Parathyroid hormone-related peptide and bone: pathological and physiological aspects

Parathyroid hormone-related peptide (PTHrP) was initially discovered as a tumor-derived systemic factor which causes humoral hypercalcemia of malignancy. When overproduced and secreted by tumor cells, PTHrP acts on target organs such as bone and kidney to cause hypercalcemia through its 'PTH-like effects'. The hypercalcemic effects of PTHrP are attributed to its N-terminal portion (1-36) which shows a limited homology with PTH and is able to bind to the common PTH/PTHrP receptor. In contrast to such pathological effects as a humoral factor, PTHrP is now recognized as a locally active cytokine produced by a variety of tissues and cell types. Gene knockout experiments have revealed critical roles for PTHrP in a wide spectrum of physiological processes including chondrogenesis. It also significantly contributes to various pathological processes such as tumor metastasis to bone and bone destruction in arthropathies, acting as a bone-resorbing cytokine. Consistent with its divergent roles, regulation of PTHrP expression as well as its mode of action seems to be much more complex than its hormonal counterpart, PTH. In this article, we will briefly review the recent progress in our understanding of both physiological and pathological aspects of PTHrP biology, with a particular focus on its roles as a bone cytokine.