134 results on '"Legeai-Mallet L"'
Search Results
2. Animal models of craniosynostosis
- Author
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Cornille, M., Dambroise, E., Komla-Ebri, D., Kaci, N., Biosse-Duplan, M., Di Rocco, F., and Legeai-Mallet, L.
- Published
- 2019
- Full Text
- View/download PDF
3. Hypochondroplasia gain-of-function mutation in FGFR3 causes defective bone mineralization in mice
- Author
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Loisay, L, Komla-Ebri, D, Morice, A, Heuzé, Y, Viaut, C, De La Seiglière, A, Kaci, N, Chan, D, Lamouroux, A, Baujat, G, Bassett, JHD, Williams, GR, and Legeai-Mallet, L
- Abstract
Hypochondroplasia (HCH) is a mild dwarfism caused by missense mutations in fibroblast growth factor receptor 3 (FGFR3), with the majority of cases resulting from a heterozygous p.Asn540Lys gain-of-function mutation. Here, we report the generation and characterization of the first mouse model (Fgfr3Asn534Lys/+) of HCH to our knowledge. Fgfr3Asn534Lys/+ mice exhibited progressive dwarfism and impairment of the synchondroses of the cranial base, resulting in defective formation of the foramen magnum. The appendicular and axial skeletons were both severely affected and we demonstrated an important role of FGFR3 in regulation of cortical and trabecular bone structure. Trabecular bone mineral density (BMD) of long bones and vertebral bodies was decreased, but cortical BMD increased with age in both tibiae and femurs. These results demonstrate that bones in Fgfr3Asn534Lys/+ mice, due to FGFR3 activation, exhibit some characteristics of osteoporosis. The present findings emphasize the detrimental effect of gain-of-function mutations in the Fgfr3 gene on long bone modeling during both developmental and aging processes, with potential implications for the management of elderly patients with hypochondroplasia and osteoporosis.
- Published
- 2023
4. Isolation, comprehensive characterization and antioxidant activities of Theobroma cacao extract
- Author
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Cádiz-Gurrea, M.L., Lozano-Sanchez, J., Contreras-Gámez, M., Legeai-Mallet, L., Fernández-Arroyo, S., and Segura-Carretero, A.
- Published
- 2014
- Full Text
- View/download PDF
5. FGFR3 overactivation in the brain is responsible for memory impairments in Crouzon syndrome mouse model
- Author
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Legeai-Mallet L., Cornille, Maxence, Moriceau, Stephanie, Khonsari, Roman H., Heuzé, Yann, Loisay, Léa, Boitez, Valérie, Morice, Anne, Arnaud, Eric, Collet, Corinne, Bensidhoum, Morad, Kaci, Nabil, Boddaert, Nathalie, Paternoster, Giovanna, Rauschendorfer, Theresa, Werner, Sabine, Mansour, Suzanne L., Di Rocco, Federico, Oury, Franck, and Legeai-Mallet, Laurence
- Subjects
musculoskeletal diseases - Abstract
Crouzon syndrome with acanthosis nigricans (CAN, a rare type of craniosynostosis characterized by premature suture fusion and neurological impairments) has been linked to a gain-of-function mutation (p.Ala391Glu) in fibroblast growth factor receptor 3 (FGFR3). To characterize the CAN mutation's impact on the skull and on brain functions, we developed the first mouse model (Fgfr3A385E/+) of this syndrome. Surprisingly, Fgfr3A385E/+ mice did not exhibit craniosynostosis but did show severe memory impairments, a structurally abnormal hippocampus, low activity-dependent synaptic plasticity, and overactivation of MAPK/ERK and Akt signaling pathways in the hippocampus. Systemic or brain-specific pharmacological inhibition of FGFR3 overactivation by BGJ398 injections rescued the memory impairments observed in Fgfr3A385E/+ mice. The present study is the first to have demonstrated cognitive impairments associated with brain FGFR3 overactivation, independently of skull abnormalities. Our results provide a better understanding of FGFR3's functional role and the impact of its gain-of-function mutation on brain functions. The modulation of FGFR3 signaling might be of value for treating the neurological disorders associated with craniosynostosis., Journal of Experimental Medicine, 219 (4), ISSN:0022-1007, ISSN:1540-0069, ISSN:1540-9538
- Published
- 2022
- Full Text
- View/download PDF
6. Familial hypochondroplasia and acanthosis nigricans with FGFR3 K650T mutation
- Author
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Cossiez Cacard, M. A., Coulombe, J., Bernard, P., Kaci, N., Bressieux, J. M., Souchon, P. F., Motte, J., Legeai-Mallet, L., Hadj-Rabia, S., and Eschard, C.
