Tumor-derived CTHRC1 mediates ITGB3-dependent osteoclast differentiation to promote prostate cancer bone metastasis.

Bone metastasis is a leading cause of mortality in advanced prostate cancer (PCa), with limited therapeutic options. This study investigates the molecular mechanisms underlying PCa bone metastasis and identifies potential therapeutic targets. Using in vitro co-culture systems and in vivo mouse models, we demonstrated that tumor-derived Collagen Triple Helix Repeat Containing 1 (CTHRC1) promotes osteoclast differentiation, thereby contributing to the development of osteolytic lesions in PCa bone metastasis. Mechanistically, CTHRC1 cooperates with receptor activator of nuclear factor-κB ligand (RANKL) signaling to promote osteoblast-derived RANKL-mediated osteoclastogenesis by disrupting the RANKL/osteoprotegerin (OPG) system. Furthermore, CTHRC1 directly binds to integrin beta 3 (ITGB3) on osteoclasts to activate the FAK/MEK/ERK1/2 pathway and dissociate SRC signaling, jointly mediating osteoclast differentiation. Blocking the CTHRC1-ITGB3 axis significantly weakened CTHRC1-induced osteoclast differentiation and bone resorption. Collectively, our findings identify CTHRC1 as a novel mediator in the bone microenvironment, providing a potential therapeutic target for inhibiting the occurrence and progression of PCa bone metastasis.