Parathyroid hormone-like proteins: Biochemical responses and receptor interactions

Humoral hypercalcemia of malignancy (HHM) was first described almost 50 yr ago (1) and is the most common paraneoplastic syndrome. It appears to result in most instances from the production by tumors of a novel class of protein hormones which share amino acid sequence homology with PTH. These PTH-like proteins (PTHLPs)¹, purified and amino-terminally sequenced from human HHM-associated tumors, appear to mimic certain of the renal and skeletal actions of PTH, thereby leading to the clinical and biochemical features of the HHM syndrome. The structure, location, and transcriptional pattern of the PTHLP gene have been elucidated and the full complementary DNA-predicted amino acid sequences of three PTHLP translation products have been revealed (2–7). Further, PTHLPs and their mRNA transcripts have been identified in a variety of normal, nonmalignant tissues (8, 9), and may have important regulatory or functional roles in these tissues. The renal tubule and skeletal osteoblast are regarded as the “classical” target tissues for the action of PTH, and recent studies indicate that synthetic amino-terminal PTHLPs interact with the PTH receptor in these “classical” tissues. PTH also induces functional responses in a variety of “non-classical” target tissues, including vascular smooth muscle, dermal fibroblasts, epidermal keratinocytes, lymphocytes, and brain. The role for PTH, if any, in the normal physiology of these tissues remains obscure. The observations that 1) PTHLPs are expressed by a spectrum of normal tissues including some of the nonclassical PTH target tissues mentioned above, and that 2) supraphysiological concentrations of PTH are generally required to induce functional responses in these tissues, raise the possibility that PTHLPs, and not PTH, may be the native or intended ligands for receptors in these nonclassical target tissues. Moreover, PTHLPs appear to mediate functional responses in some tissues which have no response to PTH, suggesting the presence of unique PTHLP receptors. The purpose of this review is to summarize the nature of PTHLP interactions with PTH receptors in classical PTH target tissues, and to explore the possible existence and role of unique PTHLP receptors in a variety of other tissues.