In vivo evidence for progressive activation of parathyroid hormone-related peptide gene transcription with tumor growth and stimulation of osteoblastic bone formation at an early stage of humoral hypercalcemia of cancer

Abstract

The present study was undertaken to clarify in vivo the temporal profile of parathyroid hormone-related peptide (PTHRP) gene expression as well as bone histomorphometric features as a function of tumor growth, using an athymic rat model associated with humoral hypercalcemia of malignancy (HHM). Tumor-bearing animals exhibited hypercalcemia, hypophosphatemia, and increased circulating levels of PTHRP, and died within 3 weeks. Steady-state PTHRP mRNA levels and the transcription rate of PTHRP gene in the tumors were markedly increased with tumor growth. RNAse mapping analysis revealed that both upstream and downstream promoters of the human PTHRP gene were utilized in the tumors and became progressively activated with time. Bone histomorphometric analysis showed that osteoclastic bone resorption was progressively increased throughout the course, whereas osteoblastic bone formation was stimulated more than 2-fold at a very early stage (day 6 after tumor implantation) and then markedly suppressed thereafter on day 12 and day 18 compared with age-matched control animals. These results provide in vivo evidence that PTHRP gene transcription is progressively activated with tumor growth and that activation of osteoblasts does occur at a very early phase of HHM syndrome in contrast to the marked suppression of bone formation at later stages.