A mutant PTH/PTHrP type I receptor in enchondromatosis

Sevan Hopyan, Nalan Gokgoz, Raymond Poon, Robert C. Gensure, Chunying Yu, William G. Cole, Robert S. Bell, Harald Jüppner, Irene L. Andrulis, Jay S. Wunder, Benjamin A. Alman

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196 Scopus citations

Abstract

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 chondrosarcoma1-3. 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)5-9. 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.

Original languageEnglish (US)
Pages (from-to)306-310
Number of pages5
JournalNature Genetics
Volume30
Issue number3
DOIs
StatePublished - Mar 2002

ASJC Scopus subject areas

  • Genetics

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    Hopyan, S., Gokgoz, N., Poon, R., Gensure, R. C., Yu, C., Cole, W. G., Bell, R. S., Jüppner, H., Andrulis, I. L., Wunder, J. S., & Alman, B. A. (2002). A mutant PTH/PTHrP type I receptor in enchondromatosis. Nature Genetics, 30(3), 306-310. https://doi.org/10.1038/ng844