Developmental and Regenerative Biology, School of Biomedical Sciences, The Chinese University of Hong Kong, Shatin, Hong Kong.
J Bone Miner Res. 2018 Jun;33(6):1183-1195. doi: 10.1002/jbmr.3413. Epub 2018 Mar 24.
Bone formation and bone homeostasis are energy-expensive processes. How they are being regulated by energy needs is not completely understood. This is of high clinical importance because diabetic-induced bone loss is common whereas the underlying mechanisms are unclear. Here, we show that Mst1/2 are important regulators for glucose uptake during osteoblast differentiation. Genetically removal of both Mst1/2 kinases simultaneously in mice in early and mature osteoblasts inhibits bone formation and bone remodeling, respectively. We found that the activity of Mst1/2 kinases is sensitive to glucose levels, and in turn, regulates glucose uptake by stabilizing key glucose transporter Glut1. In the absence of Mst1/2 kinases, Glut1 expression is loss and results in AMP-dependent protein kinase (AMPK) activation and subsequent proteasomal degradation of Runx2. The streptozotocin (STZ)-induced diabetic mouse model also recapitulates similar changes in the bone tissues. In addition, Glut1 expression regulated by Mst1/2 kinases is independent of Yap/Taz expression. Our results unravel new mechanistic insights into the orchestration of glucose level and bone homeostasis. © 2018 American Society for Bone and Mineral Research.
骨形成和骨内稳态是能量消耗过程。它们如何被能量需求所调节还不完全清楚。这具有重要的临床意义，因为糖尿病引起的骨丢失很常见，但其潜在机制尚不清楚。在这里，我们表明 Mst1/2 是成骨细胞分化过程中葡萄糖摄取的重要调节因子。在早期和成熟成骨细胞中，通过基因敲除同时去除两种 Mst1/2 激酶，分别抑制骨形成和骨重塑。我们发现 Mst1/2 激酶的活性对葡萄糖水平敏感，并通过稳定关键葡萄糖转运蛋白 Glut1 来调节葡萄糖摄取。在缺乏 Mst1/2 激酶的情况下，Glut1 的表达丢失，导致 AMP 依赖的蛋白激酶 (AMPK) 激活和随后的 Runx2 蛋白酶体降解。链脲佐菌素 (STZ) 诱导的糖尿病小鼠模型也在骨组织中重现了类似的变化。此外，Mst1/2 激酶调节的 Glut1 表达独立于 Yap/Taz 的表达。我们的研究结果揭示了葡萄糖水平与骨内稳态协调的新机制见解。
