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

Journal: Experimental cell research 2017;358(2):260-268

PMID: 28669663

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Abstract

1,25-dihydroxyvitamin D (1,25(OH)D) 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)D 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)D 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)D, 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)D altered their morphology from round to fusiform, while inducing paxillin focalization. 1,25(OH)D administration also up-regulated myeloid and OC genes, including C/EBPα, RANK, M-CSFR and V-ATPase, whose promoters contain potential 1,25(OH)D responsive elements. Finally, 1,25(OH)D 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)D triggers this lineage switch.

Address: 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: [email protected].; 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: [email protected].; 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: [email protected].; Department of Molecular and Translational Sciences, Section of Pharmacology, University of Brescia "Health and Wealth", V.le Europa, 11, 25123 Brescia, Italy. Electronic address: [email protected].; Department of Molecular and Translational Sciences, Section of Pharmacology, University of Brescia "Health and Wealth", V.le Europa, 11, 25123 Brescia, Italy. Electronic address: [email protected].; 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: [email protected].

DOI: 10.1016/j.yexcr.2017.06.023

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MeSH Terms: Bone Remodeling, Bone Resorption, Cell Proliferation, Cell Transdifferentiation, Hematopoiesis, Humans, Multiple Myeloma, Osteoclasts, Plasma Cells, Receptors, Calcitriol, Vitamin D