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

Oncogene volume 36, pages 4498–4507 (2017)Cite this article

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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.

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Acknowledgements

This work was supported by R01-CA143094 (CCL), the State of Florida Bankhead Coley Program grant 5BC-O1 (CCL) and by a Miles for Moffitt Foundation Award. This work was also supported in part by the Core Facilities of the Moffitt Cancer Center Grant P30-CA076292. The authors thank Joe Johnson (Moffitt Analytical Microscopy), Robert Sprung (Moffitt Proteomics) and Gordon Whiteley (SAIC-Frederick, NCI-Frederick) for their helpful suggestions and expertise, and Drs John Cleveland and Srikumar Chellappan for critical review of this study.

Author contributions

CCL and JSF designed all of the biological experiments. JSF conducted the majority of the in vitro and in vivo experimental assays and collection of data. GS contributed to osteoclast in vitro and in vivo analyses. RGS was responsible for the generation and initial characterization of PTHrP1–17 specific antibodies. SA assisted with the analysis of real time PCR data and statistical analyses. MB assisted with μCT experiments and analyses. JK and VI designed, performed and analysed the proteomic experiments. JSF, JK, GS, and CCL wrote, edited and proofread the manuscript.

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Authors and Affiliations

  1. Departments of Tumor Biology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA

    J S Frieling, G Shay, S T Aherne & C C Lynch

  2. Molecular Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA

    V Izumi & J Koomen

  3. Antibody Characterization Lab, Leidos Biomedical Research, Frederick, MD, USA

    R G Saul

  4. Cancer Imaging and Metabolism, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA

    M Budzevich

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  1. J S Frieling
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  2. G Shay
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Correspondence to C C Lynch.

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Frieling, J., Shay, G., Izumi, V. et al. Matrix metalloproteinase processing of PTHrP yields a selective regulator of osteogenesis, PTHrP1–17. Oncogene 36, 4498–4507 (2017). https://doi.org/10.1038/onc.2017.70

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