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T argeted therapeutics are needed to improve the prognosis of patients with osteosarcoma. Since the introduction of chemotherapy in the 1980s, 5-year survival for the often young patients with osteosarcoma has plateaued at about 50% to 60%. For patients with metastases, the outcomes remains particularly poor. By performing a serial analysis of a gene expression experiment comparing osteosarcomas with normal osteoblasts and mesenchymal stem cells, the authors identified the insulin-like growth factor (IGF) pathway and the transforming growth factor-b (TGF-b) pathway as possible targets for therapy. Since the effects of stimulation or inhibition of the TGF-b pathway on osteosarcoma cell proliferation is debatable [9], and the developed TGFb pathway inhibiting agents elicit unwanted effects [13], we will focus on the possibility of targeting the IGF pathway in osteosarcoma. The current paper emphasizes that the IGF pathway plays an important role in osteosarcoma pathogenesis, which is supported by other preclinical studies showing reduced proliferation in the majority of osteosarcoma cell lines [7] and xenografts [6] upon IGF 1 receptor (IGF-1R) inhibition. In addition, the peak incidence of osteosarcoma correlates with the increased levels of growth hormone and IGF ligands in puberty, and it has been described that the expression of several IGF pathway members (IGF1R, IGF-1, growth arrest-specific 6, and IGF binding proteins 4 [IGFBP4]) correlates with osteosarcoma prognosis [4, 7]. However, clinical trials demonstrate that only a small subset of osteosarcoma patients respond to IGF1R antibodies [3]. This illustrates the general trend with IGF-1R inhibitors. Although preclinical models have shown promising results, evidence for their efficacy in large-scale randomized controlled trials is lacking. As a This CORR Insights is a commentary on the article ‘‘Transcriptional Profiling Identifies the Signaling Axes of IGF and Transforming Growth Factor-b as Involved in the Pathogenesis of Osteosarcoma’’ by Yang and colleagues available at: DOI: 10.1007/ s11999-015-4578-1. The authors certify that they, or any members of their immediate families, have no funding or commercial associations (eg, consultancies, stock ownership, equity interest, patent/licensing arrangements, etc.) that might pose a conflict of interest in connection with the submitted article. All ICMJE Conflict of Interest Forms for authors and Clinical Orthopaedics and Related Research editors and board members are on file with the publication and can be viewed on request. The opinions expressed are those of the writers, and do not reflect the opinion or policy of CORR or The Association of Bone and Joint Surgeons. This CORR Insights comment refers to the article available at DOI: 10.1007/s11999-0154578-1. E. F. P. Peterse MSc, J. V. M. G. Bovee MD, PhD (&) Department of Pathology, Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, The Netherlands e-mail: J.V.M.G.bovee@lumc.nl CORR Insights Published online: 12 November 2015 The Author(s) 2015. This article is published with open access at Springerlink.com

clinical orthopaedics and related research

CORR Insights®: Transcriptional Profiling Identifies the Signaling Axes of IGF and Transforming Growth Factor-β as Involved in the Pathogenesis of Osteosarcoma