Obesity and Metabolism Laboratory, The Institute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem 9112001, Israel.
Department of Anatomy and Anthropology, Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv 69978, Israel.
Cells. 2021 Feb 17;10(2):414. doi: 10.3390/cells10020414.
The renal proximal tubule cells (RPTCs), well-known for maintaining glucose and mineral homeostasis, play a critical role in the regulation of kidney function and bone remodeling. Deterioration in RPTC function may therefore lead to the development of diabetic kidney disease (DKD) and osteoporosis. Previously, we have shown that the cannabinoid-1 receptor (CBR) modulates both kidney function as well as bone remodeling and mass via its direct role in RPTCs and bone cells, respectively. Here we employed genetic and pharmacological approaches that target CBR, and found that its specific nullification in RPTCs preserves bone mass and remodeling both under normo- and hyper-glycemic conditions, and that its chronic blockade prevents the development of diabetes-induced bone loss. These protective effects of negatively targeting CBR specifically in RPTCs were associated with its ability to modulate erythropoietin (EPO) synthesis, a hormone known to affect bone mass and remodeling. Our findings highlight a novel molecular mechanism by which CBR in RPTCs remotely regulates skeletal homeostasis via a kidney-to-bone axis that involves EPO.
肾近端小管细胞（RPTC）以维持葡萄糖和矿物质内稳态而闻名，在调节肾功能和骨骼重塑中起着关键作用。因此，RPTC 功能的恶化可能导致糖尿病肾病（DKD）和骨质疏松症的发生。此前，我们已经表明，大麻素-1 受体（CBR）通过其在 RPTC 和骨细胞中的直接作用分别调节肾脏功能和骨骼重塑和质量。在这里，我们采用了针对 CBR 的遗传和药理学方法，发现其在 RPTC 中的特异性缺失在正常血糖和高血糖条件下均可保留骨量和重塑，而其慢性阻断可预防糖尿病引起的骨丢失。这些针对 RPTC 中 CBR 的负向靶向的保护作用与其调节促红细胞生成素（EPO）合成的能力有关，EPO 是一种已知影响骨量和重塑的激素。我们的研究结果强调了一种新的分子机制，即通过涉及 EPO 的肾脏到骨骼轴，RPTC 中的 CBR 远程调节骨骼内稳态。
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