Research ArticleCancer

RANKL blockade prevents and treats aggressive osteosarcomas

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Science Translational Medicine  09 Dec 2015:
Vol. 7, Issue 317, pp. 317ra197
DOI: 10.1126/scitranslmed.aad0295

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  • Response to Walkley and Martin comment on RANKL blockade

    We are happy to respond to your concerns regarding our paper entitled “RANKL blockade prevents and treats aggressive osteosarcomas” published in Science Translational Medicine, Vol 7, issue 317 (317 ra 197) on Dec 9, 2015.
    First, our goal was to generate a conditional deletion of Rank in osteoclasts, without causing osteopetrosis, and the inducible Mx1-Cre was ideal to allow deletion after the bones had matured. This promoter has been shown to target osteoclasts (1). The suggested inducible cathepsin K-Cre mice (2) only became available in 2012 after these particular experiments were done, and constitutive cathepsin K-Cre expressing mice can present additional unwarranted drawback due to unexpected germline deletion of gene in mice (3). With regard to off-target effects: RANK immunohistochemistry and TRAP staining showed that, although our treatment with pIpC induced extensive osteoclast inactivation ahead of tumorigenesis, there still existed many RANK positive cells within the bone(Fig S6). B) Although Mx1-Cre mediated Rank deletion might occur in skeletal stem and progenitors that give rise to osteoblasts, this is not of concern here because i) RANK is not expressed in normal osteoblasts, although it is ectopically expressed in some osteosarcomas; ii) we provided evidence that Col1α1-Cre mediated Rank deletion in the osteoblast lineage alone has no impact on tumor development or progression in the MOTO GEMM.
    With regard to our pIpC induction regimen: To comp...

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    Competing Interests: None declared.
  • RE: RANKL blockade prevents and treats aggressive osteosarcomas. Yan Chen, Marco A. Di Grappa, Sam D. Molyneux, Trevor D. McKee, Paul Waterhouse, Josef M. Penninger and Rama Khokha (December 9, 2015). Science Translational Medicine 7 (317), 317ra197.
    • Carl Walkley, St Vincent's Institute
    • Other Contributors:
      • T John Martin, St Vincent's Institute

    We read with interest the recent study from Chen and colleagues describing the impact of RANKL blockade in osteosarcoma. There is an urgent need for new therapeutic approaches in OS and this study represents an important preclinical evaluation of a potential new treatment. Several of the experiments and conclusions based on them caught our attention and raised questions that were not addressed either in the main text nor supplemental information.

    Firstly, the authors claim to demonstrate that osteoclast specific deletion of Rank impacted on OS. The authors have used Mx1-Cre to undertake these studies and treated the mice with pIpC to induce Cre activity to delete a conditional Rank allele. Whilst this is a good model for somatic deletion of Rank, it is not able to be interpreted as osteoclast specific nor hematopoietic restricted. There are a large number of studies demonstrating that Mx1-Cre induces recombination of loxP flanked alleles very broadly in hematopoietic cells including hematopoietic stem and progenitors, skeletal stem and progenitor cells (that give rise to osteoblasts and would be potentially forming the OS in these models) and many other tissues in the mouse. See amongst a large number of studies PMID: 7660125, 17574022, 16754850, 22385654, 19322176, 16598206, 21123947 and https://www.jax.org/strain/005673. Furthermore the induction regimen used is considerably different from that contained in previous...

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    Competing Interests: None declared.

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