GPR84 potently inhibits osteoclastogenesis and alleviates osteolysis in bone metastasis of colorectal cancer.

The expression of GPR84 in bone marrow-derived monocytes/macrophages (BMMs) can inhibit osteoclast formation; however, its role in bone metastasis of colorectal cancer (CRC) is still unknown. To investigate the effects of GPR84 on bone metastasis of CRC, the murine CRC cell line MC-38 was injected into tibial bone marrow. We found that the expression of GPR84 in BMMs was gradually downregulated during bone metastasis of CRC, and the activation of GPR84 significantly prevented osteoclastogenesis in the tumor microenvironment. Mechanistically, the MAPK pathway mediated the effects of GPR84 on osteoclast formation. Moreover, we found that IL-11 at least partly inhibited the expression of GPR84 in the tumor microenvironment through the inactivation of STAT1. Additionally, activation of GPR84 could prevent osteolysis during bone metastasis of CRC. Our results suggest that CRC cells downregulate the expression of GPR84 in BMMs to promote osteoclastogenesis in an IL-11-dependent manner. Thus, GPR84 could be a potential therapeutic target to attenuate bone destruction induced by CRC metastasis.