Abstract
Bone loss occurs in obesity and cancer-associated complications including wasting. This study determined whether a high-fat diet and a deficiency in monocyte chemotactic protein-1 (MCP-1) altered bone structural defects in male C57BL/6 mice with Lewis lung carcinoma (LLC) metastases in lungs. Compared to non-tumor-bearing mice, LLC reduced bone volume fraction, connectivity density, trabecular number, trabecular thickness and bone mineral density and increased trabecular separation in femurs. Similar changes occurred in vertebrae. The high-fat diet compared to the AIN93G diet exacerbated LLC-induced detrimental structural changes; the exacerbation was greater in femurs than in vertebrae. Mice deficient in MCP-1 compared to wild-type mice exhibited increases in bone volume fraction, connectivity density, trabecular number and decreases in trabecular separation in both femurs and vertebrae, and increases in trabecular thickness and bone mineral density and a decrease in structure model index in vertebrae. Lewis lung carcinoma significantly decreased osteocalcin but increased tartrate-resistant acid phosphatase 5b (TRAP 5b) in plasma. In LLC-bearing mice, the high-fat diet increased and MCP-1 deficiency decreased plasma TRAP 5b; neither the high-fat diet nor MCP-1 deficiency resulted in significant changes in plasma concentration of osteocalcin. In conclusion, pulmonary metastasis of LLC is accompanied by detrimental bone structural changes; MCP-1 deficiency attenuates and high-fat diet exacerbates the metastasis-associated bone wasting.
Highlights
Metastasis is the most devastating aspect of cancer, which is accompanied by wasting that eventually results in cachexia characterized by a significant skeletal muscle loss and multi-organ functional failures
The present study showed that the presence of Lewis lung carcinoma (LLC) and its pulmonary metastases deteriorated trabecular and cortical structure and reduced bone mineral density in mice, indicating the significance of malignancy in bone wasting
These findings indicate that Monocyte chemotactic protein-1 (MCP-1) contributes to cancerassociated bone loss
Summary
Metastasis is the most devastating aspect of cancer, which is accompanied by wasting that eventually results in cachexia characterized by a significant skeletal muscle loss and multi-organ functional failures. Limited studies indicate that bone loss can occur during cancer-associated wasting. Pathways that induce muscular wasting may promote bone loss during cachexia [3]. MCP-1 has functions beyond tissue repair; it participates in the development and progression of many pathophysiological conditions, including cancer [5,6,7]. Elevated expression of MCP-1 is associated with poor outcomes and short disease-free intervals [5,6,7], and it has prognostic value for cancer patients. In support of the clinical observations, animal studies show that MCP1 participates in primary tumor growth and metastasis [8,9,10]. In vitro studies show that MCP-1 stimulates the formation of osteoclasts [12]
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