Abstract
Upregulation of cytokines and chemokines is a frequent finding in multiple myeloma (MM). CCL3 (also known as MIP-1α) is a pro-inflammatory chemokine, levels of which in the MM microenvironment correlate with osteolytic lesions and tumor burden. CCL3 and its receptors, CCR1 and CCR5, contribute to the development of bone disease in MM by supporting tumor growth and regulating osteoclast (OC) differentiation. In this study, we identify inhibition of osteoblast (OB) function as an additional pathogenic mechanism in CCL3-induced bone disease. MM-derived and exogenous CCL3 represses mineralization and osteocalcin production by primary human bone marrow stromal cells and HS27A cells. Our results suggest that CCL3 effects on OBs are mediated by ERK activation and subsequent downregulation of the osteogenic transcription factor osterix. CCR1 inhibition reduced ERK phosphorylation and restored both osterix and osteocalcin expression in the presence of CCL3. Finally, treating SCID-hu mice with a small molecule CCR1 inhibitor suggests an upregulation of osteocalcin expression along with OC downregulation. Our results show that CCL3, in addition to its known catabolic activity, reduces bone formation by inhibiting OB function, and therefore contributes to OB/OC uncoupling in MM.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Bone Marrow Cells / metabolism
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Bone Remodeling / physiology*
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Calcification, Physiologic / physiology*
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Cell Line, Tumor / metabolism
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Chemokine CCL3 / physiology*
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Down-Regulation
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Extracellular Signal-Regulated MAP Kinases / biosynthesis
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Extracellular Signal-Regulated MAP Kinases / genetics
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Gene Expression Regulation, Neoplastic / physiology*
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Humans
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Mesenchymal Stem Cells / metabolism
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Mice
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Mice, SCID
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Multiple Myeloma / complications*
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Multiple Myeloma / metabolism
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Multiple Myeloma / pathology
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Neoplasm Proteins / biosynthesis
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Neoplasm Proteins / genetics
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Neoplasm Proteins / physiology*
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Neoplasm Transplantation
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Osteoblasts / physiology*
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Osteocalcin / biosynthesis*
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Osteocalcin / genetics
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Osteoclasts / physiology
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Osteogenesis / physiology*
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Osteolysis / etiology*
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Osteolysis / metabolism
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Osteolysis / pathology
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Receptors, CCR1 / biosynthesis
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Receptors, CCR1 / genetics
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Receptors, CCR5 / biosynthesis
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Receptors, CCR5 / genetics
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Sp7 Transcription Factor
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Stromal Cells / metabolism
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Transcription Factors / biosynthesis
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Transcription Factors / genetics
Substances
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CCL3 protein, human
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CCR1 protein, human
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Chemokine CCL3
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Neoplasm Proteins
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Receptors, CCR1
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Receptors, CCR5
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Sp7 Transcription Factor
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SP7 protein, human
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Transcription Factors
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Osteocalcin
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Extracellular Signal-Regulated MAP Kinases