Abstract
Approximately 30% of patients with renal cell carcinoma (RCC) develop bone metastasis, which is characterized by extensive osteolysis leading to severe bone pain and pathologic fracture. Although the mechanism of RCC-induced osteolysis is unknown, studies of bone metastasis have shown that tumor-induced changes in bone remodeling are likely mediated by alterations in the bone microenvironment. Here, we report the discovery of a novel osteoclast stimulatory factor secreted by RCC bone metastasis (RBM). Through microarray analysis, we found expression of the chemokine, macrophage inflammatory protein-1 delta (MIP-1 delta), to be increased in RBM versus patient-matched primary RCC tissues and confirmed this finding by quantitative reverse transcription-PCR (qRT-PCR) and ELISA (P < 0.05). Furthermore, MIP-1 delta expression in RBM tissues was significantly (P < 0.001) higher than in human bone marrow, suggesting a potential alteration of the bone microenvironment. The receptors for MIP-1 delta, CCR1 and CCR3, were expressed in both osteoclast precursors and mature, bone-resorbing osteoclasts as shown by qRT-PCR and Western analysis. In functional studies, MIP-1 delta stimulated chemotaxis of two osteoclast precursor cell types: murine bone marrow mononuclear cells (BM-MNC) and RAW 264.7 cells. Furthermore, MIP-1 delta treatment of murine calvaria caused increased bone resorption as determined by measurement of released calcium. Correspondingly, MIP-1 delta significantly enhanced osteoclast formation and activity in response to RANKL in both BM-MNC and RAW 264.7 cells. Taken together, these data suggest that MIP-1 delta expression is increased in RBM relative to RCC and bone marrow, and may promote RBM-induced osteolysis by stimulating the recruitment and differentiation of osteoclast precursors into mature osteoclasts.
Highlights
Renal cell carcinoma (RCC) is the most common malignant tumor arising from the kidney, accounting for f30,000 new cases per year in the United States
Studies suggest that macrophage inflammatory protein (MIP)-1a plays a role in mediating osteolysis associated with multiple myeloma
We performed quantitative reverse transcription-PCR (qRT-PCR) to directly compare the MIP-1y mRNA expression levels in the RCC bone metastasis (RBM) and RCC tissue samples used for microarray analysis
Summary
Renal cell carcinoma (RCC) is the most common malignant tumor arising from the kidney, accounting for f30,000 new cases per year in the United States. Doi:10.1158/0008-5472.CAN-07-6122 pathologic fracture [1] These complications result from the ability of RCC cells to disrupt the delicate balance of bone remodeling, leading to pathologic bone loss. Despite increased research, the mechanisms through which RCC cells alter the bone remodeling process remain unknown. Chemokines are well-known for mediating inflammatory responses by stimulating the recruitment of leukocytes; recent evidence suggests that they may play a role in mediating pathologic bone loss. Studies suggest that macrophage inflammatory protein (MIP)-1a plays a role in mediating osteolysis associated with multiple myeloma. Bone marrow plasma from multiple myeloma patients show increased levels of MIP-1a relative to normal controls [4]. MIP-1a stimulates osteoclast development in human bone marrow cultures [5]
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