Abstracts
Résumé
La croissance des os longs se fait selon un processus complexe impliquant la migration et la condensation de cellules mésenchymateuses en cellules chondrogéniques qui se différencient en chondrocytes produisant la matrice cartilagineuse pour former la plaque de croissance. De nombreux facteurs protéiques sont impliqués dans la régulation de ces phénomènes parmi lesquels des facteurs transcriptionnels, des facteurs de signalisation et des protéines de la matrice extracellulaire dont le rôle a été révélé grâce aux études de génétique moléculaire sur des dysplasies osseuses humaines et à la création de modèles animaux reproduisant certaines de ces maladies. Cet article se focalise sur deux récepteurs, FGFR3 et PTHR1, dont l’importance dans la croissance des os longs est illustrée par le groupe de dysplasies osseuses qui leurs sont associées. Des résultats récents indiquent que prolifération et différenciation chondrocytaires sont étroitement liées et que la croissance harmonieuse des os longs repose sur un équilibre strict entre différentes voies de signalisation dont celles contrôlées par ces facteurs.
Summary
Skeletal development is a highly sophisticated process involving, as a first step, migration and condensation of mesenchymal cells into osteoprogenitor cells. These cells further differentiate into chondrocytes and osteoblasts through multiple differentiation stages requiring a set of specific transcriptional factors. Defective endochondral ossification in human is associated with a large number of inherited skeletal dysplasias caused by mutations in genes encoding extracellular matrix components, growth factors and their receptors, signaling molecules and transcription factors. This review summarizes some of the recent findings on a series of chondrodysplasias caused by mutations in FGFR3 and PTHR1, two receptors expressed in the cartilage growth plate and mediating two main signaling pathways. Data from human diseases and relevant animal models provide new clues for understanding how signaling molecules and their interaction with key transcription factors control and regulate the development and growth of long bones.
Appendices
Références
- 1. Hall CM. International nosology and classification of constitutional disorders of bone (2001). Am J Med Genet 2002 ; 113 : 65-77.
- 2. Chapman KL, Mortier GR, Chapman K, et al. Mutations in the region encoding the von Willebrand factor A domain of matrilin-3 are associated with multiple epiphyseal dysplasia. Nat Genet 2001 ; 28 : 393-6.
- 3. Kronenberg HM. Developmental regulation of the growth plate. Nature 2003 ; 423 : 332-6.
- 4. Karsenty G. The complexities of skeletal biology. Nature 2003 ; 423 : 316-8.
- 5. Zelzer E, Olsen BR. The genetic basis for skeletal diseases. Nature 2003 ; 423 : 343-8.
- 6. Kobayashi T, Kronenberg H. Minireview : transcriptional regulation in development of bone. Endocrinology 2005 ; 146 : 1012-7.
- 7. Johnson RL, Tabin CJ. Molecular models for vertebrate limb development. Cell 1997 ; 90 : 979-90.
- 8. Lewandoski M, Sun X, Martin GR. Fgf8 signalling from the AER is essential for normal limb development. Nat Genet 2000 ; 26 : 460-3.
- 9. Xu X, Weinstein M, Li C, et al. Fibroblast growth factor receptor 2 (FGFR2)-mediated reciprocal regulation loop between FGF8 and FGF10 is essential for limb induction. Development 1998 ; 125 : 753-65.
- 10. Vogt TF, Duboule D. Antagonists go out on a limb. Cell 1999 ; 99 : 563-6.
- 11. Hall BK, Miyake T. All for one and one for all : condensations and the initiation of skeletal development. Bioessays 2000 ; 22 : 138-47.
- 12. Kolpakova E, Olsen BR. Wnt/beta-catenin: a canonical tale of cell-fate choice in the vertebrate skeleton. Dev Cell 2005 ; 8 : 626-7.
- 13. Akiyama H, Chaboissier MC, Martin JF, et al. The transcription factor Sox9 has essential roles in successive steps of the chondrocyte differentiation pathway and is required for expression of Sox5 and Sox6. Genes Dev 2002 ; 16 : 2813-28.
- 14. Bi W, Deng JM, Zhang Z, et al. Sox9 is required for cartilage formation. Nat Genet 1999 ; 22 : 85-9.
