Abstract
An essential cytokine system for the osteoclast biology in multiple myeloma (MM) consists of the receptor of activator of NF-κB ligand (RANKL), its receptor (RANK), and the soluble decoy receptor, osteoprotegerin (OPG). Myeloma cells cause imbalance in OPG/RANKL interactions. We measured serum levels of OPG, soluble (s) RANKL, sRANKL/OPG ratio, markers of disease activity [LDH, CRP, interleukin-6 (IL-6), β2-microglobulin (B2M)], and angiogenic factors [hepatocyte growth factor (HGF), vascular endothelial growth factor (VEGF)], in 54 newly diagnosed MM patients and in 25 of them in plateau phase. All the above values were higher in MM patients compared to controls and decreased in plateau phase. sRANKL and RANKL/OPG were higher with advancing disease stage and skeletal grade. Significant correlations were found among RANKL and RANKL/OPG with HGF, LDH, VEGF, IL-6, and B2M. In conclusion, RANKL and OPG play significant roles in MM pathophysiology, as regulators of bone turnover and mediators of angiogenesis.
Highlights
Multiple myeloma is a malignant plasma cell proliferation localized in the bone marrow with debilitating skeletal involvement
Much of its morbidity is accounted to bone pain and pathologic fractures due to the imbalance between bone formation and breakdown in favor of the latter [1,2,3,4]. These complications are due to an excessive osteoclast activity, which are stimulated by osteoclast-activating factors, including Tumor Necrosis Factor (TNF), Interleukin1 (IL-1), Interleukin-6 (IL-6), the chemokines Macrophage Inflammatory Protein-1a (MIP-1a), Macrophage Inflammatory Protein-1β (MIP-1β), and Stroma cell-Derived Factor1a (SDF-1a) [2, 5, 6]
0 OPG before treatment OPG after treatment were increased in patients compared to controls, whereas soluble RANKL (sRANKL)/OPG ratio did not show significant difference
Summary
Multiple myeloma is a malignant plasma cell proliferation localized in the bone marrow with debilitating skeletal involvement. Much of its morbidity is accounted to bone pain and pathologic fractures due to the imbalance between bone formation and breakdown in favor of the latter [1,2,3,4]. These complications are due to an excessive osteoclast activity, which are stimulated by osteoclast-activating factors, including Tumor Necrosis Factor (TNF), Interleukin (IL-1), Interleukin-6 (IL-6), the chemokines Macrophage Inflammatory Protein-1a (MIP-1a), Macrophage Inflammatory Protein-1β (MIP-1β), and Stroma cell-Derived Factor1a (SDF-1a) [2, 5, 6]. Myeloma plasma cells have been found to induce an imbalance in the OPG/RANKL interactions, increasing RANKL expression and decreasing OPG availability in the bone microenvironment, inducing an enhancement of the osteoclastic activation and increased bone resorption [8, 11]
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