Endochondral ossification, an important process in vertebrate bone formation, is highly dependent on correct functioning of growth plate chondrocytes1. Proliferation of these cells determines longitudinal bone growth and the matrix deposited provides a scaffold for future bone formation. However, these two energy-dependent anabolic processes occur in an avascular environment1,2. In addition, the centre of the expanding growth plate becomes hypoxic, and local activation of the hypoxia-inducible transcription factor HIF-1α is necessary for chondrocyte survival by unidentified cell-intrinsic mechanisms3–6. It is unknown whether there is a requirement for restriction of HIF-1α signalling in the other regions of the growth plate and whether chondrocyte metabolism controls cell function. Here we show that prolonged HIF-1α signalling in chondrocytes leads to skeletal dysplasia by interfering with cellular bioenergetics and biosynthesis. Decreased glucose oxidation results in an energy deficit, which limits proliferation, activates the unfolded protein response and reduces collagen synthesis. However, enhanced glutamine flux increases α-ketoglutarate levels, which in turn increases proline and lysine hydroxylation on collagen. This metabolically regulated collagen modification renders the cartilaginous matrix more resistant to protease-mediated degradation and thereby increases bone mass. Thus, inappropriate HIF-1α signalling results in skeletal dysplasia caused by collagen overmodification, an effect that may also contribute to other diseases involving the extracellular matrix such as cancer and fibrosis.Increased glutamine metabolism caused by unregulated HIF-1α signalling in mouse chondrocytes results in increased post-translational modification of collagen and skeletal dysplasia, demonstrating that strict regulation of HIF-1α signalling in chondrocytes is essential for normal bone growth.

中文翻译：

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HIF-1α 代谢控制软骨细胞中的胶原蛋白合成和修饰

软骨内骨化是脊椎动物骨形成的一个重要过程，高度依赖于生长板软骨细胞的正常功能1。这些细胞的增殖决定了纵向骨生长，沉积的基质为未来的骨形成提供了支架。然而，这两个依赖能量的合成代谢过程发生在无血管环境中 1,2。此外，扩张的生长板的中心变得缺氧，缺氧诱导转录因子 HIF-1α 的局部激活是软骨细胞存活所必需的，这是通过未知的细胞内在机制 3-6。目前尚不清楚是否需要限制生长板其他区域的 HIF-1α 信号传导以及软骨细胞代谢是否控制细胞功能。在这里，我们表明软骨细胞中延长的 HIF-1α 信号通过干扰细胞生物能学和生物合成导致骨骼发育不良。葡萄糖氧化减少导致能量不足，从而限制增殖、激活未折叠蛋白反应并减少胶原蛋白合成。然而，增强的谷氨酰胺通量会增加 α-酮戊二酸水平，从而增加胶原蛋白上的脯氨酸和赖氨酸羟基化。这种代谢调节的胶原蛋白修饰使软骨基质更能抵抗蛋白酶介导的降解，从而增加骨量。因此，不适当的 HIF-1α 信号传导会导致由胶原蛋白过度修饰引起的骨骼发育不良，这种影响也可能导致其他涉及细胞外基质的疾病，如癌症和纤维化。