Tumor-Derived CTHRC1 Mediates ITGB3-Dependent Osteoclast Differentiation to Promote Prostate Cancer Bone Metastasis

Background: Bone metastasis represents the most common and fatal stage of advanced prostate cancer (PCa) with the poor prognosis. This study aims to elucidate the mechanisms underlying the development and progression of bone-metastatic PCa and to identify potential therapeutic targets. Methods: Bioinformatics analysis and immunohistochemistry were employed to identify the key gene Collagen Triple Helix Repeat Containing 1 (CTHRC1) involved in PCa bone metastasis. In vivo models, including left cardiac ventricle and tibial injections, were utilized to investigate changes in bone metastasis mediated by CTHRC1 secreted by PCa. In addition, an in vitro co culture system of PCa cells with osteoclasts and osteoblasts was established to explore the role and potential mechanism of CTHRC1 in mediating osteoclast differentiation and promoting bone metastasis. Results: We utilize in vitro co-culture systems and in vivo mice models to demonstrate that CTHRC1 promotes osteoclast differentiation, leading to osteolytic change in PCa bone metastasis. Mechanistically, CTHRC1 binds to integrin beta 3 (ITGB3) on osteoclasts, activating the SRC/FAK/ERK1/2 signaling cascade to initiate the osteoclastogenesis. Furthermore, CTHRC1 cooperates with receptor activator of nuclear factor-κB ligand (RANKL) signaling to enhance osteoblast-mediated osteoclast differentiation by modulating the RANKL/osteoprotegerin system. Blocking CTHRC1 with anti-ITGB3 can reduce the progression of bone metastasis in mouse models, providing a new perspective for the treatment of PCa bone metastasis Conclusion: Our findings identify CTHRC1 as a novel mediator in the bone microenvironment, offering a potential therapeutic target for inhibiting the occurrence and progression of PCa bone metastasis.