Parathyroid hormone–related protein is a therapeutic target in idiopathic pulmonary fibrosis

The crosstalk between immune or alveolar epithelial cells and fibroblasts mediated by paracrine signaling molecules is associated with the pathogenesis of idiopathic pulmonary fibrosis (IPF). However, studies investigating the active involvement of soluble mediators derived from bronchial epithelial cells in fibroblast activation and the development of pulmonary fibrosis are limited. Reanalysis of bulk and single-cell RNA-sequencing data from human bronchus and IPF lung tissue revealed marked upregulation of parathyroid hormone-like hormone (PTHLH) in IPF lung tissue compared with normal tissue, with expression predominantly localized to bronchial epithelial cells. parathyroid hormone-related protein (PTHrP) translated from PTHLH was significantly increased in the bronchial epithelium of IPF patients and bleomycin-induced pulmonary fibrosis mice. Furthermore, the paracrine peptide PTHrP_1-34, generated through post-translational processing of PTHrP, was elevated in lung homogenates and bronchoalveolar lavage fluid obtained from fibrotic lungs. Cell- and animal-based experiments showed that PTHrP_1-34 activated fibroblasts and extracellular matrix production, resulting in the progression of pulmonary fibrosis. In a preclinical evaluation using a bleomycin-induced pulmonary fibrosis mouse model, attenuating effects against pulmonary fibrosis were observed using neutralizing antibodies, peptides, and gene silencing strategies targeting the PTHrP_1-34/parathyroid hormone 1 receptor axis. In conclusion, our results suggest that PTHrP_1-34 derived from bronchial epithelial cells is involved in the pathogenesis of IPF and is a promising target for alleviating disease progression.