Targeting hedgehog-GLI-2 pathway in osteosarcoma. Osteosarcoma is the most common primary malignant tumor of bone. Patients with localized osteosarcoma are routinely treated with chemotherapy and surgery. However, many of these patients eventually relapse after these treatments. In such cases, there are limited treatment options for these patients and most will eventually die with metastatic disease. Therefore, it is imperative to identify better therapeutic strategies. Hedgehog-GLI is responsible for the development of vertebrate embryonic and tumorigenesis. Specifically, the transcription factor, GLI-2, plays a key role in development of normal prostate. Aberrant activation of GLI-2 is correlated with various malignancies. We observe that GLI-2 is highly expressed in osteosarcoma cell lines, and this correlates with poor clinical outcomes in patients. Knockdown of GLI-2 by siRNA decreases osteosarcoma cell proliferation and viability, which eventually induces cell death as revealed in both in 2D and 3D cultures. In addition, we notice that administration of GLI-2 siRNA can increase the sensitivity of osteosarcoma cells to chemotherapeutic drugs. These findings suggest GLI-2 is required for osteosarcoma cell proliferation and survival. GLI-2 may be exploited as a therapeutic target for the treatment of osteosarcoma patients.Copyright © 2012 Orthopaedic Research Society.