PTHrP(12-48) Modulates the Bone Marrow Microenvironment and Suppresses Human Osteoclast Differentiation and Lifespan

Archana Kamalakar, Charity L. Washam, Nisreen S. Akel, Bethany J. Allen, Diarra K. Williams, Frances L. Swain, Kim Leitzel, Allan Lipton, Dana Gaddy, Larry J. Suva

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4 Scopus citations

Abstract

Bone is a common site for metastasis in breast cancer patients and is associated with a series of complications that significantly compromise patient survival, partially due to the advanced stage of disease at the time of detection. Currently, no clinically-approved biomarkers can identify or predict the development of bone metastasis. We recently identified a unique peptide fragment of parathyroid hormone-related protein (PTHrP), PTHrP(12-48), as a validated serum biomarker in breast cancer patients that correlates with and predicts the presence of bone metastases. In this study, the biological activity and mode of action of PTHrP(12-48) was investigated. Sequence-based and structure-based bioinformatics techniques predicted that the PTHrP(12-48) fragment formed an alpha helical core followed by an unstructured region after residue 40 or 42. Thereafter, detailed structure alignment and molecular docking simulations predicted a lack of interaction between PTHrP(12-48) and the cognate PTH1 receptor (PTHR1). The in silico prediction was confirmed by the lack of PTHrP(12-48)-stimulated cAMP accumulation in PTHR1-expressing human SaOS2 cells. Using a specific human PTHrP(12-48) antibody that we developed, PTHrP(12-48) was immunolocalized in primary and bone metastatic human breast cancer cells, as well as within human osteoclasts (OCLs) in bone metastasis biopsies, with little or no localization in other resident bone or bone marrow cells. In vitro, PTHrP(12-48) was internalized into cultured primary human OCLs and their precursors within 60 min. Interestingly, PTHrP(12-48) treatment dose-dependently suppressed osteoclastogenesis, via the induction of apoptosis in both OCL precursors as well as in mature OCLs, as measured by the activation of cleaved caspase 3. Collectively, these data suggest that PTHrP(12-48) is a bioactive breast cancer–derived peptide that locally regulates the differentiation of hematopoietic cells and the activity of osteoclasts within the tumor–bone marrow microenvironment, perhaps to facilitate tumor control of bone.

Original languageEnglish (US)
Pages (from-to)1421-1431
Number of pages11
JournalJournal of Bone and Mineral Research
Volume32
Issue number7
DOIs
StatePublished - Jul 2017

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All Science Journal Classification (ASJC) codes

  • Endocrinology, Diabetes and Metabolism
  • Orthopedics and Sports Medicine

Cite this

Kamalakar, A., Washam, C. L., Akel, N. S., Allen, B. J., Williams, D. K., Swain, F. L., Leitzel, K., Lipton, A., Gaddy, D., & Suva, L. J. (2017). PTHrP(12-48) Modulates the Bone Marrow Microenvironment and Suppresses Human Osteoclast Differentiation and Lifespan. Journal of Bone and Mineral Research, 32(7), 1421-1431. https://doi.org/10.1002/jbmr.3142