-S-35和[H-3] GlcN对分离的细胞进行稳态放射性标记。对于双糖链蛋白聚糖和核心蛋白聚糖，艾杜糖醛酸含量与年龄呈线性相关（在胎儿和60岁之间增加1.5倍）。对于syndecan样硫酸乙酰肝素PG，出生后细胞的N-硫酸化增加超过3.5倍，直到在生命的第40年期间达到平台。O-连接的低聚糖的量也被发现减少作为增加正常供体年龄的函数，而代谢前体池的比活性保持恒定，无论供体年龄。这些与年龄相关的翻译后修饰的变化，然后被用来证明，成骨细胞来源于成骨细胞没有表现出一个过早老化的方面，而是在胎儿样的表型状态被捕。富含血小板反应蛋白的生长基质改变了成骨细胞中的PG代谢，导致产生和分泌胎儿样（富含O-连接寡糖）形式的核心蛋白聚糖和双糖蛋白聚糖。这种作用与转化生长因子-β的作用在性质上不同，转化生长因子-β主要改变GAG而不是O-连接寡糖。没有其他Arg-Gly-Asp蛋白（纤连蛋白、玻连蛋白、I型胶原、骨桥蛋白和骨唾液酸蛋白）对骨细胞中PG代谢有任何可检测的影响。这些结果表明，一个适当的基质化学计量是至关重要的前列腺素代谢。
Proteoglycans (PGs) are a family of molecules that undergo extensive post-translational modifications that include addition of glycosaminoglycan (GAG) chains as well as N- and O-linked oligosaccharides to the protein core. PG composition and structure have been reported to alter with age. To test whether the post-translational modifications to PGs can serve as in vitro surrogate end point markers for chronological age, the extent of GAG modifications was determined for PGs derived from normal human bone cells of 14 donors (age range, fetal to 60 years). Isolated cells were steady state radiolabeled with (SO42-)-S-35 and [H-3]GlcN. For biglycan and decorin, iduronate content was linearly correlated with age (increased 1.5X between fetal and age 60 years). For the syndecan-like heparan sulfate PG, the N-sulfation of post-natal cells increased over 3.5-fold until reaching a plateau during the 4th decade of life. The amount of O-linked oligosaccharides was also found to decrease as a function of increasing normal donor age, whereas the specific activity of the metabolic precursor pool remained constant regardless of donor age. These age-related changes in post-translational modifications were then used to demonstrate that osteoblasts derived from patients with osteogenesis imperfecta did not exhibit facets of a pre-mature aging, but rather were arrested in a fetal-like phenotypic state. A growth matrix rich in thrombospondin altered PG metabolism in osteoblastic cells, resulting in the production and secretion of the fetal-like (rich in O-linked oligosaccharides) forms of decorin and biglycan. This effect was qualitatively different from the effect of transforming growth factor-beta, which predominantly altered GAGs rather than O-linked oligosaccharides. No other Arg-Gly-Asp protein (fibronectin, vitronectin, type I collagen, osteopontin, and bone sialoprotein) showed any detectable effect on PG metabolism in bone cells. These results indicate that a proper matrix stoichiometry is critical for metabolism of PGs.