Abstracts
Résumé
Les ostéoclastes sont des acteurs essentiels du remodelage osseux, et des anomalies de leur différenciation ou de leur activité conduisent à l’apparition de maladies osseuses, dont des défauts de résorption osseuse qui se traduisent par l’apparition d’une ostéopétrose. Différents modèles murins développant une ostéopétrose secondaire à l’apparition de mutations spontanées ou à l’invalidation de gènes ont permis de décrypter, au moins en partie, les mécanismes impliqués dans la différenciation et l’activité des ostéoclastes. Chez l’être humain, en revanche, seules des anomalies d’activité de l’ostéoclaste ont été décrites. Trois modèles murins, les souris oc/oc, gl/gl et Clcn7-/-, présentent un phénotype proche de celui de patients atteints d’ostéopétrose maligne infantile, la forme d’ostéopétrose la plus sévère chez l’homme. Des mutations dans les gènes TCIRG1, GL et CLCN7 ont donc été recherchées chez des patients ostéopétrotiques, et retrouvées majoritairement dans l’ostéopétrose maligne infantile et dans l’ostéopétrose de type II. Une telle correspondance phénotypique et génétique fait de ces trois mutants de souris des modèles particulièrement adaptés à l’étude de l’ostéopétrose humaine.
Summary
The osteoclast is the main effector of bone resorption. Failure in osteoclast differentiation or function leads to osteopetrosis, a bone disease characterized by an impaired bone resorption. Analysis of mouse models developing osteopetrosis as a consequence of naturally occuring mutations or gene knockouts allowed to establish the osteoclast differentiation pathway. Among these models, the oc/oc, the gl/gl and the Clcn7–/– mice present a phenotype similar to the one displayed by patients with infantile malignant osteopetrosis, the most severe form of osteopetrosis in human. Analysis of these models led to the identification of different mutations in the corresponding human genes TCIRG1, GL and CLCN7, in osteopetrotic patients. Mutations in the TCIRG1 gene seem the most frequent cause of malignant osteopetrosis and mutations in the CLCN7 gene seem the most frequent cause of type II osteopetrosis. Therefore, these three mouse models appear to be particularly well suited for the study of the osteoclast function in order to provide new insights in the therapy of osteopetrosis.
Appendices
Références
- 1. Teitelbaum SL. Bone resorption by osteoclasts. Science 2000; 289: 1504-8.
- 2. Tondravi MM, McKercher SR, Anderson K, et al. Osteopetrosis in mice lacking haematopoietic transcription factor PU.1. Nature 1997; 386:81-4.
- 3. Yoshida H, Hayashi S, Kunisada T, et al. The murine mutation osteopetrosis is in the coding region of the macrophage colony stimulating factor gene. Nature 1990; 345: 442-4.
- 4. Dai XM, Ryan GR, Hapel AJ, et al. Targeted disruption of the mouse colony-stimulating factor 1 receptor gene results in osteopetrosis, mononuclear phagocyte deficiency, increased primitive progenitor cell frequencies, and reproductive defects. Blood 2002; 99: 111-20.
- 5. Grigoriadis AE, Wang ZQ, Cecchini MG, et al. c-Fos: a key regulator of osteoclast-macrophage lineage determination and bone remodeling. Science 1994; 266: 443-8.
- 6. Miyamoto T, Ohneda O, Arai F, et al. Bifurcation of osteoclasts and dendritic cells from common progenitors. Blood 2001; 98: 2544-54.
- 7. Simonet WS, Lacey DL, Dunstan CR, et al. Osteoprotegerin: a novel secreted protein involved in the regulation of bone density. Cell 1997; 89: 309-19.
- 8. Kong YY, Yoshida H, Sarosi I, et al. OPGL is a key regulator of osteoclastogenesis, lymphocyte development and lymph-node organogenesis. Nature 1999; 397: 315-23.
- 9. Dougall WC, Glaccum M, Charrier K, et al. RANK is essential for osteoclast and lymph node development. Genes Dev 1999; 13: 2412-24.
- 10. Snapper CM, Zelazowski P, Rosas FR, et al. B cells from p50/NF-kappa B knockout mice have selective defects in proliferation, differentiation, germ-line CH transcription, and Ig class switching. J Immunol 1996; 156: 183-91.
- 11. Sha WC, Liou HC, Tuomanen EI, et al. Targeted disruption of the p50 subunit of NF-kappa B leads to multifocal defects in immune responses. Cell 1995; 80: 321-30.
- 12. Franzoso G, Carlson L, Xing L, et al. Requirement for NF-kappaB in osteoclast and B-cell development. Genes Dev 1997; 11: 3482-96.
- 13. Iotsova V, Caamano J, Loy J, et al. Osteopetrosis in mice lacking NF-kappaB1 and NF-kappaB2. Nat Med 1997; 3: 1285-9.
- 14. Duong LT, Rodan GA. Integrin-mediated signaling in the regulation of osteoclast adhesion and activation. Front Biosci 1998; 3: d757-68.
- 15. Lomaga MA, Yeh WC, Sarosi I, et al. TRAF6 deficiency results in osteopetrosis and defective interleukin-1, CD40, and LPS signaling. Genes Dev 1999; 13: 1015-24.
- 16. Soriano P, Montgomery C, Geske R, et al. Targeted disruption of the c-src proto-oncogene leads to osteopetrosis in mice. Cell 1991; 64: 693-702.
- 17. McHugh KP, Hodivala-Dilke K, Zheng MH, et al. Mice lacking beta3 integrins are osteosclerotic because of dysfunctional osteoclasts. J Clin Invest 2000; 105 : 433-40.
