Matrix metalloproteinase processing of PTHrP yields a selective regulator of osteogenesis, PTHrP1–17
| Autor: | G Shay, Conor C. Lynch, M Budzevich, Jeremy S. Frieling, V Izumi, S T Aherne, R G Saul, John M. Koomen |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Cancer Research medicine.medical_specialty Osteolysis Regulator Osteoblast Biology Matrix metalloproteinase medicine.disease Bone resorption Bone remodeling Cell biology 03 medical and health sciences 030104 developmental biology 0302 clinical medicine Endocrinology medicine.anatomical_structure Osteoclast 030220 oncology & carcinogenesis Internal medicine Calcium flux Genetics medicine Molecular Biology |
| Zdroj: | Oncogene. 36:4498-4507 |
| ISSN: | 1476-5594 0950-9232 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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