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Modulating hedgehog signaling can attenuate the severity of osteoarthritis

Nature Medicine volume 15, pages 1421–1425 (2009)Cite this article

A Corrigendum to this article was published on 01 January 2010

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Abstract

Osteoarthritis is associated with the irreversible degeneration of articular cartilage. Notably, in this condition, articular cartilage chondrocytes undergo phenotypic and gene expression changes that are reminiscent of their end-stage differentiation in the growth plate during skeletal development1,2. Hedgehog (Hh) signaling regulates normal chondrocyte growth and differentiation3,4,5,6,7,8; however, the role of Hh signaling in chondrocytes in osteoarthritis is unknown. Here we examine human osteoarthritic samples and mice in which osteoarthritis was surgically induced and find that Hh signaling is activated in osteoarthritis. Using several genetically modified mice, we found that higher levels of Hh signaling in chondrocytes cause a more severe osteoarthritic phenotype. Furthermore, we show in mice and in human cartilage explants that pharmacological or genetic inhibition of Hh signaling reduces the severity of osteoarthritis and that runt-related transcription factor-2 (RUNX2) potentially mediates this process by regulating a disintegrin and metalloproteinase with thrombospondin type 1 motif-5 (ADAMTS5) expression. Together, these findings raise the possibility that Hh blockade can be used as a therapeutic approach to inhibit articular cartilage degeneration.

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Figure 1: Hh signaling targets are expressed in osteoarthritis.
Figure 2: Activation of Hh signaling predisposes to osteoarthritis in mice.
Figure 3: Hh signaling blockade attenuates the severity of surgically induced osteoarthritis in mice.
Figure 4: Hh modulation regulates the expression of genes implicated in osteoarthritis in human samples.

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Change history

  • 07 January 2010

    In the version of this article initially published, the author name Amanda S. Ali was incorrect. The correct name is S. Amanda Ali. The error has been corrected in the HTML and PDF versions of the article.

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Acknowledgements

We wish to thank D. Backstein and A. Gross (Mount Sinai Hospital, Toronto) for assistance obtaining human cartilage samples, T. Mak (University Health Network, Toronto) for assistance obtaining the hedgehog blocking agent, L. Morikawa for assistance with sectioning and histology, P. Roughley (McGill University) for providing the COL2-rtTA-Cre mice and R. Ward and C.-C. Hui for their assistance with the Ptch1+/− mice. The Canada Research Chair program supports B.A.A. A.C.L. and C.H. are supported by Canadian Institutes of Health Research studentships; L.H. and S.A.A. are supported by Ontario graduate scholarships. This work was supported by the Canadian Institutes of Health Research grant FRN: 79436.

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Authors and Affiliations

  1. Program in Developmental and Stem Cell Biology, Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada

    Alvin C Lin, Brian L Seeto, Justyna M Bartoszko, Michael A Khoury, Heather Whetstone, Louisa Ho, Claire Hsu, S Amanda Ali & Benjamin A Alman

  2. Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada

    Alvin C Lin, Claire Hsu, S Amanda Ali & Benjamin A Alman

  3. Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada

    Alvin C Lin, Louisa Ho, Claire Hsu, S Amanda Ali & Benjamin A Alman

  4. Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada

    Benjamin A Alman

  5. Division of Orthopaedic Surgery and Department of Surgery, University of Toronto, Toronto, Ontario, Canada

    Benjamin A Alman

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Contributions

A.C.L. and B.A.A. designed the experiments, interpreted the data and wrote the manuscript. A.C.L. performed the experiments with the assistance of B.L.S., J.M.B. and M.A.K., who helped with the mouse experiments; H.W., who performed histology and immunostaining; L.H., who performed siRNA experiments; and C.H. and S.A.A., who performed RNA expression studies. B.A.A. supervised the project.

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Correspondence to Benjamin A Alman.

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Lin, A., Seeto, B., Bartoszko, J. et al. Modulating hedgehog signaling can attenuate the severity of osteoarthritis. Nat Med 15, 1421–1425 (2009). https://doi.org/10.1038/nm.2055

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