Parathyroid‐targeted overexpression of Regulator of G‐Protein Signaling 5 (RGS5) causes hyperparathyroidism in transgenic mice

Abstract

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 abnormal PTH secretion. 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 over‐expressing 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 supporting the setpoint hypothesis of parathyroid neoplasia and define a role for RGS5 in the pathogenesis of PHPT through inhibition of CASR signaling.Support or Funding InformationPhRMA Foundation and American Cancer Society research grants.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.