Role of parathyroid hormone-related peptide and Indian hedgehog in skeletal development

Parathyroid hormone-related peptide (PTHrP), which frequently causes the humoral hypercalcemia of malignancy syndrome, is an autocrine/paracrine regulator of chondrocyte proliferation and differentiation that acts through the PTH/PTHrP receptor (PTH1R). PTHrP is generated in response to Indian hedgehog (Ihh), which mediates its actions through the membrane receptor patched, but interacts also with hedgehog-interacting protein (Hip). Mice lacking PTHrP show accelerated chondrocyte differentiation, and thus premature ossification of those bones that are formed through an endochondral process, and similar but more-severe abnormalities are observed in PTH1R-ablated animals. The mirror image of these skeletal findings, i.e., a severe delay in chondrocyte differentiation and endochondral ossification, is observed in transgenic mice that overexpress PTHrP under the control of the alpha1(II) procollagen promoter. Severe abnormalities in chondrocyte proliferation and differentiation are also observed in two genetic disorders in humans that are most likely caused by mutations in the PTH1R. Heterozygous PTH1R mutations that lead to constitutively activity were identified in Jansen metaphyseal chondrodysplasia, and homozygous or compound heterozygous mutations that lead to less-active or completely inactive receptors were identified in patients with Blomstrand lethal chondrodysplasia. Based on the growth plate abnormalities observed in these human disorders and in mice with abnormal expression of either PTHrP or the PTH1R, it appears plausible that impaired expression of PTHrP and/or its receptor contributes to the growth abnormalities in children with end-stage renal disease. In fact, mild-to-moderate renal failure leads in animals to a reduction in PTH1R expression in growth plates and impaired growth, but it remains uncertain whether this contributes to altered chondrocyte growth and differentiation.