Balenga Nariman, Koh James, Azimzadeh Pedram, Hogue Joyce, Gabr Mostafa, Stains Joseph P, Olson John A
Division of General and Oncologic Surgery, Department of Surgery, University of Maryland School of Medicine, Baltimore, MD, USA.
Department of Surgery, University of California at San Francisco, San Francisco, CA, USA.
J Bone Miner Res. 2019 May;34(5):955-963. doi: 10.1002/jbmr.3674. Epub 2019 Feb 28.
The relationship between impaired calcium sensing, dysregulated parathyroid hormone (PTH) secretion, and parathyroid cell proliferation in parathyroid neoplasia is not understood. We previously reported that a GTPase activating protein, regulator of G-protein signaling 5 (RGS5) is overexpressed in a subset of parathyroid tumors associated with primary hyperparathyroidism (PHPT) and that RGS5 can inhibit signaling from the calcium-sensing receptor (CASR). In vivo, we found that RGS5-null mice have abnormally low PTH levels. To gain a better understanding of the potential role of RGS5 overexpression in parathyroid neoplasia and PHPT and to investigate whether inhibition of CASR signaling can lead to parathyroid neoplasia, we created and characterized a transgenic mouse strain overexpressing RGS5 specifically in the parathyroid gland. These mice develop hyperparathyroidism, bone changes reflective of elevated PTH, and parathyroid neoplasia. Further, expression of exogenous RGS5 in normal human parathyroid cells results in impaired signaling from CASR and negative feedback on PTH secretion. These results provide evidence that RGS5 can modulate signaling from CASR and support a role for RGS5 in the pathogenesis of PHPT through inhibition of CASR signaling. © 2019 American Society for Bone and Mineral Research.
甲状旁腺肿瘤中钙感知受损、甲状旁腺激素（PTH）分泌失调与甲状旁腺细胞增殖之间的关系尚不清楚。我们之前报道过，一种GTP酶激活蛋白，即G蛋白信号调节因子5（RGS5），在与原发性甲状旁腺功能亢进症（PHPT）相关的一部分甲状旁腺肿瘤中过表达，并且RGS5可以抑制钙敏感受体（CASR）的信号传导。在体内，我们发现RGS5基因敲除小鼠的PTH水平异常低。为了更好地理解RGS5过表达在甲状旁腺肿瘤和PHPT中的潜在作用，并研究抑制CASR信号传导是否会导致甲状旁腺肿瘤，我们创建并鉴定了一种在甲状旁腺中特异性过表达RGS5的转基因小鼠品系。这些小鼠出现甲状旁腺功能亢进、反映PTH升高的骨骼变化以及甲状旁腺肿瘤。此外，在正常人甲状旁腺细胞中外源RGS5的表达导致CASR信号传导受损以及对PTH分泌的负反馈。这些结果提供了证据，证明RGS5可以调节CASR的信号传导，并支持RGS5通过抑制CASR信号传导在PHPT发病机制中的作用。© 2019美国骨与矿物质研究学会。
