ABSTRACT: SaOS2 osteosarcoma cells were cultured with or without atorvastatin (10 µM) for 6, 15 or 24h (2 biological replcates). RNA were isolated and hybridized to RNG microarrays. Background Osteosarcoma is the most common primary tumor of bone. The rapid development of metastatic lesions and resistance to chemotherapy remain major mechanisms responsible for the failure of treatments and poor survival rate for patients. Methods We previously showed that the HMGCoA reductase inhibitors statins exhibit anti-tumoral effects on osteosarcoma cells. Here, using microarray analysis, we identify cyr61/CCN1 as a new target of statins. Modulations of expression of cyr61 were performed in human and murine osteosarcoma cell lines to investigate in vitro cell viability, migratory potential and invasiveness. Cyr61 expression was evaluated in 231 tissue cores from osteosarcoma patients using tissue microarray. Tumor behavior and metastases occurence were analysed by IM injection of modified osteosarcoma cells to BALB/c mice. Results Transcriptome comparisons revealed that statins down-regulate cyr61 expression in SaOS2 cells. Cyr61 silencing in human and murine osteosarcoma cell lines enhanced cell death, but reduced cell migration and cell invasion compared to parental cells whereas cyr61 overexpression had opposite effects. Tissue microarray analysis demonstrated that cyr61 protein expression is higher in human osteosarcoma compared to normal bone tissue and is further increased in metastatic tissues. In vivo, cyr61 overexpression in osteosarcoma cells enhanced lung metastases development whereas cyr61 silencing strongly reduced metastases in mice. Conclusion The results reveal that cyr61 expression increases with tumor grade in human osteosarcoma and demonstrate that cyr61 silencing inhibits in vitro osteosarcoma cell invasion and migration as well as in vivo lung metastases in mice. These data provide a novel molecular target for therapeutic intervention in metastatic osteosarcoma. Dye balance-experiment comparing atorvastatin versus untreated cells at 6, 15 and 24 hours using 2 biological replicates.