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 NH 2 -terminal fragment resulted in a significant increase of intracellular Ca 2þ influx, cyclic adenosine monophosphate (cAMP) content, and expression of receptor activator of NF-kB 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.

FGF23 is elevated in multiple myeloma and increases heparanase expression by tumor cells

“…MM-related anemia is due to impaired iron utilization, rather than low iron per se [ 43 ], with most MM patients having normal or high iron status, making it unlikely to explain high FGF23. Parathyroid hormone receptor activation increases bone expression of FGF23 [ 44 ], and MM cells may secrete its ligand, PTHrP [ 45 ]. Factors that can influence FGF23 levels should be explored in a larger cohort of MM patients, including 1,25-dihydroxyvitamin D, PTHrP, other FGFs, low pH and high serum phosphate/calcium ratio [ 46 ].…”

Pathogenesis of bone disease in multiple myeloma: from bench to bedside

“…Soluble RANKL produced by MM cells has been implicated in the development of bone destruction in MM patients 19 , 20 . Furthermore, plasma cells also secrete PTHrP that in turn stimulates RANKL expression by osteoblasts and BMSCs via paracrine way 21 . In addition, MM cells express syndecan-1, an heparan sulfate proteoglycan, that binds to OPG.…”

The effects of proteasome inhibitors on bone remodeling in multiple myeloma

“…In addition to RANK, the expression and/or activity of many other osteoclast-activating factors are altered by MM cells including parathyroid hormone-related protein (PTHrP) [28], activin [29], macrophage inflammatory protein-1α [30], macrophage colony-stimulating factor [31], monocyte chemoattractant protein 1 [32], stromal derived factor-1α [33], tumor necrosis factor-α [34,35], and interleukin-3 [36]. MM cells may also affect the activity of osteoclasts through their deregulation of the Notch signaling pathway, as pharmacologic inhibition of the Notch pathway has been found to result in the abrogation of RANKL-induced osteoclast differentiation in vitro and a reduction in the number of osteolytic lesions in a murine model of MM [37].…”