PTHrP Action on Skeletal Development: A Key for the Controlled Growth of Endochondral Bones

Abstract

Parathyroid hormone-related protein (PTHrP) was initially identified as a humoral factor that causes the humoral hypercalcemia of malignancies. PTHrP is expressed in tumors and a variety of tissues, acting on the formation and maintenance of these tissues in a paracrine manner. Skeletal formation is one of the notable developmental events in which PTHrP acts as a master regulator. During endochondral ossification, PTHrP is expressed in periarticular regions of fetal cartilage (also referred to as the growth plate) and the perichondrium, whereas the PTH/PTHrP receptor (PPR) is expressed strongly in pre-hypertrophic chondrocytes and weakly in columnar proliferating chondrocytes. Genetic studies have revealed that PTHrP-PPR signaling regulates the differentiation of chondrocytes to maintain a certain length of the growth plate via a negative feedback loop with Indian hedgehog (Ihh) expressed in pre-hypertrophic and hypertrophic chondrocytes. The Ihh-PTHrP negative feedback loop is central to the proper growth of endochondral skeletons. Ihh also exerts a PTHrP-independent function during endochondral ossification; it directly stimulates chondrocyte proliferation and differentiates progenitors into osteoblasts, the bone-forming cells. To further extend our knowledge of the Ihh-PTHrP negative feedback loop, we need to understand the gene regulatory network underlying the actions of PTHrP and Ihh through combinatorial approaches to genome-wide analyses and mouse genetics, which will open a new avenue for the application of the Ihh-PTHrP negative feedback system to the treatment of skeletal disorders.