A mutant PTH/PTHrP type I receptor in enchondromatosis.
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 chondrosarcoma. The extent of skeletal involvement is variable in enchondromatosis and may include dysplasia that is not directly attributable to enchondromas. 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). 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.
Hopyan
Sevan
S
Program in Developmental Biology, Research Institute, The Hospital for Sick Children, Toronto, Ontario, Canada.
Gokgoz
Nalan
N
Poon
Raymond
R
Gensure
Robert C
RC
Yu
Chunying
C
Cole
William G
WG
Bell
Robert S
RS
Jüppner
Harald
H
Andrulis
Irene L
IL
Wunder
Jay S
JS
Alman
Benjamin A
BA
D000818:Animals; D001859:Bone Neoplasms / Q000235:genetics / Q000503:physiopathology*; D019556:COS Cells; D004687:Enchondromatosis / Q000235:genetics / Q000503:physiopathology*; D053823:Hedgehog Proteins; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D016297:Mutagenesis, Site-Directed; D009154:Mutation; D044168:Receptor, Parathyroid Hormone, Type 1; D018016:Receptors, Parathyroid Hormone / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D015290:Second Messenger Systems; D015398:Signal Transduction; D015534:Trans-Activators / Q000378:metabolism
D053823:Hedgehog Proteins; D044168:Receptor, Parathyroid Hormone, Type 1; D018016:Receptors, Parathyroid Hormone; D015534:Trans-Activators