Parathyroid hormone and parathyroid hormone-related peptide effects on growth plate chondrocytes: An overview

Long bone growth is determined by the growth plate, a migrating zone of cartilage near the bone ends. Within the growth plate, chondrocytes undergo synchronized changes, beginning with proliferation and ending with a differentiated state characterized by a large volume increase (hypertrophy) and mineralization of the cartilage. Parathyroid hormone (PTH) and parathyroid hormone-related peptide (PTHrP) are among numerous extracellular peptide signaling molecules that influence growth plate chondrocyte differentiation. In vitro, PTH or PTHrP act both as mitogens and as suppressers of the differentiated phenotype in growth plate chondrocytes. The mechanism of delivery of PTH and PTHrP to the growth plate is only partially understood. PTH is a systemic hormone that may have limited access to growth plate chondrocytes. In contrast, PTHrP is produced in varying concentrations within the epiphysis, and acts as a paracrine and/or autocrine factor. We present evidence suggesting that the articular cartilage of juvenile chicks may serve as one source of PTHrP for the growth plate. In chondrocytes, as in other cells, PTH and PTHrP activate multiple intracellular signals through a seven transmembrane receptor linked to trimeric G-proteins. The activation of protein kinase A is sufficient for effecting the mitogenic response in chondrocytes, but the role of protein kinase C has not been clarified. In summary, there is a large body of evidence demonstrating the requirement for PTHrP in normal growth plate development. The source of PTHrP, and the targets of the signaling downstream of the PTHrP receptor in chondrocytes are less well understood.