A mutant PTH/PTHrP type I receptor in enchondromatosis

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 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.

Functional conservation of the human EXT1 tumor suppressor gene and its Drosophila homolog tout velu

“…The growth factors are involved in chondrocyte differentiation and proliferation and alteration of their signaling could lead to formation of exostosis (Hopyan et al 2002;Koziel et al 2004). As EXT1 and EXT2 are copolymerases, HME arising from loss of EXT2 may result from the same molecular mechanism.…”

Mutant IDH is sufficient to initiate enchondromatosis in mice

“…There is a potential for malignant progression to chondrosarcoma that may be greater than 50% in some cases of multiple enchondromatosis (i.e., Maffucci syndrome) (3-7). Many chondrosarcomas are thought to derive from enchondromas, and such sarcomas are termed central chondrosarcomas (3).The hedgehog (Hh) signaling pathway is constitutively active in enchondromas and chondrosarcomas (8,9). Hh is important in growth-plate chondrocyte differentiation, where it cooperates with parathyroid hormone-like hormone in a negative feedback loop to inhibit the differentiation of proliferative growth-plate chondrocytes (6,(10)(11)(12)(13)(14).…”

Dysplasies osseuses héréditaires et voies de signalisation associées aux récepteurs FGFR3 et PTHR1

“…Les résultats de l'analyse moléculaire suggèrent une hétérogénéité génétique de l'enchondromatose. Une mutation (Arg150Cys) dans le gène PTHR1 a été identifiée chez deux malades atteints de maladie d'Ollier [32]. Le récepteur mutant PTHR1 Arg150Cys paraît être activé de façon constitutive, cependant la mutation est associée à un défaut d'expression à la membrane cellulaire.…”