Prostate cancer-induced bone formation controlled by bone resorptive inflammatory cytokine IL-1.
Sugasaki M., Ikeda K., Furukawa A., Watanabe K., Kasuga U., Shimizu K., Takatoya M., Matsumoto C., Miyaura C., Tominari T., Itoh Y., Hirata M., Inada M.
Prostate cancer frequently metastasizes to the bones, leading to irregular bone formation and an inflammatory response. Interleukin 1 (IL-1) is a potent inflammatory cytokine that promotes bone resorption; however, its role in prostate cancer (PC)-induced bone formation remains unclear. In this study, we investigated the role of IL-1 in irregular bone formation induced by prostate cancer. The newly invented osteogenic co-culture system (osteoblasts and PC cells) increased the number of alkaline phosphatase-positive osteoblasts and calcified bone nodules. Bone formation is associated with an upregulated expression of osteogenic genes, such as Bmp2, Wnt5a, Runx2, and Il1a, in osteoblasts. Similarly, co-culture with fixed PC cells also resulted in an increased formation of calcified bone nodules, associated with an upregulated expression of osteogenic genes and Il1a. Treatment of osteoblasts with IL-1 promoted bone formation, which induced rapid phosphorylation of JNK, ERK, and p38 MAPKs in osteoblasts. Inhibition of MAPK signaling, specifically with JNK and p38 inhibitors, clearly suppressed IL-1-induced bone formation. These findings suggest that PC-induced IL-1 is a crucial factor in promoting irregular bone formation through the JNK and p38 signaling pathways in osteoblasts at the site of bone metastasis. The phenotype induced by IL-1, which promotes bone formation, represents an essential mechanism for understanding the regulation of bone formation involved in post-inflammatory repair.