title: 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 PTHrP1-36hormone is processed by matrix metalloproteinases to yield a stable product, PTHrP1-17. PTHrP1-17retains the ability to signal through PTH1R to induce calcium flux and ERK phosphorylation but not cyclic AMP production or CREB phosphorylation. Notably, PTHrP1-17promotes osteoblast migration and mineralization in vitro, and systemic administration of PTHrP1-17augments ectopic bone formation in vivo. Further, in contrast to PTHrP1-36, PTHrP1-17does not affect osteoclast formation/function in vitro or in vivo. Finally, immunoprecipitation-mass spectrometry analyses using PTHrP1-17-specific antibodies establish that PTHrP1-17is 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.
authors.affiliation: Departments of Tumor Biology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA.
authors.forename: J S
authors.initials: JS
authors.lastname: Frieling
authors.affiliation: Departments of Tumor Biology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA.
authors.forename: G
authors.initials: G
authors.lastname: Shay
authors.affiliation: Molecular Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA.
authors.forename: V
authors.initials: V
authors.lastname: Izumi
authors.affiliation: Departments of Tumor Biology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA.
authors.forename: S T
authors.initials: ST
authors.lastname: Aherne
authors.affiliation: Antibody Characterization Lab, Leidos Biomedical Research, Frederick, MD, USA.
authors.forename: R G
authors.initials: RG
authors.lastname: Saul
authors.affiliation: Cancer Imaging and Metabolism, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA.
authors.forename: M
authors.initials: M
authors.lastname: Budzevich
authors.affiliation: Molecular Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA.
authors.forename: J
authors.initials: J
authors.lastname: Koomen
authors.affiliation: Departments of Tumor Biology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA.
authors.forename: C C
authors.initials: CC
authors.lastname: Lynch
mesh_terms: D000818:Animals; D001862:Bone Resorption / Q000209:etiology; D002454:Cell Differentiation; D002460:Cell Line; D002465:Cell Movement; D005260:Female; D006801:Humans; D020782:Matrix Metalloproteinases / Q000502:physiology*; D051379:Mice; D010006:Osteoblasts / Q000166:cytology / Q000502:physiology; D010012:Osteogenesis; D044162:Parathyroid Hormone-Related Protein / Q000502:physiology*
chemical_list: D044162:Parathyroid Hormone-Related Protein; D020782:Matrix Metalloproteinases