{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T04:16:35Z","timestamp":1788236195763,"version":"build-2803163510"},"reference-count":56,"publisher":"Oxford University Press (OUP)","issue":"7","license":[{"start":{"date-parts":[[2017,3,29]],"date-time":"2017-03-29T00:00:00Z","timestamp":1490745600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2017,7,1]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:sec>\n                    <jats:title>\u2003<\/jats:title>\n                    <jats:p>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\u2009min. 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\u2013derived peptide that locally regulates the differentiation of hematopoietic cells and the activity of osteoclasts within the tumor\u2013bone marrow microenvironment, perhaps to facilitate tumor control of bone. \u00a9 2017 American Society for Bone and Mineral Research.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/jbmr.3142","type":"journal-article","created":{"date-parts":[[2017,3,29]],"date-time":"2017-03-29T09:06:36Z","timestamp":1490778396000},"page":"1421-1431","source":"Crossref","is-referenced-by-count":22,"title":["PTHrP(12-48) Modulates the Bone Marrow Microenvironment and Suppresses Human Osteoclast Differentiation and Lifespan"],"prefix":"10.1093","volume":"32","author":[{"given":"Archana","family":"Kamalakar","sequence":"first","affiliation":[{"name":"Department of Orthopaedic Surgery, Center for Orthopaedic ResearchUniversity of Arkansas for Medical Sciences (UAMS)Little RockARUSA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charity L","family":"Washam","sequence":"additional","affiliation":[{"name":"Department of Orthopaedic Surgery, Center for Orthopaedic ResearchUniversity of Arkansas for Medical Sciences (UAMS)Little RockARUSA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nisreen S","family":"Akel","sequence":"additional","affiliation":[{"name":"Department of Orthopaedic Surgery, Center for Orthopaedic ResearchUniversity of Arkansas for Medical Sciences (UAMS)Little RockARUSA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bethany J","family":"Allen","sequence":"additional","affiliation":[{"name":"Department of Orthopaedic Surgery, Center for Orthopaedic ResearchUniversity of Arkansas for Medical Sciences (UAMS)Little RockARUSA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diarra K","family":"Williams","sequence":"additional","affiliation":[{"name":"Department of Veterinary Physiology and Pharmacology, College of Veterinary Medicine and Biomedical SciencesTexas A&M UniversityCollege StationTXUSA"},{"name":"Department of Orthopaedic Surgery, Center for Orthopaedic ResearchUniversity of Arkansas for Medical Sciences (UAMS)Little RockARUSA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frances L","family":"Swain","sequence":"additional","affiliation":[{"name":"Department of Orthopaedic Surgery, Center for Orthopaedic ResearchUniversity of Arkansas for Medical Sciences (UAMS)Little RockARUSA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kim","family":"Leitzel","sequence":"additional","affiliation":[{"name":"Department of MedicinePenn State University, Milton S. Hershey Medical CenterHersheyPAUSA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Allan","family":"Lipton","sequence":"additional","affiliation":[{"name":"Department of MedicinePenn State University, Milton S. Hershey Medical CenterHersheyPAUSA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dana","family":"Gaddy","sequence":"additional","affiliation":[{"name":"Veterinary Integrative Biosciences, College of Veterinary Medicine and Biomedical SciencesTexas A&M UniversityCollege StationTXUSA"},{"name":"Department of Orthopaedic Surgery, Center for Orthopaedic ResearchUniversity of Arkansas for Medical Sciences (UAMS)Little RockARUSA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2892-9757","authenticated-orcid":false,"given":"Larry