Abstract
Multiple myeloma is a malignant expansion of plasma cells and aggressively affects bone health. We show that P2X7 receptor altered myeloma growth, which affects primary bone cells in vitro. Expression on six human myeloma cell lines confirmed the heterogeneity associated with P2X7 receptor. Pharmacology with 2′(3′)-O-(4-benzoylbenzoyl) adenosine 5′-triphosphate (BzATP) as agonist showed dose-dependent membranal pores on RPMI-8226 (p = 0.0027) and blockade with P2X7 receptor antagonists. Ca2+ influx with increasing doses of BzATP (p = 0.0040) was also inhibited with antagonists. Chronic P2X7 receptor activation reduced RPMI-8226 viability (p = 0.0208). No apoptosis or RPMI-8226 death was observed by annexin V/propidium iodide (PI) labeling and caspase-3 cleavage, respectively. However, bromodeoxyuridine (BrdU) labelling showed an accumulation of RPMI-8226 in the S phase of cell cycle progression (61.5%, p = 0.0114) with significant decline in G0/G1 (5.2%, p = 0.0086) and G2/M (23.5%, p = 0.0015) phases. As myeloma pathology depends on a positive and proximal interaction with bone, we show that P2X7 receptor on RPMI-8226 inhibited the myeloma-induced suppression on mineralization (p = 0.0286) and reversed the excessive osteoclastic resorption. Our results demonstrate a view of how myeloma cell growth is halted by P2X7 receptor and the consequences on myeloma–osteoblast and myeloma–osteoclast interaction in vitro.
Highlights
Multiple myeloma (MM) is a malignant growth of plasma cells and a unique neoplasia of hematologic origin
Factors released during the bone remodeling favor myeloma growth and, in turn, myeloma cells contribute to cytokines that disrupt homeostatic bone turnover
We address that P2X7 receptor alters myeloma growth and the downstream events following P2X7 receptor activation
Summary
Multiple myeloma (MM) is a malignant growth of plasma cells and a unique neoplasia of hematologic origin. The latter is due to the bone-related complications in approximately 90% of MM patients owing to excessive bone destruction and insufficient bone formation [1]. Factors released during the bone remodeling favor myeloma growth and, in turn, myeloma cells contribute to cytokines that disrupt homeostatic bone turnover. Bisphosphonates are the mainstay treatment to preserve bone integrity, but morbidity and mortality remain significant [2]. Strategies counteracting the dependence of MM growth on the bone microenvironment have guided key discoveries including immunomodulators, Cells 2020, 9, 2341; doi:10.3390/cells9112341 www.mdpi.com/journal/cells. Cells 2020, 9, 2341 surface antibodies, and immune checkpoint agents [3]. Whilst advances have extended survival in many patients, more avenues are needed to achieve a complete remission
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