Frontiers review
Parathyroid hormone-related protein and lung biology

https://doi.org/10.1016/j.resp.2004.05.007Get rights and content

Abstract

Parathyroid hormone-related protein (PTHrP) is expressed in normal and malignant lung and has roles in development, homeostasis, and pathophysiology of injury and cancer. Its effects in developing lung include regulation of branching morphogenesis and type II cell maturation. In adult lung, PTHrP stimulates disaturated phosphatidylcholine secretion, inhibits type II cell growth, and sensitizes them to apoptosis. In lung cancer, PTHrP may play a role in carcinoma progression, or metastasis. The protein could be a useful marker for assessing lung maturity or type II cell function, predicting risk of injury, and detecting lung cancer. PTHrP-based therapies could also prove useful in lung injury and lung cancer.

Introduction

Parathyroid hormone-related protein (PTHrP) was named for its similarity in primary and secondary structure with the amino terminal portion of parathyroid hormone (PTH) (Kemp et al., 1987). The two proteins share some effects but serve different purposes. In contrast to the global endocrine action of PTH, PTHrP generally functions in a local paracrine or autocrine manner. Furthermore, the most important biologic consequences of the protein relate to cell growth and apoptosis, calcium transport, and smooth muscle relaxation, not to serum calcium homeostasis (Goltzman et al., 1989). The effects are mediated at several sites. PTHrP is a secretory protein (Deftos et al., 1993) and it exerts paracrine or autocrine effects at cell surface receptors. In addition, it can enter the nucleus to mediate changes in function or growth, actions known as intracrine effects. The effects of PTHrP have been studied in a wide variety of organs, including bone, kidney, prostate, skin, heart, brain and recently lung. PTHrP is an oncofetal protein in some tissues because its expression is restricted to the period of fetal development or to malignancy. However, many normal tissues produce PTHrP throughout life. The molecule is expressed in fetal lung, adult lung, and lung cancer, and has roles in development, normal pulmonary physiology, and the pathophysiology of lung injury and lung cancer. This review article will summarize pertinent background information regarding the molecular biology of PTHrP and discuss the importance of the molecule in pulmonary biology.

Section snippets

PTHrP gene

The human PTHrP gene displays a complex organization that enables expression to be regulated through alternative messenger RNA (mRNA) splicing and multiple promoters. The sequence spans more than 15 kilobases and consists of seven exons, six introns, three separate promoters, and multiple 3′-non-coding regions (Yang and Stewart, 1996). The gene codes for three separate isoforms in humans through production of different 3′ transcripts: PTHrP 1–141, a truncated PTHrP 1–139 version, and PTHrP

Pulmonary PTHrP and PTH-1R expression

PTHrP mRNA and protein are expressed in bronchial epithelium of the developing lung, beginning at days 14–16 of gestation in rats (term 21–23 d) and 7–12 weeks in humans (term 38–40 weeks) (Moniz et al., 1990, Senior et al., 1990, Campos et al., 1991, Moseley et al., 1991). Levels peak shortly before birth. Expression is largely restricted to the epithelial cells, while PTH-1R is found in the adjacent mesenchymal tissues (Lee et al., 1995). This hand-in-glove distribution between ligand and

PTHrP in adult lung

Type II cells make PTHrP in lungs of adult rats and rabbits, just as in fetal lung. Immunoassay, immunohistochemistry and in situ hybridization studies demonstrate PTHrP protein and mRNA in the parenchyma and protein in bronchoalveolar lavage liquid (BAL) (Hastings et al., 1994, 1996, 2002b). Cultured adult rat type II cells make PTHrP, but immunoreactive PTHrP or PTHrP mRNA have not been observed in type I cells, endothelial cells or fibroblasts. Freshly isolated alveolar macrophages and

PTHrP in lung injury

Various types of lung injury can result in damage to the alveolar epithelium, particularly to the alveolar type I epithelial cells that form the thin epithelial portion of the blood–gas barrier. With type I cells injured or missing, proteinaceous fluid and inflammatory cells can flood across the denuded epithelial basement membrane, leading to abnormalities in gas exchange and lung mechanics (Bachofen and Weibel, 1977). If the barrier is repaired, the injury and resulting effects can be

PTHrP expression

PTHrP was originally discovered in BEN cells, a squamous cell lung carcinoma line (Moseley et al., 1987), and PTHrP expression is a common characteristic of lung cancer cells of all histologic types (Brandt et al., 1991). Over half (estimates between 55–95%) of all lung cancer cell lines and human lung tumors express PTHrP (Asa et al., 1990, Brandt et al., 1991, Kitazawa et al., 1991, Davidson et al., 1996, Nishigaki et al., 1999). Expression may be more common in squamous cell carcinoma and

Conclusion

PTHrP is a versatile regulatory molecule in the field of pulmonary biology with potential roles in lung development, normal alveolar physiology, recovery from lung injury, regulation of cell growth and death, and the pathophysiology of lung cancer (Fig. 9). The protein may be a useful marker for assessing lung maturity, predicting risk of injury, evaluating type II cell function, detecting lung cancer, or following response to chemotherapy. Given its role in these processes, future work might

Acknowledgements

This work was supported by a VA Merit Review Award, NIEHS grant ES09227, the California Tobacco-Related Disease Research Program Grant Number 10RT-0161, and a grant from the Flight Attendants Medical Research Institute.

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