Intracellular biosynthesis of lipids and cholesterol by Scap and Insig in mesenchymal cells regulates long bone growth and chondrocyte homeostasis.
Intracellular biosynthesis of lipids and cholesterol by Scap and Insig in mesenchymal cells regulates long bone growth and chondrocyte homeostasis.
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DOI：
10.1242/dev.162396
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发表时间：
2018-07-09
期刊：
影响因子：
--
通讯作者：
Alman BA
中科院分区：
文献类型：
--
作者：
Tsushima H;Tang YJ;Puviindran V;Hsu SC;Nadesan P;Yu C;Zhang H;Mirando AJ;Hilton MJ;Alman BA
在软骨内骨化过程中，间充质细胞表达调节细胞内胆固醇和脂质生物合成的基因。在这里，我们研究了Scap或Insig1和Insig2的条件性缺失（Scap抑制细胞内生物合成，Insig蛋白激活细胞内生物合成）。在间充质祖细胞中缺乏Scap的小鼠中，间充质凝聚和软骨形成被破坏，而在间充质祖细胞中缺乏Insig基因的小鼠四肢短，但软骨形成正常。软骨细胞中缺乏Scap的小鼠表现出严重的侏儒症和异位肥大细胞，而软骨细胞中Insig基因的缺失导致轻度侏儒症和肥大区缩短。体外研究表明，软骨细胞中的细胞内胆固醇可以来自外源性和内源性来源，但外源性来源不能完全克服Scap缺乏的表型效应。编码胆固醇生物合成蛋白的基因受Hedgehog（Hh）信号传导的调节，并且Hh信号传导也受软骨细胞中的细胞内胆固醇的调节，这表明软骨细胞分化中存在反馈回路。软骨细胞稳态和长骨生长需要细胞内生物合成的精确调节，这些数据支持胆固醇生物合成的药理学调节作为选择软骨病变的治疗。总结：在间充质细胞或软骨细胞中调节细胞内胆固醇生物合成的基因的条件性缺失表明生物合成的精确调节是软骨细胞稳态和长骨生长所需的。
During enchondral ossification, mesenchymal cells express genes regulating the intracellular biosynthesis of cholesterol and lipids. Here, we have investigated conditional deletion of Scap or of Insig1 and Insig2 (Scap inhibits intracellular biosynthesis and Insig proteins activate intracellular biosynthesis). Mesenchymal condensation and chondrogenesis was disrupted in mice lacking Scap in mesenchymal progenitors, whereas mice lacking the Insig genes in mesenchymal progenitors had short limbs, but normal chondrogenesis. Mice lacking Scap in chondrocytes showed severe dwarfism, with ectopic hypertrophic cells, whereas deletion of Insig genes in chondrocytes caused a mild dwarfism and shortening of the hypertrophic zone. In vitro studies showed that intracellular cholesterol in chondrocytes can derive from exogenous and endogenous sources, but that exogenous sources cannot completely overcome the phenotypic effect of Scap deficiency. Genes encoding cholesterol biosynthetic proteins are regulated by Hedgehog (Hh) signaling, and Hh signaling is also regulated by intracellular cholesterol in chondrocytes, suggesting a feedback loop in chondrocyte differentiation. Precise regulation of intracellular biosynthesis is required for chondrocyte homeostasis and long bone growth, and these data support pharmacological modulation of cholesterol biosynthesis as a therapy for select cartilage pathologies. Summary: Conditional deletion of genes that regulate intracellular cholesterol biosynthesis in mesenchymal cells or chondrocytes shows that precise regulation of biosynthesis is required for chondrocyte homeostasis and long bone growth.
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影响因子：
3.5
作者：
Gofflot, F;Hars, C;Roux, C
通讯作者：
Roux, C
影响因子：
4.2
作者：
Dietschy, JM
通讯作者：
Dietschy, JM
影响因子：
56.9
作者：
Porter, JA;Young, KE;Beachy, PA
通讯作者：
Beachy, PA
DOI：
10.1073/pnas.96.20.11041
发表时间：
1999-09-28
影响因子：
11.1
作者：
Brown, MS;Goldstein, JL
通讯作者：
Goldstein, JL
影响因子：
3.7
作者：
CORWIN, LM;HUMPHREY, LP;SHLOSS, J
通讯作者：
SHLOSS, J