- Published
- 2016
- Full Text
- View/download PDF
7. Tyrosine kinases regulate chondrocyte hypertrophy: promising drug targets for Osteoarthritis
- Author
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Ferrao Blanco, M.N., primary, Domenech Garcia, H., additional, Legeai-Mallet, L., additional, and van Osch, G.J.V.M., additional
- Published
- 2021
- Full Text
- View/download PDF
8. Tyrosine kinases regulate chondrocyte hypertrophy: promising drug targets for Osteoarthritis
- Author
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Ferrao Blanco, M. N. (author), Domenech Garcia, H. (author), Legeai-Mallet, L. (author), van Osch, G.J.V.M. (author), Ferrao Blanco, M. N. (author), Domenech Garcia, H. (author), Legeai-Mallet, L. (author), and van Osch, G.J.V.M. (author)
- Abstract
Osteoarthritis (OA) is a major health problem worldwide that affects the joints and causes severe disability. It is characterized by pain and low-grade inflammation. However, the exact pathogenesis remains unknown and the therapeutic options are limited. In OA articular chondrocytes undergo a phenotypic transition becoming hypertrophic, which leads to cartilage damage, aggravating the disease. Therefore, a therapeutic agent inhibiting hypertrophy would be a promising disease-modifying drug. The therapeutic use of tyrosine kinase inhibitors has been mainly focused on oncology, but the Food and Drug Administration (FDA) approval of the Janus kinase inhibitor Tofacitinib in Rheumatoid Arthritis has broadened the applicability of these compounds to other diseases. Interestingly, tyrosine kinases have been associated with chondrocyte hypertrophy. In this review, we discuss the experimental evidence that implicates specific tyrosine kinases in signaling pathways promoting chondrocyte hypertrophy, highlighting their potential as therapeutic targets for OA., Biomaterials & Tissue Biomechanics
- Published
- 2021
- Full Text
- View/download PDF
9. Tyrosine kinases regulate chondrocyte hypertrophy:promising drug targets for Osteoarthritis
- Author
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Ferrao Blanco, M. N., Domenech Garcia, H., Legeai-Mallet, L., van Osch, G. J.V.M., Ferrao Blanco, M. N., Domenech Garcia, H., Legeai-Mallet, L., and van Osch, G. J.V.M.
- Abstract
Osteoarthritis (OA) is a major health problem worldwide that affects the joints and causes severe disability. It is characterized by pain and low-grade inflammation. However, the exact pathogenesis remains unknown and the therapeutic options are limited. In OA articular chondrocytes undergo a phenotypic transition becoming hypertrophic, which leads to cartilage damage, aggravating the disease. Therefore, a therapeutic agent inhibiting hypertrophy would be a promising disease-modifying drug. The therapeutic use of tyrosine kinase inhibitors has been mainly focused on oncology, but the Food and Drug Administration (FDA) approval of the Janus kinase inhibitor Tofacitinib in Rheumatoid Arthritis has broadened the applicability of these compounds to other diseases. Interestingly, tyrosine kinases have been associated with chondrocyte hypertrophy. In this review, we discuss the experimental evidence that implicates specific tyrosine kinases in signaling pathways promoting chondrocyte hypertrophy, highlighting their potential as therapeutic targets for OA.
