Bone-resorbing activity from cholesterol-exposed macrophages due to enhanced expression of interleukin-1alpha

The presence of cholesterol crystals, macrophages, and foreign giant cells has been associated with impaired bone healing of periapical lesions. Therefore, we investigated whether macrophages exposed to cholesterol crystals can release factors changing the activity of bone-resorbing osteoclasts. Mouse peritoneal macrophages treated with cholesterol crystals in vitro produced factor(s) that stimulated the release of 45Ca and 3H from mouse calvariae pre-labeled with 45Ca(CaCl2) or [3H]-proline, respectively. No bone-resorbing activity was released by epithelial cells, fibroblasts, or osteoblasts exposed to cholesterol crystals. Interleukin-1 receptor antagonist protein and antiserum neutralizing mouse interleukin-1alpha (IL-1alpha) inhibited 45Ca release induced by cholesterol-activated macrophages. The addition of cholesterol to the macrophages augmented the release of IL-1alpha protein and the expression of IL-1alpha mRNA. These findings indicate that frustrated phagocytosis by macrophages exposed to cholesterol crystals results in release of factors stimulating osteoclastic bone resorption, primarily due to increased transcription of the IL-1alpha gene.