Age-related osteoporosis in biglycan-deficient mice is related to defects in bone marrow stromal cells
Age-related osteoporosis in biglycan-deficient mice is related to defects in bone marrow stromal cells
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DOI：
10.1359/jbmr.2002.17.2.331
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发表时间：
2002-02-01
影响因子：
6.2
通讯作者：
Young, MF
中科院分区：
文献类型：
--
作者：
Chen, XD;Shi, ST;Young, MF
双糖链蛋白聚糖（bgn）是一种细胞外基质蛋白聚糖，在骨骼及其他骨骼结缔组织中含量丰富。此前，我们培育出了bgn基因缺陷型小鼠，并发现它们会出现年龄相关性骨质减少。为了确定可能导致这种进行性骨质疏松的细胞事件，我们测量了正常小鼠和突变小鼠骨髓中骨生成前体细胞的数量。集落数量可反映成纤维细胞集落形成单位（CFU - F）的潜能，该数量随年龄增长逐渐减少。到24周龄时，bgn基因敲除（KO）小鼠的集落形成数量比野生型（wt）小鼠显著减少得更多。这种与年龄相关的减少与先前通过对24周龄bgn KO小鼠进行X射线分析和组织学检查所显示的严重骨质减少情况相符。由于先前已表明bgn可结合并调节转化生长因子β（TGF - β）的活性，我们还探究了这种生长因子是否会影响集落形成。TGF - β处理显著增加了野生型集落的大小。相比之下，TGF - β对bgn集落的大小没有显著影响。还观察到bgn缺陷型骨髓基质细胞（BMSCs）的凋亡增加。如果增殖减少和凋亡增加这两种情况在体内发生，将会导致成熟成骨细胞生成不足，这足以解释bgn KO小鼠出现的骨质减少现象。bgn KO小鼠在Ⅰ型胶原信使核糖核酸（mRNA）和蛋白质的合成方面也存在缺陷。这一结果支持了这样一种观点，即细胞外基质的组成可能受包括bgn在内的特定基质成分的调节。
Biglycan (bgn) is an extracellular matrix proteoglycan that is enriched in bone and other skeletal connective tissues. Previously, we generated bgn-deficient mice and showed that they developed age-dependent osteopenia. To identify the cellular events that might contribute to this progressive osteoporosis, we measured the number of osteogenic precursors in the bone marrow of normal and mutant mice. The number of colonies, indicative of the colony-forming unit potential of fibroblasts (CFU-F), gradually decreased with age. By 24 weeks of age, colony formation in the bgn knockout (KO) mice was significantly more reduced than that in the wild type (wt) mice. This age-related reduction was consistent with the extensive osteopenia previously shown by X-ray analysis and histological examination of 24-week-old bgn KO mice. Because bgn has been shown previously to bind and regulate transforming growth factor beta (TGF-beta) activity, we also asked whether this growth factor would affect colony formation. TGF-beta treatment significantly increased the size of the wt colonies. In contrast, TGF-beta did not significantly influence the size of the bgn colonies. An increase in apoptosis in bgn-deficient bone marrow stromal cells (BMSCs) was observed also. The combination of decreased proliferation and increased apoptosis, if it occurred in vivo, would lead to a deficiency in the generation of mature osteoblasts and would be sufficient to account for the osteopenia developed in the bgn KO mice. The bgn KO mice also were defective in the synthesis of type I collagen messenger RNA (mRNA) and protein. This result supports the suggestion that the composition of the extracellular matrix may be regulated by specific matrix components including bgn.