Parathyroid hormone related peptide (PTHrP) and bone metabolism

Abstract

The discovery of PTHrP was the result of research on the mechanisms by which some cancers cause hypercalcemia (humoral hypercalcemia of malignancy) without necessarily metastasizing to bone. PTHrP is also present in various normal adult and fetal tissues. Its concentration is normally very low (picomolar) in blood, but it is more abundant in milk (nanomolar concentration). PTHrP seems able to exert autocrine/paracrine as well as endocrine effects on bone metabolism. A major role for PTHrP in regulation of fetal bone metabolism has been demonstrated in mice. Homologous recombination has been used in these rodents to remove the major coding exon from one copy of the mouse PTHrP gene in embryonic stem cells. Subsequently generated chimeric mice transmit the mutant PTHrP allele through the germline. Homozygous mutants died immediately after birth and had a multitude of skeletal abnormalities. So PTHrP seems necessary to embryonic development of the skeleton. PTHrP (1-34), like PTH (1-34) fragments, might be responsible for both bone resorption and formation. Although the effects of the carboxyl-terminal fragments are still controversial, PTHrP (107-111) fragment seems able to inhibit osteoclast activity. PTHrP (1-34), whose 8 of the first 13 amino-acids are identical with those in PTH (1-34), acts through the same receptor as PTH on osteoblasts and renal cells membrane. The PTHrP/PTH receptor sequence is now well established. PTHrP-receptor coupling is mediated by cyclic AMP and/or inositols-phosphate. The consequent activation of protein kinase A and intracellular calcium or protein kinase C, respectively, locally induces growth factors or cytokines secretion, responsible for the observed effects. The role of PTHrP appears important during pregnancy and lactation, when it stimulates fetal bone growth by increasing calcium transport from the dam to its fetus and maternal bone resorption allowing calcium supply for milk production, respectively. Such a role would be particularly important in domestic ruminants, which are often simultaneously pregnant and lactating. The role of PTHrP during aging (especially in post-menopausal women in which bone loss may induce osteoporosis) remains unknown and might be of peculiar interest since PTHrP (1-34) and (107-111) are able to restore bone loss induced by ovariectomy in rats.