title: PTHrP produced by myeloma plasma cells regulates their survival and pro-osteoclast activity for bone disease progression.
abstract: To promote their survival and progression in the skeleton, osteotropic malignancies of breast, lung, and prostate produce parathyroid hormone-related protein (PTHrP), which induces hypercalcemia. PTHrP serum elevations have also been described in multiple myeloma (MM), although their role is not well defined. When we investigated MM cells from patients and cell lines, we found that PTHrP and its receptor (PTH-R1) are highly expressed, and that PTHrP is secreted both as a full-length molecule and as small subunits. Among these subunits, the mid-region, including the nuclear localization sequence (NLS), exerted a proliferative effect because it was accumulated in nuclei of MM cells surviving in starvation conditions. This was confirmed by increased transcription of several genes enrolled in proliferation and apoptosis control. PTHrP was also found to stimulate PTH-R1 in MM cells. PTH-R1's selective activation by the full-length PTHrP molecule or the NH2 -terminal fragment resulted in a significant increase of intracellular Ca(2+) influx, cyclic adenosine monophosphate (cAMP) content, and expression of receptor activator of NF-κB ligand (RANKL) and monocyte chemoattractant protein-1 (MCP-1). Our data definitely clarify the role of PTHrP in MM. The PTHrP peptide is functionally secreted by malignant plasma cells and contributes to MM tumor biology and progression, both by intracrine maintenance of cell proliferation in stress conditions and by autocrine or paracrine stimulation of PTH-R1, which in turn reinforces the production of osteoclastogenic factors. © 2014 American Society for Bone and Mineral Research.
authors.affiliation: Department of Biomedical Sciences and Human Oncology, Section of Internal Medicine and Oncology, University of Bari "Aldo Moro,", Bari, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Cafforio
authors.forename: Annalisa
authors.initials: A
authors.lastname: Savonarola
authors.forename: Stefania
authors.initials: S
authors.lastname: Stucci
authors.forename: Monica
authors.initials: M
authors.lastname: De Matteo
authors.forename: Marco
authors.initials: M
authors.lastname: Tucci
authors.forename: Anna Elisabetta
authors.initials: AE
authors.lastname: Brunetti
authors.forename: Vita Mariagrazia
authors.initials: VM
authors.lastname: Vecchio
authors.forename: Francesco
authors.initials: F
authors.lastname: Silvestris
mesh_terms: D045744:Cell Line, Tumor; D049109:Cell Proliferation; D018932:Chemokine CCL2 / Q000096:biosynthesis; D000242:Cyclic AMP / Q000378:metabolism; D018450:Disease Progression; D006801:Humans; D009101:Multiple Myeloma / Q000378:metabolism*; D044162:Parathyroid Hormone-Related Protein / Q000096:biosynthesis*; D010446:Peptide Fragments / Q000096:biosynthesis / Q000494:pharmacology; D010950:Plasma Cells / Q000378:metabolism*; D053246:Receptor Activator of Nuclear Factor-kappa B / Q000096:biosynthesis; D044168:Receptor, Parathyroid Hormone, Type 1 / Q000096:biosynthesis* / Q000378:metabolism
chemical_list: C111835:CCL2 protein, human; D018932:Chemokine CCL2; D044162:Parathyroid Hormone-Related Protein; D010446:Peptide Fragments; D053246:Receptor Activator of Nuclear Factor-kappa B; D044168:Receptor, Parathyroid Hormone, Type 1; D000242:Cyclic AMP
keywords: CELL SURVIVAL; MULTIPLE MYELOMA; NLS REGION; OSTEOCLASTOGENESIS; PTHRP