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(American Journal of Pathology. 2002;161:1325-1335.)
© 2002 American Society for Investigative Pathology

Regular Articles

Parathyroid Hormone Receptor Type 1/Indian Hedgehog Expression Is Preserved in the Growth Plate of Human Fetuses Affected with Fibroblast Growth Factor Receptor Type 3 Activating Mutations

Sarah Cormier*, Anne-Lise Delezoide{dagger}, Catherine Benoist-Lasselin{ddagger}, Laurence Legeai-Mallet{ddagger}, Jacky Bonaventure{ddagger} and Caroline Silve*

From Institut National de la Santé et de la Recherche Médicale U426* and the Service de Biologie du Développement,{dagger} Assistance Publique-Hôpitaux de Paris, Hôpital Robert Debré, Paris and Institut Fédératif de Recherche 02, Faculté de Médecine Xavier Bichat, Paris; and Institut National de la Santé et de la Recherche Médicale U393{ddagger} and Département de Génétique, Assistance Publique-Hôpitaux de Paris, Groupe Hospitalier Necker Enfants Malades, Paris, France

The fibroblast growth factor receptor type 3 (FGFR3) and Indian hedgehog (IHH)/parathyroid hormone (PTH)/PTH-related peptide receptor type 1 (PTHR1) systems are both essential regulators of endochondral ossification. Based on mouse models, activation of the FGFR3 system is suggested to regulate the IHH/PTHR1 pathway. To challenge this possible interaction in humans, we analyzed the femoral growth plates from fetuses carrying activating FGFR3 mutations (9 achondroplasia, 21 and 8 thanatophoric dysplasia types 1 and 2, respectively) and 14 age-matched controls by histological techniques and in situ hybridization using riboprobes for human IHH, PTHR1, type 10 and type 1 collagen transcripts. We show that bone-perichondrial ring enlargement and growth plate increased vascularization in FGFR3-mutated fetuses correlate with the phenotypic severity of the disease. PTHR1 and IHH expression in growth plates, bone-perichondrial rings and vascular canals is not affected by FGFR3 mutations, irrespective of the mutant genotype and age, and is in keeping with cell phenotypes. These results indicate that in humans, FGFR3 signaling does not down-regulate the main players of the IHH/PTHR1 pathway. Furthermore, we show that cells within the bone-perichondrial ring in controls and patients express IHH, PTHR1, and type 10 and type 1 collagen transcripts, suggesting that bone-perichondrial ring formation involves cells of both chondrocytic and osteoblastic phenotypes.




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