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Oncogene. 2017 Aug;36(31):4498-4507. doi: 10.1038/onc.2017.70. Epub 2017 Apr 3.

Matrix metalloproteinase processing of PTHrP yields a selective regulator of osteogenesis, PTHrP1-17.

Author information

1
Departments of Tumor Biology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA.
2
Molecular Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA.
3
Antibody Characterization Lab, Leidos Biomedical Research, Frederick, MD, USA.
4
Cancer Imaging and Metabolism, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA.

Abstract

Parathyroid hormone-related protein (PTHrP) is a critical regulator of bone resorption and augments osteolysis in skeletal malignancies. Here we report that the mature PTHrP1-36 hormone is processed by matrix metalloproteinases to yield a stable product, PTHrP1-17. PTHrP1-17 retains the ability to signal through PTH1R to induce calcium flux and ERK phosphorylation but not cyclic AMP production or CREB phosphorylation. Notably, PTHrP1-17 promotes osteoblast migration and mineralization in vitro, and systemic administration of PTHrP1-17 augments ectopic bone formation in vivo. Further, in contrast to PTHrP1-36, PTHrP1-17 does not affect osteoclast formation/function in vitro or in vivo. Finally, immunoprecipitation-mass spectrometry analyses using PTHrP1-17-specific antibodies establish that PTHrP1-17 is indeed generated by cancer cells. Thus, matrix metalloproteinase-directed processing of PTHrP disables the osteolytic functions of the mature hormone to promote osteogenesis, indicating important roles for this circuit in bone remodelling in normal and disease contexts.

PMID:
28368420
DOI:
10.1038/onc.2017.70
[Indexed for MEDLINE]

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