1,25(OH)2 vitamin D(3) contributes to osteoclast-like trans-differentiation of malignant plasma cells

Paola Cafforio; Stella D'Oronzo; Claudia Felici; Sandra Sigala; Martina Fragni; Francesco Silvestris

doi:10.1016/j.yexcr.2017.06.023

1,25(OH)2 vitamin D(3) contributes to osteoclast-like trans-differentiation of malignant plasma cells

Exp Cell Res. 2017 Sep 15;358(2):260-268. doi: 10.1016/j.yexcr.2017.06.023. Epub 2017 Jun 29.

Authors

Paola Cafforio¹, Stella D'Oronzo², Claudia Felici³, Sandra Sigala⁴, Martina Fragni⁵, Francesco Silvestris⁶

Affiliations

¹ Department of Biomedical Sciences and Human Oncology, Section of Internal Medicine and Clinical Oncology, University of Bari Aldo Moro, P.za G. Cesare, 11, 70124 Bari, Italy. Electronic address: paola.cafforio@uniba.it.
² Department of Biomedical Sciences and Human Oncology, Section of Internal Medicine and Clinical Oncology, University of Bari Aldo Moro, P.za G. Cesare, 11, 70124 Bari, Italy. Electronic address: stella.doronzo@uniba.it.
³ Department of Biomedical Sciences and Human Oncology, Section of Internal Medicine and Clinical Oncology, University of Bari Aldo Moro, P.za G. Cesare, 11, 70124 Bari, Italy. Electronic address: claudia.felici@uniba.it.
⁴ Department of Molecular and Translational Sciences, Section of Pharmacology, University of Brescia "Health and Wealth", V.le Europa, 11, 25123 Brescia, Italy. Electronic address: sandra.sigala@unibs.it.
⁵ Department of Molecular and Translational Sciences, Section of Pharmacology, University of Brescia "Health and Wealth", V.le Europa, 11, 25123 Brescia, Italy. Electronic address: martina.fragni@unibs.it.
⁶ Department of Biomedical Sciences and Human Oncology, Section of Internal Medicine and Clinical Oncology, University of Bari Aldo Moro, P.za G. Cesare, 11, 70124 Bari, Italy. Electronic address: francesco.silvestris@uniba.it.

PMID: 28669663
DOI: 10.1016/j.yexcr.2017.06.023

Abstract

1,25-dihydroxyvitamin D (1,25(OH)₂D) exerts pleiotropic effects including bone turnover and immune system regulation. It inhibits both T and B cell proliferation while decreasing the secretion of inflammatory cytokines and immunoglobulins. 1,25(OH)₂D also modulates monocyte-macrophage and osteoclast (OC) maturation. Since we have previously described that malignant plasma cells may trans-differentiate towards the myeloid lineage participating to skeletal devastation in multiple myeloma (MM), we here evaluated in vitro the role of 1,25(OH)₂D in this lineage switch. We investigated the gene and protein expression of vitamin D receptor (VDR) in MM cell lines. Thus, after cell treatment with 1,25(OH)₂D, we analyzed their morphology and the expression of myeloid and OC markers. Finally, we assessed their bone resorption property on calcium phosphate slices. All MM cells expressed VDR in nuclear and perinuclear sites. Treatment with 1,25(OH)₂D altered their morphology from round to fusiform, while inducing paxillin focalization. 1,25(OH)₂D administration also up-regulated myeloid and OC genes, including C/EBPα, RANK, M-CSFR and V-ATPase, whose promoters contain potential 1,25(OH)₂D responsive elements. Finally, 1,25(OH)₂D increased MM cell capability to generate pits of erosion on calcium phosphate discs. This data suggest that myeloma cells may undergo a functional trans-differentiation into OCs and, under appropriate experimental conditions, 1,25(OH)₂D triggers this lineage switch.

Keywords: Bone erosion; Multiple myeloma; Osteoclasts; Plasma cells; Vitamin D.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Bone Remodeling / drug effects
Bone Resorption / drug therapy
Cell Proliferation / drug effects
Cell Transdifferentiation / drug effects*
Hematopoiesis / drug effects
Humans
Multiple Myeloma / drug therapy
Multiple Myeloma / pathology
Osteoclasts / cytology
Plasma Cells / drug effects*
Plasma Cells / pathology
Receptors, Calcitriol / genetics
Vitamin D / analogs & derivatives*
Vitamin D / pharmacology

Substances

Receptors, Calcitriol
Vitamin D
1,25-dihydroxyvitamin D