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CTHRC1 promotes bone metastasis in prostate cancer

ABSTRACT: Prostate cancer causes a high frequency of bone metastases. The purpose of this study was to identify molecules that regulate prostate cancer bone metastasis as potential therapeutic and/or prognostic targets in prostate cancer, using integrative genome-wide data. Based on the biological characterization of prostate cancer cell lines and integrated big data analysis of clinical samples, we identified CTHRC1 as a candidate gene that regulates prostate cancer bone metastasis. The knockdown of CTHRC1 suppressed cell migration and cell adhesion, but not cell proliferation, in vitro and in vivo. In a mouse tibia xenograft model, CTHRC1 knockdown markedly suppressed metastatic growth of prostate cancer cells in the bone microenvironment. CTHRC1 also promoted in vitro osteoclast differentiation. The analysis of 343 human prostate cancer biopsy samples showed that CTHRC1 expression was positively correlated with bone metastasis, indicating that CTHRC1 could be a useful predictive marker for bone metastasis. Our findings illustrate the clinical relevance of CTHRC1 and demonstrate that CTHRC1 plays an important role in prostate cancer bone metastasis. CTHRC1 may be useful for predicting prostate cancer bone metastasis and may lead to the development of new methods for the prevention and treatment of metastasis.

ORGANISM(S): Homo sapiens

PROVIDER: GSE293083 | GEO | 2026/03/24

REPOSITORIES: GEO

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Project description:Bone remodeling is characterized by the sequential, local tethering of osteoclasts and osteoblasts, and is key to the maintenance of bone integrity. While bone matrix-mobilized growth factors, such as TGF-β, are proposed to regulate remodeling, no in vivo evidence exists that an osteoclast-produced molecule is the enigmatic coupling factor. We have identified Cthrc1, a protein secreted by mature bone-resorbing osteoclasts, that targets stromal cells so as to stimulate osteogenesis. The expression of Cthrc1 is robustly induced when mature osteoclasts are placed on dentin or hydroxyapatite, and also by increasing extracellular calcium. Cthrc1 expression in bone increases in a high turnover state, such as that which is induced by RANKL injections in vivo, whereas it decreases with aging or following alendronate treatment, conditions associated with suppressed bone turnover. The targeted deletion of the Cthrc1 gene eliminates Cthrc1 expression in bone, whereas its deficiency in osteoblasts does not exert any significant effect. Osteoclast-specific deletion of the Cthrc1 gene results in osteopenia due to reduced bone formation: it also impairs the coupling process following resorption induced by RANKL injections, with a resultant impairment of bone mass recovery. Thus, Cthrc1 is an osteoclast-secreted “coupling factor” that regulates bone remodeling and hence, skeletal integrity. Total bone marrow cells were prepared from the femurs and tibias of 8-10-week-old C57BL/6 mice and cultured in the presence of M-CSF (100ng/ml) for 3 days as described previously (Takeshita et al., 2000 JBMR 15:1477-1488). Cells were harvested with 0.02% EDTA/PBS and used as bone marrow macrophages (BMMs). These BMMs were cultured in the presence of M-CSF (100 ng/ml) and RANKL (100ng/ml) for 2 days. TRAP positive mononuclear cells were harvested and used as pre-osteoclasts (pOC). These pOC cells were further cultured in the presence of M-CSF and RANKL for 2 days in normal plastic plate or on dentin slices. After 2 days, multinucleated TRAP positive mature osteoclasts were generated as mature osteoclasts on plate (mOCp) and mature resorbing osteoclasts on dentin (mOCd), respectively. RNAs were extracted from four different stages of osteoclast lineage cells; BMMs, pOC, mOCp and mOCd, and used for microarray analysis.

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CTHRC1 promotes bone metastasis in prostate cancer

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