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Macrophage Inflammatory Protein–1: A Novel Osteoclast Stimulating Factor Secreted by Renal Cell Carcinoma Bone Metastasis

Department of Orthopaedic Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland

Requests for reprints: Scott L. Kominsky, Department of Orthopaedic Surgery, 720 Rutland Avenue, Ross Building, Room 209, Johns Hopkins University School of Medicine, Baltimore, MD 21205. Phone: 410-502-6406; Fax: 410-502-6414; E-mail: kominsc{at}jhmi.edu.

Key Words: RCC • bone metastasis • MIP • osteoclast • osteolysis

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 (MIP-1), 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 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, 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 stimulated chemotaxis of two osteoclast precursor cell types: murine bone marrow mononuclear cells (BM-MNC) and RAW 264.7 cells. Furthermore, MIP-1 treatment of murine calvaria caused increased bone resorption as determined by measurement of released calcium. Correspondingly, MIP-1 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 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. [Cancer Res 2008;68(5):1261–6]