Open AccessMatrix metalloproteinase processing of PTHrP yields a selective regulator of osteogenesis, PTHrP1–17
Author(s) -
Jeremy S. Frieling,
Gemma Shay,
Victoria Izumi,
Sinéad Aherne,
Richard G. Saul,
Mikalai M. Budzevich,
John M. Koomen,
Conor C. Lynch
Publication year - 2017
Publication title -
oncogene
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.395
H-Index - 342
eISSN - 1476-5594
pISSN - 0950-9232
DOI - 10.1038/onc.2017.70
Subject(s) - bone resorption , osteoclast , biology , matrix metalloproteinase , osteoblast , osteolysis , endocrinology , microbiology and biotechnology , medicine , parathyroid hormone , phosphorylation , regulator , bone remodeling , cancer research , in vitro , calcium , biochemistry , surgery , gene
Parathyroid hormone-related protein (PTHrP) is a critical regulator of bone resorption and augments osteolysis in skeletal malignancies. Here we report that the mature PTHrP 1-36 hormone is processed by matrix metalloproteinases to yield a stable product, PTHrP 1-17 . PTHrP 1-17 retains the ability to signal through PTH1R to induce calcium flux and ERK phosphorylation but not cyclic AMP production or CREB phosphorylation. Notably, PTHrP 1-17 promotes osteoblast migration and mineralization in vitro, and systemic administration of PTHrP 1-17 augments ectopic bone formation in vivo. Further, in contrast to PTHrP 1-36 , PTHrP 1-17 does not affect osteoclast formation/function in vitro or in vivo. Finally, immunoprecipitation-mass spectrometry analyses using PTHrP 1-17 -specific antibodies establish that PTHrP 1-17 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.