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

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.

journal_name

Oncogene

journal_title

Oncogene

authors

Frieling JS,Shay G,Izumi V,Aherne ST,Saul RG,Budzevich M,Koomen J,Lynch CC

doi

10.1038/onc.2017.70

subject

Has Abstract

pub_date

2017-08-01 00:00:00

pages

4498-4507

issue

31

eissn

0950-9232

issn

1476-5594

pii

onc201770

journal_volume

36

pub_type

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