J","family":"Suva","sequence":"additional","affiliation":[{"name":"Department of Veterinary Physiology and Pharmacology, College of Veterinary Medicine and Biomedical SciencesTexas A&M UniversityCollege StationTXUSA"},{"name":"Department of Orthopaedic Surgery, Center for Orthopaedic ResearchUniversity of Arkansas for Medical Sciences (UAMS)Little RockARUSA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2017,3,29]]},"reference":[{"issue":"4","key":"2024021014200450400_jbmr3142-bib-0001","doi-asserted-by":"crossref","first-page":"271","DOI":"10.3322\/caac.21349","article-title":"Cancer treatment and survivorship statistics, 2016","volume":"66","author":"Miller","year":"2016","journal-title":"CA Cancer J Clin"},{"issue":"1","key":"2024021014200450400_jbmr3142-bib-0002","doi-asserted-by":"crossref","first-page":"7","DOI":"10.3322\/caac.21332","article-title":"Cancer statistics. 2016","volume":"66","author":"Siegel","year":"2016","journal-title":"CA Cancer J Clin"},{"issue":"1","key":"2024021014200450400_jbmr3142-bib-0003","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1038\/nrendo.2015.185","article-title":"The best of both worlds - managing the cancer, saving the bone","volume":"12","author":"Makhoul","year":"2016","journal-title":"Nat Rev Endocrinol"},{"issue":"8","key":"2024021014200450400_jbmr3142-bib-0004","doi-asserted-by":"crossref","first-page":"584","DOI":"10.1038\/nrc867","article-title":"Metastasis to bone: causes, consequences and therapeutic opportunities","volume":"2","author":"Mundy","year":"2002","journal-title":"Nat Rev Cancer"},{"issue":"2","key":"2024021014200450400_jbmr3142-bib-0005","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1007\/s11914-010-0012-5","article-title":"Adjuvant bisphosphonates in breast cancer: the ABCSG-12 study","volume":"8","author":"Suva","year":"2010","journal-title":"Curr Osteoporos Rep"},{"issue":"6","key":"2024021014200450400_jbmr3142-bib-0006","doi-asserted-by":"crossref","first-page":"411","DOI":"10.1038\/nrc3055","article-title":"Cancer to bone: a fatal attraction","volume":"11","author":"Weilbaecher","year":"2011","journal-title":"Nat Rev Cancer"},{"issue":"9","key":"2024021014200450400_jbmr3142-bib-0007","doi-asserted-by":"crossref","first-page":"997","DOI":"10.1016\/S1470-2045(14)70302-X","article-title":"Adjuvant zoledronic acid in patients with early breast cancer: final efficacy analysis of the AZURE (BIG 01\/04) randomised open-label phase 3 trial","volume":"15","author":"Coleman","year":"2014","journal-title":"Lancet Oncol"},{"issue":"4817","key":"2024021014200450400_jbmr3142-bib-0008","doi-asserted-by":"crossref","first-page":"893","DOI":"10.1126\/science.3616618","article-title":"A parathyroid hormone-related protein implicated in malignant hypercalcemia: cloning and expression","volume":"237","author":"Suva","year":"1987","journal-title":"Science"},{"issue":"6","key":"2024021014200450400_jbmr3142-bib-0009","doi-asserted-by":"crossref","first-page":"1122","DOI":"10.1046\/j.1523-1747.1998.00428.x","article-title":"PTHrP regulates epidermal differentiation in adult mice","volume":"111","author":"Foley","year":"1998","journal-title":"J Invest Dermatol"},{"key":"2024021014200450400_jbmr3142-bib-0010","doi-asserted-by":"crossref","first-page":"431","DOI":"10.1146\/annurev.physiol.60.1.431","article-title":"The physiology of parathyroid hormone-related protein: an emerging role as a developmental factor","volume":"60","author":"Wysolmerski","year":"1998","journal-title":"Annu Rev Physiol"},{"issue":"33","key":"2024021014200450400_jbmr3142-bib-0011","doi-asserted-by":"crossref","first-page":"10553","DOI":"10.1021\/bi00033a030","article-title":"Probing the bimolecular interactions of parathyroid hormone and the human parathyroid hormone\/parathyroid hormone-related protein receptor. 2. 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