- 15. Wagner T, Wirth J, Meyer J, et al. Autosomal sex reversal and campomelic dysplasia are caused by mutations in and around the SRY-related gene SOX9. Cell 1994 ; 79 : 1111-20.
- 16. Long F, Zhang XM, Karp S, et al. Genetic manipulation of hedgehog signaling in the endochondral skeleton reveals a direct role in the regulation of chondrocyte proliferation. Development 2001 ; 128 : 5099-108.
- 17. Karsenty G, Wagner EF. Reaching a genetic and molecular understanding of skeletal development. Dev Cell 2002 ; 2 : 389-406.
- 18. Beier F, Ali Z, Mok D, et al. TGFbeta and PTHrP control chondrocyte proliferation by activating cyclin D1 expression. Mol Biol Cell 2001 ; 12 : 3852-63.
- 19. Schlessinger J. Cell signaling by receptor tyrosine kinases. Cell 2000 ; 103 : 211-25.
- 20. Rousseau F, Bonaventure J, Legeai-Mallet L, et al. Mutations in the gene encoding fibroblast growth factor receptor-3 in achondroplasia. Nature 1994 ; 371 : 252-4.
- 21. Vajo Z, Francomano CA, Wilkin DJ. The molecular and genetic basis of fibroblast growth factor receptor 3 disorders : the achondroplasia family of skeletal dysplasias, Muenke craniosynostosis, and Crouzon syndrome with acanthosis nigricans. Endocrinol Rev 2000 ; 21 : 23-39.
- 22. Ornitz DM, Marie PJ. FGF signaling pathways in endochondral and intramembranous bone development and human genetic disease. Genes Dev 2002 ; 16 : 1446-65.
- 23. Legeai-Mallet L, Benoist-Lasselin C, Munnich A, et al. Overexpression of FGFR3, Stat1, Stat5 and p21Cip1 correlates with phenotypic severity and defective chondrocyte differentiation in FGFR3-related chondrodysplasias. Bone 2004 ; 34 : 26-36.
- 24. Lievens PM, Mutinelli C, Baynes D, et al. The kinase activity of fibroblast growth factor receptor 3 with activation loop mutations affects receptor trafficking and signaling. J Biol Chem 2004 ; 279 : 43254-60.
- 25. Segev O, Chumakov I, Nevo Z, et al. Restrained chondrocyte proliferation and maturation with abnormal growth plate vascularization and ossification in human FGFR-3(G380R) transgenic mice. Hum Mol Genet 2000 ; 9 : 249-58.
- 26. Iwata T, Chen L, Li C, et al. A neonatal lethal mutation in FGFR3 uncouples proliferation and differentiation of growth plate chondrocytes in embryos. Hum Mol Genet 2000 ; 9 : 1603-13.
- 27. Chen L, Li C, Qiao W, et al. A Ser(365)->Cys mutation of fibroblast growth factor receptor 3 in mouse downregulates Ihh/PTHrP signals and causes severe achondroplasia. Hum Mol Genet 2001 ; 10 : 457-65.
- 28. Clemens TL, Cormier S, Eichinger A, et al. Parathyroid hormone-related protein and its receptors : nuclear functions and roles in the renal and cardiovascular systems, the placental trophoblasts and the pancreatic islets. Br J Pharmacol 2001 ; 134 : 1113-36.
- 29. Cormier S, Delezoide AL, Benoist-Lasselin C, et al. 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. Am J Pathol 2002 ; 161 : 1325-35.
- 30. Jüppner H, Schipani E, Silve C. Jansen’s metaphyseal chondrodysplasia and Blomstrand’s lethal chondrodysplasia : two genetic disorders caused by PTH/PTHrP receptor mutations. In : Bilezikian J, Raisz L, Rodan G, eds. Principles of bone biology, vol. 2. San Diego, CA : Academic Press, 2002 : 1117-35.
- 31. Duchatelet S, Ostergaard E, Cortes D, et al. Recessive mutations in PTHR1 cause contrasting skeletal dysplasias in Eiken and Blomstrand syndromes. Hum Mol Genet 2005 ; 14 : 1-5.
- 32. Hopyan S, Gokgoz N, Poon R, et al. A mutant PTH/PTHrP type I receptor in enchondromatosis. Nat Genet 2002 ; 30 : 306-10.