Bone marrow stromal cells derived MCP-1 reverses the inhibitory effects of multiple myeloma cells on osteoclastogenesis by upregulating the RANK expression

• Published in: PloS one Vol. 8; no. 12; p. e82453
• Main Authors: Liu, Zhiqiang, Xu, Jingda, Li, Haiyan, Zheng, Yuhuan, He, Jin, Liu, Huan, Zhong, Yuping, Lu, Yong, Hong, Bangxing, Zhang, Mingjun, Lin, Pei, Du, Juan, Hou, Jian, Qian, Jianfei, Kwak, Larry W, Yi, Qing, Yang, Jing
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 10.12.2013; Public Library of Science (PLoS)
• Subjects: Aberration; Analysis; Biocompatibility; Biology; Bone diseases; Bone marrow; Bone Marrow Cells - metabolism; Bone Marrow Cells - pathology; Bone resorption; Cancer; Cell activation; Chemokine CCL2 - metabolism; Chemokines; Coculture Techniques; Crosstalk; Cytokines; Female; Gene expression; Gene Expression Regulation, Neoplastic; Genes; Hematology; Humans; Immunoglobulins; Immunology; Inhibition; Interleukin 10; Interleukin-10 - biosynthesis; Kinases; Ligands; Lymphoma; Male; Medical research; Medicine; Monocyte chemoattractant protein 1; Monocytes; Monocytes - metabolism; Monocytes - pathology; Multiple myeloma; Multiple Myeloma - metabolism; Multiple Myeloma - pathology; Neoplasm Proteins - metabolism; Osteoclastogenesis; Osteoclasts - metabolism; Osteoclasts - pathology; Osteoporosis; Phosphatase; Proteins; Rankings; Receptor Activator of Nuclear Factor-kappa B - biosynthesis; Signaling; Stat3 protein; Stromal cells; Stromal Cells - metabolism; Stromal Cells - pathology; TRANCE protein; Tumor Cells, Cultured; Up-Regulation; Cleveland Ohio; Ohio; United States > US; Texas
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0082453

Multiple myeloma (MM) cells are responsible for aberrant osteoclast (OC) activation. However, when cocultured monocytes, but not OC precursors, with MM cells, we made a novel observation that MM cells inhibited receptor activator of nuclear factor κB ligand (RANKL)-induced increase of OC differentiation, OC gene expression, signaling pathways and bone resorption activity. Our results showed that MM cells produced multiple inhibitory cytokines of osteoclastogenesis, such as IL-10, which activated STAT3 signaling and induce OC inhibition. However, cocultures of bone marrow stromal cells (BMSCs) reversed MM-induced OC inhibition. We found that MM cells increased production of MCP-1 from BMSCs and BMSC-derived MCP-1 enhanced OC formation. Mechanistic studies showed that IL-10 downregulated RANK expression in monocytes and thus, inhibited RANKL-induced OC formation. In contrast, MCP-1 upregulated RANK expression and thus, enhanced OC formation. Overall, our studies for the first time demonstrated that MM cell have inhibitory effects on osteoclastogenesis by producing inhibitory cytokines. Our results further indicate that activation of osteoclastogenesis in bone marrow requests the crosstalk of MM cells, BMSCs and their produced cytokines. Thus, our studies provide evidences that targeting bone marrow microenvironmental cells and/or cytokines may be a new approach to treating MM bone destruction.