Abstract
The tyrosine phosphatase SHP2, encoded by PTPN11, is required for the survival, proliferation and differentiation of various cell types1,2. Germline activating mutations in PTPN11 cause Noonan syndrome, whereas somatic PTPN11 mutations cause childhood myeloproliferative disease and contribute to some solid tumours. Recently, heterozygous inactivating mutations in PTPN11 were found in metachondromatosis, a rare inherited disorder featuring multiple exostoses, enchondromas, joint destruction and bony deformities3,4. The detailed pathogenesis of this disorder has remained unclear. Here we use a conditional knockout (floxed) Ptpn11 allele (Ptpn11fl) and Cre recombinase transgenic mice to delete Ptpn11 specifically in monocytes, macrophages and osteoclasts (lysozyme M-Cre; LysMCre) or in cathepsin K (Ctsk)-expressing cells, previously thought to be osteoclasts. LysMCre;Ptpn11fl/fl mice had mild osteopetrosis. Notably, however, CtskCre;Ptpn11fl/fl mice developed features very similar to metachondromatosis. Lineage tracing revealed a novel population of CtskCre-expressing cells in the perichondrial groove of Ranvier that display markers and functional properties consistent with mesenchymal progenitors. Chondroid neoplasms arise from these cells and show decreased extracellular signal-regulated kinase (ERK) pathway activation, increased Indian hedgehog (Ihh) and parathyroid hormone-related protein (Pthrp, also known as Pthlh) expression and excessive proliferation. Shp2-deficient chondroprogenitors had decreased fibroblast growth factor-evoked ERK activation and enhanced Ihh and Pthrp expression, whereas fibroblast growth factor receptor (FGFR) or mitogen-activated protein kinase kinase (MEK) inhibitor treatment of chondroid cells increased Ihh and Pthrp expression. Importantly, smoothened inhibitor treatment ameliorated metachondromatosis features in CtskCre;Ptpn11fl/fl mice. Thus, in contrast to its pro-oncogenic role in haematopoietic and epithelial cells, Ptpn11 is a tumour suppressor in cartilage, acting through a FGFR/MEK/ERK-dependent pathway in a novel progenitor cell population to prevent excessive Ihh production.
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16 April 2014
A Correction to this paper has been published: https://doi.org/10.1038/nature13170
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Acknowledgements
We thank S. Kato for Ctsk-Cre mice, A. Craft for review of the manuscript, X. Wang and P. Monfils for help with histology and J. Cao for helping with μ-CT analysis. This publication was made possible by the National Institutes of Health (NIH) and the National Institute for General Medicine Sciences (NIGMS) grant no. 8P20GM103468. This work was also funded by NIH R21AR57156 (to W.Y.) and R37CA49152 (to B.G.N.), the Rhode Island Hospital Orthopaedic Foundation and a grant from the Pediatric Orthopaedic Society of North America and the Orthopaedic Research and Education Foundation (to W.Y.). B.G.N. is a Canada Research Chair, Tier 1, and is also supported in part by the Ontario Ministry of Health and Long Term Care and the Princess Margaret Cancer Foundation.
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W.Y. and B.G.N. conceived the project. J.W., D.M., H.L. and W.Y. carried out most of the experiments. M.D. and W.Y. conducted FACS sorting and analysis. H.L. performed the SMOi animal treatment experiment. J.W. performed gene expression and western blot analysis. M.D. and J.W. carried out bone marrow transplantation experiments with the advice of P.J.Q. M.D., H.L. and W.Y. performed CPC multi-lineage differentiation assays. Q.W. and R.T. performed histological staining and data interpretation. Q.C. and M.G.E. provided technical and intellectual support. W.Y. and B.G.N. analysed the data and wrote the manuscript with the help of all authors.
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W.Y. and B.G.N. have filed a provisional patent application on the use of Smoothened inhibitors for the treatment of metachondromatosis (Title: Hedgehog Pathway Inhibition for Cartilage Tumor and Metachondromatosis Treatment; UPA#61/614,449)
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Supplementary Figures
This file contains Supplementary Figures 1-9. (PDF 760 kb)
Improved Joint Function in Ctsk-KO
Video clips 1 and 2 show that Ctsk-KO mice treated with SMOi, but not Vehicle, have dramatically improved joint function. In each clip, one mouse is wild type, one is a Ctsk-KO mouse treated with SMOi, and the third is Ctsk-KO mouse treated with vehicle alone. SMOi treatment of Control mice has no apparent effect on mobility. (MOV 23455 kb)
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Yang, W., Wang, J., Moore, D. et al. Ptpn11 deletion in a novel progenitor causes metachondromatosis by inducing hedgehog signalling. Nature 499, 491–495 (2013). https://doi.org/10.1038/nature12396
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DOI: https://doi.org/10.1038/nature12396
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