title: Bone marrow stromal cells derived MCP-1 reverses the inhibitory effects of multiple myeloma cells on osteoclastogenesis by upregulating the RANK expression.
abstract: 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.
authors: Department of Lymphoma and Myeloma, Division of Cancer Medicine, Center for Cancer Immunology Research, The University of Texas M D Anderson Cancer Center, Houston, Texas, United States of America.
authors: Zhiqiang
authors: Z
authors: Liu
authors: Jingda
authors: J
authors: Xu
authors: Haiyan
authors: H
authors: Li
authors: Yuhuan
authors: Y
authors: Zheng
authors: Jin
authors: J
authors: He
authors: Huan
authors: H
authors: Liu
authors: Yuping
authors: Y
authors: Zhong
authors: Yong
authors: Y
authors: Lu
authors: Bangxing
authors: B
authors: Hong
authors: Mingjun
authors: M
authors: Zhang
authors: Pei
authors: P
authors: Lin
authors: Juan
authors: J
authors: Du
authors: Jian
authors: J
authors: Hou
authors: Jianfei
authors: J
authors: Qian
authors: Larry W
authors: LW
authors: Kwak
authors: Qing
authors: Q
authors: Yi
authors: Jing
authors: J
authors: Yang
mesh_terms: D001854:Bone Marrow Cells / Q000378:metabolism* / Q000473:pathology; D018932:Chemokine CCL2 / Q000378:metabolism*; D018920:Coculture Techniques; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D016753:Interleukin-10 / Q000096:biosynthesis; D008297:Male; D009000:Monocytes / Q000378:metabolism / Q000473:pathology; D009101:Multiple Myeloma / Q000378:metabolism* / Q000473:pathology; D009363:Neoplasm Proteins / Q000378:metabolism*; D010010:Osteoclasts / Q000378:metabolism* / Q000473:pathology; D053246:Receptor Activator of Nuclear Factor-kappa B / Q000096:biosynthesis*; D017154:Stromal Cells / Q000378:metabolism / Q000473:pathology; D014407:Tumor Cells, Cultured; D015854:Up-Regulation
chemical_list: C111835:CCL2 protein, human; D018932:Chemokine CCL2; C508609:IL10 protein, human; D009363:Neoplasm Proteins; D053246:Receptor Activator of Nuclear Factor-kappa B; C505686:TNFRSF11A protein, human; D016753:Interleukin-10