Fan Yi, Bi Ruiye, Densmore Michael J, Sato Tadatoshi, Kobayashi Tatsuya, Yuan Quan, Zhou Xuedong, Erben Reinhold G, Lanske Beate
*Department of Oral Medicine, Infection and Immunity, Harvard School of Dental Medicine, Boston, Massachusetts, USA; State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, China; West China School of Stomatology, Sichuan University, Chengdu, Sichuan, China; Endocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA; and Institute of Physiology, Pathophysiology and Biophysics, Department of Biomedical Sciences, University of Veterinary Medicine, Vienna, Austria.
*Department of Oral Medicine, Infection and Immunity, Harvard School of Dental Medicine, Boston, Massachusetts, USA; State Key Laboratory of Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, Sichuan, China; West China School of Stomatology, Sichuan University, Chengdu, Sichuan, China; Endocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA; and Institute of Physiology, Pathophysiology and Biophysics, Department of Biomedical Sciences, University of Veterinary Medicine, Vienna, Austria
FASEB J. 2016 Jan;30(1):428-40. doi: 10.1096/fj.15-278184. Epub 2015 Oct 1.
Parathyroid-hormone-type 1 receptor (PTH1R) is extensively expressed in key regulatory organs for systemic mineral ion homeostasis, including kidney and bone. We investigated the bone-specific functions of PTH1R in modulating mineral ion homeostasis by generating a novel mouse model in which PTH1R is ablated in the limb mesenchyme using Prx1Cre transgenic mice. Such ablation decreased FGF23 protein and serum levels by 50%, despite normal Fgf23 mRNA levels in long bones. Circulating calcium and PTH levels were unchanged, but inorganic phosphate and 1,25(OH)2D3 levels were significantly decreased and accompanied by elevated urinary calcium and phosphate wasting. Key renal genes for balancing mineral ion homeostasis, calbindinD28k, Klotho, and Napi2a were suppressed by 30-40%. Intermittent hPTH(1-34) injections increased Fgf23 mRNA (7.3-fold), Nurr1 mRNA (3.1-fold), and serum intact-FGF23 (1.6-fold) in controls, but failed to induce Fgf23, Nurr1 mRNA, or intact FGF23 production in mutants. Moreover, a significant elevation in serum C-terminal-FGF23 levels (4-fold) was detected in both genotypes. PTH markedly downregulated Galnt3 expression (2.7-fold) in controls but not in mutants. These results demonstrate the pivotal role of PTH1R in long bones to regulate systemic mineral ion homeostasis and the direct induction of FGF23 by PTH1R signaling.
甲状旁腺激素1型受体（PTH1R）在全身矿物质离子稳态的关键调节器官中广泛表达，包括肾脏和骨骼。我们通过利用Prx1Cre转基因小鼠构建一种新型小鼠模型，其中PTH1R在肢体间充质中被敲除，来研究PTH1R在调节矿物质离子稳态中的骨骼特异性功能。尽管长骨中Fgf23 mRNA水平正常，但这种敲除使FGF23蛋白和血清水平降低了50%。循环钙和甲状旁腺激素水平未发生变化，但无机磷酸盐和1,25(OH)2D3水平显著降低，并伴有尿钙和磷酸盐排泄增加。平衡矿物质离子稳态的关键肾脏基因，钙结合蛋白D28k、Klotho和Napi2a被抑制了30 - 40%。间歇性注射hPTH(1 - 34)可使对照组的Fgf23 mRNA（7.3倍）、Nurr1 mRNA（3.1倍）和血清完整FGF23（1.6倍）增加，但在突变体中未能诱导Fgf23、Nurr1 mRNA或完整FGF23的产生。此外，在两种基因型中均检测到血清C末端FGF23水平显著升高（4倍）。甲状旁腺激素在对照组中显著下调Galnt3表达（2.7倍），但在突变体中则不然。这些结果证明了PTH1R在长骨中调节全身矿物质离子稳态的关键作用以及PTH1R信号对FGF23的直接诱导作用。
