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Menin Inactivation Leads to Loss of Transforming Growth Factor ß Inhibition of Parathyroid Cell Proliferation and Parathyroid Hormone Secretion

¹ Division of Endocrinology/Metabolism, Neurology and Hematology/Oncology, Department of Clinical Molecular Medicine and ² Division of Molecular Pathology, Department of Biomedical Informatics, Kobe University Graduate School of Medicine, Kobe, Japan; ³ Tumor Endocrinology Project, National Cancer Center Research Institute, Tokyo, Japan; and ⁴ Departments of Medicine, Physiology, and Human Genetics, McGill University and Royal Victoria Hospital, Montreal, Quebec, Canada

Primary hyperparathyroidism is a common endocrine disorder caused by parathyroid gland enlargement and excessive parathyroid hormone (PTH) secretion. However, the precise mechanisms of tumorigenesis of the parathyroids are unknown. Here we have investigated the roles of transforming growth factor (TGF)-ß and menin, the product of the multiple endocrine neoplasia type 1 (Men1) gene, in the proliferation and PTH production of parathyroid cells from either patients with secondary hyperparathyroidism or Men1. TGF-ß was expressed in the parathyroid endocrine cells. Addition of TGF-ß to parathyroid cells from patients with secondary hyperparathyroidism inhibited their proliferation and PTH secretion. These responses to TGF-ß were lost when menin was specifically inactivated by antisense oligonucleotides. Moreover, TGF-ß did not affect the proliferation and PTH production of parathyroid cells from a Men1 patient. These results indicate that menin is required for TGF-ß action in the parathyroid. We conclude that TGF-ß is an important autocrine/paracrine negative regulator of parathyroid cell proliferation and PTH secretion and that loss of TGF-ß signaling due to menin inactivation contributes to parathyroid tumorigenesis.

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