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 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.

Primary and secondary hyperparathyroidism present different expressions of calcium-sensing receptor

“…Deficient calcium sensing and disrupted feedback to PTH occur early in the pathogenic process of parathyroid cells’ hyperplastic expansion [ 14 ]. Koh et al have shown that abnormal upregulation of the Regulator Of G Protein Signaling 5 ( RGS5 ) gene can influence CaSR signaling in the PHPT [ 4 , 15 ]. Furthermore, vitro study has demonstrated that the Glial Cells Missing Transcription Factor 2 (GCM2) protein regulates the CaSR expression [ 16 ].…”

“…Furthermore, vitro study has demonstrated that the Glial Cells Missing Transcription Factor 2 (GCM2) protein regulates the CaSR expression [ 16 ]. In PHPT, impaired calcium sensing results in elevated PTH secretion and parathyroid neoplasia [ 15 ].…”

“…Likewise, a high level of CaSR expression reduction was also observed in PHPT, however, most likely due to inherited or acquired genetic mutation-associated aberrant stimulation of parathyroid glands [12]. Cyclin D1 Of G Protein Signaling 5 (RGS5) gene can influence CaSR signaling in the PHPT [4,15]. Furthermore, vitro study has demonstrated that the Glial Cells Missing Transcription Factor 2 (GCM2) protein regulates the CaSR expression [16].…”

“…Furthermore, vitro study has demonstrated that the Glial Cells Missing Transcription Factor 2 (GCM2) protein regulates the CaSR expression [16]. In PHPT, impaired calcium sensing results in elevated PTH secretion and parathyroid neoplasia [15]. Differences in the extent of CaSR reduction in PHPT and SHPT compared to healthy control suggest an involvement of diverse pathomechanisms.…”

Effect of Regulator of G Protein Signaling Proteins on Bone

“…By creating the transgenic mouse with overexpression of RGS5 in the parathyroid gland, the authors found that these mice showed hyperparathyroidism and increased bone mass. Further, the forced overexpression of RGS5 in parathyroid cells impaired CASR signaling and negatively feedback on PTH secretion, demonstrating that RGS5 plays a critical role in bone formation through regulating PTH and CASR signaling (51).…”