- 18. Luchin A, Suchting S, Merson T, et al. Genetic and physical interactions between microphthalmia transcription factor and PU.1 are necessary for osteoclast gene expression and differentiation. J Biol Chem 2001; 276: 36703-10.
- 19. Hodgkinson CA, Moore KJ, Nakayama A, et al. Mutations at the mouse microphthalmia locus are associated with defects in a gene encoding a novel basic-helix-loop-helix-zipper protein. Cell 1993; 74: 395-404.
- 20. Chalhoub N, Benachenhou N, Rajapurohitam V, et al. Grey-lethal mutation induces severe malignant autosomal recessive osteopetrosis in mouse and human. Nat Med 2003; 9: 399-406.
- 21. Hayman AR, Jones SJ, Boyde A, et al. Mice lacking tartrate-resistant acid phosphatase (Acp 5) have disrupted endochondral ossification and mild osteopetrosis. Development 1996; 122: 3151-62.
- 22. Gowen M, Lazner F, Dodds R, et al. Cathepsin K knockout mice develop osteopetrosis due to a deficit in matrix degradation but not demineralization. J Bone Miner Res 1999; 14: 1654-63.
- 23. Nishi T, Forgac M. The vacuolar (h+)-ATPases - nature’s most versatile proton pumps. Nat Rev Mol Cell Biol 2002; 3: 94-103.
- 24. Seifert MF, Marks SC Jr. Morphological evidence of reduced bone resorption in the osteosclerotic (oc) mouse. Am J Anat 1985; 172: 141-53.
- 25. Kornak U, Kasper D, Bosl MR, et al. Loss of the ClC-7 chloride channel leads to osteopetrosis in mice and man. Cell 2001; 104: 205-15.
- 26. Scimeca JC, Franchi A, Trojani C, et al. The gene encoding the mouse homologue of the human osteoclast-specific 116-kDa V-ATPase subunit bears a deletion in osteosclerotic (oc/oc) mutants. Bone 2000; 26: 207-13.
- 27. Li YP, Chen W, Liang Y, et al. Atp6i-deficient mice exhibit severe osteopetrosis due to loss of osteoclast-mediated extracellular acidification. Nat Genet 1999; 23: 447-51.
- 28. Kawasaki-Nishi S, Bowers K, Nishi T, et al. The amino-terminal domain of the vacuolar proton-translocating ATPase a subunit controls targeting and in vivo dissociation, and the carboxyl- terminal domain affects coupling of proton transport and ATP hydrolysis. J Biol Chem 2001; 276: 47411-20.
- 29. Nakamura I, Takahashi N, Udagawa N, et al. Lack of vacuolar proton ATPase association with the cytoskeleton in osteoclasts of osteosclerotic (oc/oc) mice. FEBS Lett 1997; 401: 207-12.
- 30. Key L, Ries W. Osteopetrosis. In: Bilezikian J, Raisz L, Rodan G, eds. Principles of bone biology. New York: Academic Press, 2002: 1217-27.
- 31. Kornak U, Schulz A, Friedrich W, et al. Mutations in the a3 subunit of the vacuolar H(+)-ATPase cause infantile malignant osteopetrosis. Hum Mol Genet 2000; 9: 2059-63.
- 32. Frattini A, Orchard PJ, Sobacchi C, et al. Defects in TCIRG1 subunit of the vacuolar proton pump are responsible for a subset of human autosomal recessive osteopetrosis. Nat Genet 2000; 25: 343-6.
- 33. Sobacchi C, Frattini A, Orchard P, et al. The mutational spectrum of human malignant autosomal recessive osteopetrosis. Hum Mol Genet 2001; 10: 1767-73.
- 34. Scimeca JC, Quincey D, Parrinello H, et al. New mutations in the gene encoding the a3 subunit of the vacuolar proton pump in patients affected by infantile malignant osteopetrosis. Hum Mutat 2003; 21: 151-7.
- 35. Cleiren E, Benichou O, Van Hul E, et al. Albers-Schonberg disease (autosomal dominant osteopetrosis, type II) results from mutations in the ClCN7 chloride channel gene. Hum Mol Genet 2001; 10: 2861-7.
- 36. Frattini A, Pangrazio A, Susani L, et al. Chloride channel ClCN7 mutations are responsible for severe recessive, dominant, and intermediate osteopetrosis. J Bone Miner Res 2003; 18: 1740-7.
- 37. Gerritsen EJ, Vossen JM, Fasth A, et al. Bone marrow transplantation for autosomal recessive osteopetrosis. A report from the working party on inborn errors of the European bone marrow transplantation group. J Pediatr 1994; 125: 896-902
- 38. Cavazzana-Calvo M, Hacein-Bey S, de Saint Basile G, et al. Gene therapy of human severe combined immunodeficiency (SCID)-X1 disease. Science 2000; 288: 669-72.
- 39. Hughes AE, Ralston SH, Marken J, et al. Mutations in TNFRSF11A, affecting the signal peptide of RANK, cause familial expansile osteolysis. Nat Genet 2000; 24: 45-8.
- 40. Whyte M, Obrecht S, Finnegan P, et al. Osteoprotegerin deficiency and juvenile Paget’s disease. J Exp Med 2002; 347: 175-84
- 41. Gelb BD, Shi GP, Chapman HA, et al. Pycnodysostosis, a lysosomal disease caused by cathepsin K deficiency. Science 1996; 273: 1236-8.