Deletion of PTHrP nuclear localization sequence and carboxyl terminus leads to lung dysplasia.

Abstract

Parathyroid hormone-related peptide (PTHrP) is a factor that plays an important role in the growth and development of multiple organs. The role of PTHrP in lung development has not been characterized. In order to further investigate the in vivo functions of PTHrP nuclear localization sequence (NLS) and C-terminus, Professor Andrew Karaplis and Professor Dengshun Miao et al. used genetic engineering technology to knock in (KI) a stop codon (TGA) after the 84th amino acid sequence of PTHrP and constructed a mouse model expressing only PTHrP (1-84), but not NLS and C-terminus, namely PTHrP NLS and C-terminal knockout mice (also PTHrP KI mice). Using this genetically modified mouse model, we have characterized its effect on early postnatal lung development. Compared with those in littermate wild-type (WT) mice, the body size and lung volume were significantly reduced and the lung weight index was significantly increased in PTHrP KI mice. Histologically, deletion of the NLS and C-terminus of PTHrP could reduce lung cell proliferation, facilitate cell apoptosis, increase the expression of inflammatory factors, cause increased oxidative stress and DNA damage, and lead to lung dysplasia. Meanwhile, deletion of the NLS and C-terminus of PTHrP could also induce pulmonary fibrosis by activating the TGF-β/Smad signaling pathway. We conclude that PTHrP NLS and C-terminus play important roles in lung development.