Prostate cancer-induced bone formation controlled by bone resorptive inflammatory cytokine IL-1

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.