NUCLEAR PARATHYROID HORMONE‐RELATED PROTEIN IS NECESSARY FOR PITUITARY SOMATOTROPHS AND GROWTH HORMONE PRODUCTION Waleed J. Hashmi1, Noriko Kantake2, Shiu Yuan2,3, Ibiaghani Max Harry2,3, Nathan K. Hoggard1, Alex H. Fishbach2, Ramiro E. Toribio4, Thomas J. Rosol2,3, Department of Biomedical Sciences, Translation Biomedical Sciences Program, Ohio University, Athens, 45701, OH1,Department of Biomedical Sciences, Heritage College of Osteopathic Medicine, Ohio University2, Department of

Abstract

Parathyroid hormone‐related protein (PTHrP) is an important regulator of bone growth, energy metabolism, and lung development. PTHrP is expressed by the pituitary endocrine cells. The pituitary gland plays an important role in homeostasis, energy metabolism, and development. The first phylogenetic identification of PTHrP in animals has shown that it originally developed as a secretory pituitary hormone in fishes. PTHrP is both a secreted and nuclear protein. A novel knock‐in mouse (PTHrP∆/∆) with a lack of the nuclear localization sequence (NLS) of PTHrP was developed. The mice fail to grow and die 4 to 5 days after birth. We hypothesized that the nuclear localization sequence (NLS) of PTHrP was necessary to many tissues for normal development and physiological processes. Histological analysis was performed to study the morphological structure of the pituitaries in these mice. Compared to the wildtype and heterozygote mice(PTHrP+/∆), the pituitary pars distalis from 1‐day‐old PTHrP∆/∆ mice was hypocellular, with a decreased density of pituitary epithelial cells throughout the gland (hypoplasia of the pituitary pars distalis). Occasional pituitary epithelial cells were apoptotic with shrunken pyknotic or fragmented nuclei, with increased cytoplasmic eosinophilia. The pituitary pars intermedia, pars nervosa, and rathke pouch epithelium was unaffected. Immunohistochemistry using GH primary antibody showed decreased GH secretion in somatotrophs which may contribute to early senescence in the mice. Immunoreactivity to GH was strongest in the pituitary epithelial cells within lateral areas of the pars distalis in PTHrP+/∆ mice. The GH immunoreactive cells in the pituitary epithelial cells of PTHrP∆/∆ mice was low compared to PTHrP+/∆ mice. The GH is expressed at low levels in the pituitaries from the PTHrP∆/∆ mice compared to PTHrP+/∆mice as verified by PCR. Understanding the mechanisms and functions of nuclear PTHrP in the pituitary provides the platform for improved medical therapies for endocrine diseases as well as novel insights into the impact of the PTHrP on processes such as growth and metabolism.