Enchondromas are common benign cartilage tumors of bone. They can occur as solitary lesions or as multiple lesions in enchondromatosis (Ollier and Maffucci diseases). Clinical problems caused by enchondromas include skeletal deformity and the potential for malignant change to chondrosarcoma1,2,3. The extent of skeletal involvement is variable in enchondromatosis and may include dysplasia that is not directly attributable to enchondromas4. Enchondromatosis is rare, obvious inheritance of the condition is unusual and no candidate loci have been identified. Enchondromas are usually in close proximity to, or in continuity with, growth-plate cartilage. Consequently, they may result from abnormal regulation of proliferation and terminal differentiation of chondrocytes in the adjoining growth plate. In normal growth plates, differentiation of proliferative chondrocytes to post-mitotic hypertrophic chondrocytes is regulated in part by a tightly coupled signaling relay involving parathyroid hormone related protein (PTHrP) and Indian hedgehog (IHH)5,6,7,8,9. PTHrP delays the hypertrophic differentiation of proliferating chondrocytes, whereas IHH promotes chondrocyte proliferation. We identified a mutant PTH/PTHrP type I receptor (PTHR1) in human enchondromatosis that signals abnormally in vitro and causes enchondroma-like lesions in transgenic mice. The mutant receptor constitutively activates Hedgehog signaling, and excessive Hedgehog signaling is sufficient to cause formation of enchondroma-like lesions.
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We thank affected individuals and their families for their cooperation, C.-C. Hui for Gli2 and Gli2-luciferase cDNA, U.-I. Chung for PTHR1−/− embryonic stem cells, Y. Yamada for Col2A1 promoter/enhancer cDNA, T. Ingolia (Ontogeny) for Shh-N protein, A. Karaplis for c-Myc–tagged PTHR1 cDNA (Hkrk), F. de Sauvage (Genentech) for Smo cDNA, S. Tondat and L. Schwartz for pronuclear microinjections, L. Morikawa for histology, M. Ho for anti-c-Myc immunohistochemistry, M. To for assistance with cAMP assays, S. Cheon for assistance with SSCP analysis, A. Davis for help with statistical analysis, J. Ahier for patient contact, members of the Andrulis and Alman labs for support, A. Gross, C. Hutchison and J. Wright for tissue specimens; and J. Aubin, U. Chung, J. Dennis, S. Egan, J. Haigh, C.-C. Hui, H. Kronenberg and J. Rossant for critical advice. This work was supported by grants from the National Cancer Institute of Canada with funds from the Terry Fox Run (to B.A.A., I.L.A. and R.S.B.), the Canadian Institutes of Health Research (to J.S.W., B.A.A. and W.G.C.) and The Hospital for Sick Children Research Institute Trainees' Start-Up Fund (to S.H.). S.H. is supported by a Clinician-Scientist Fellowship from the Research Training Centre of The Hospital for Sick Children Research Institute, and B.A.A. is supported by the Canadian Research Chair Program.
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