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

• Published in: Cancer research (Chicago, Ill.) Vol. 68; no. 5; pp. 1261 - 1266
• Main Authors: KOMINSKY, Scott L, ABDELMAGID, Samir M, DOUCET, Michele, BRADY, Kelly, WEBER, Kristy L
• Format: Journal Article
• Language: English
• Published: Philadelphia, PA American Association for Cancer Research 01.03.2008
• Subjects: Animals; Antineoplastic agents; Biological and medical sciences; Bone and Bones - metabolism; Bone and Bones - pathology; Carcinoma, Renal Cell - metabolism; Carcinoma, Renal Cell - pathology; Cell Differentiation; Cell Movement; Diseases of the osteoarticular system; Gene Expression Regulation, Neoplastic; Humans; Kidney Neoplasms - metabolism; Kidney Neoplasms - pathology; Kidneys; Leukocytes, Mononuclear - metabolism; Macrophage Inflammatory Proteins - chemistry; Macrophage Inflammatory Proteins - physiology; Medical sciences; Mice; Neoplasm Metastasis; Nephrology. Urinary tract diseases; Osteoclasts - metabolism; Pharmacology. Drug treatments; RANK Ligand - metabolism; Reverse Transcriptase Polymerase Chain Reaction; Tumors; Tumors of striated muscle and skeleton; Tumors of the urinary system; Kidney disease; Urinary system disease; Carcinoma; Secretion; Diseases of the osteoarticular system; Osteoclast; Malignant tumor; Osteoarticular system; Bone metastasis; Kidney cancer; Grawitz tumor; Bone; Macrophage inflammatory protein; Cancer
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.CAN-07-6122

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.