Parathyroid Hormone Related Protein (PTHrP)-Associated Molecular Signatures in Tissue Differentiation and Non-Tumoral Diseases

SIMPLE SUMMARY: Parathyroid-hormone-related protein (PTHrP) is a protein hormone of 139, 141, or 173 amino acids, which may be cleaved into smaller bioactive forms, comprising amino terminus, mid-region, and carboxy terminus peptides, active as key controllers of viability, proliferation, and differentiation in diverse normal and pathological cell and tissue model systems via the reprogramming of gene expression and intracellular signalization. Within the large number of data available in the literature on this matter, the objective of this review is to review selected studies that report the detection of molecular markers of exposure to PTHrP, either as full-length protein or as discrete peptides, in peculiar normal or non-neoplastic biological contexts. In particular, the data presented relate to adipose, bone, dental, cartilaginous, and skin tissues, as well as intestinal, renal, hepatic, pulmonary, and pancreatic epithelia, with a focus on hepatic fibrosis-, pancreatitis-, and diabetes-related changes, as demonstrated by molecular profiling, briefly recapitulating the biological implications of the specific gene and/or pathway activation or inactivation. ABSTRACT: Parathyroid-hormone-related protein (PTHrP) is encoded by the PTHLH gene which, via alternative promoter usage and splicing mechanisms, can give rise to at least three isoforms of 139, 141, and 173 amino acids with distinct C-terminals. PTHrP is subjected to different post-translational processing that generates smaller bioactive forms, comprising amino terminus, mid-region (containing a nuclear/nucleolar targeting signal), and carboxy terminus peptides. Both the full-length protein and the discrete peptides are key controllers of viability, proliferation, differentiation, and apoptosis in diverse normal and pathological biological systems via the reprogramming of gene expression and remodulation of PKA or PKC-mediated signalization mechanisms. The aim of this review is to pick up selected studies on PTHrP-associated signatures as revealed by molecular profiling assays, focusing on the available data about exemplary differentiating, differentiated, or nontumoral cell and tissue models. In particular, the data presented relate to adipose, bone, dental, cartilaginous, and skin tissues, as well as intestinal, renal, hepatic, pulmonary, and pancreatic epithelia, with a focus on hepatic fibrosis-, pancreatitis-, and diabetes-related changes as diseased states. When reported, the biochemical and/or physiological aspects associated with the specific molecular modulation of gene expression and signal transduction pathways in the target model systems under examination are also briefly described.