- Published
- 2021
10. Theobroma cacaoimproves bone growth by modulating defective ciliogenesis in a mouse model of achondroplasia
- Author
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Martin, L., primary, Kaci, N., additional, Benoist-Lasselin, C., additional, Mondoloni, M., additional, Decaudaveine, S., additional, Estibals, V., additional, Cornille, M., additional, Loisay, L., additional, Flipo, J., additional, Demuynck, B., additional, de la Luz Cádiz-Gurrea, M., additional, Barbault, F., additional, Fernández-Arroyo, S., additional, Schibler, L., additional, Segura-Carretero, A., additional, Dambroise, E., additional, and Legeai-Mallet, L., additional
- Published
- 2021
- Full Text
- View/download PDF
11. Genotype-phenotype correlation in hereditary multiple exostoses
- Author
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Francannet, C, Cohen-Tanugi, A, Le Merrer, M, Munnich, A, Bonaventure, J, and Legeai-Mallet, L
- Published
- 2001
12. S3-17 SESSION 3
- Author
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Khonsari, R. H., primary, Haber, S., additional, Paternoster, G., additional, Fauroux, B., additional, Morisseau-Durand, M.-P., additional, Leikola, J., additional, Hennocq, Q., additional, Viot-Blanc, V., additional, Guerin, P., additional, Baujat, G., additional, Collet, C., additional, Cormier-Daire, V., additional, Legeai-Mallet, L., additional, James, S., additional, Couloigner, V., additional, Tomat, C., additional, Diner, P., additional, Legros, C., additional, Meyer, P., additional, and Arnaud, E., additional
- Published
- 2019
- Full Text
- View/download PDF
13. Loss of heterozygozity at the EXT and EXT-like loci in osteochondromas and secondary chondrosarcomas of hereditary multiples exostose patients
- Author
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Legeai-Mallet, L., Noel, F., Cohen-Tanugi, A., Benoist-Lasselin, C., Munnich, A., and Bonaventure, J.
- Subjects
Human genetics -- Research ,Genetic disorders -- Research ,Exostosis -- Genetic aspects ,Biological sciences - Published
- 2001
14. Abnormal signalling pathway caused by FGFR 3 mutations in the cartilage of Achondroplasia and Thanatophoric Dysplasia patients
- Author
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Legeai-Mallet, L., Benoist-Lasselin, C., El Ghouzzi, V., Munnich, A., and Bonaventure, J.
- Subjects
Genetic research -- Analysis ,Human genetics -- Research ,Achondroplasia -- Genetic aspects ,Dysplasia -- Genetic aspects ,Biological sciences - Published
- 2000
15. The impact of polyphenols on chondrocyte growth and survival: a preliminary report
- Author
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Universitat Rovira i Virgili, Fernández-Arroyo S, Huete-Toral F, Pérez de Lara MJ, de la Luz Cádiz-Gurrea M, Legeai-Mallet L, Micol V, Segura-Carretero A, Joven J, Pintor J., Universitat Rovira i Virgili, and Fernández-Arroyo S, Huete-Toral F, Pérez de Lara MJ, de la Luz Cádiz-Gurrea M, Legeai-Mallet L, Micol V, Segura-Carretero A, Joven J, Pintor J.
- Abstract
Background: Imbalances in the functional binding of fibroblast growth factors (FGFs) to their receptors (FGFRs) have consequences for cell proliferation and differentiation that in chondrocytes may lead to degraded cartilage. The toxic, proinflammatory, and oxidative response of cytokines and FGFs can be mitigated by dietary polyphenols. Objective: We explored the possible effects of polyphenols in the management of osteoarticular diseases using a model based on the transduction of a mutated human FGFR3 (G380R) in murine chondrocytes. This mutation is present in most cases of skeletal dysplasia and is responsible for the overexpression of FGFR3 that, in the presence of its ligand, FGF9, results in toxic effects leading to altered cellular growth. Design: Different combinations of dietary polyphenols derived from plant extracts were assayed in FGFR3 (G380R) mutated murine chondrocytes, exploring cell survival, chloride efflux, extracellular matrix (ECM) generation, and grade of activation of mitogen-activated protein kinases. Results: Bioactive compounds from Hibiscus sabdariffa reversed the toxic effects of FGF9 and restored normal growth, suggesting a probable translation to clinical requests in humans. Indeed, these compounds activated the intracellular chloride efflux, increased ECM generation, and stimulated cell proliferation. The inhibition of mitogen-activated protein kinase phosphorylation was interpreted as the main mechanism governing these beneficial effects. Conclusions: These findings support the rationale behind the encouragement of the development of drugs that repress the overexpression of FGFRs and suggest the dietary incorporation of supplementary nutrients in the management of degraded cartilage.
- Published
- 2015
16. Familial hypochondroplasia and acanthosis nigricans with FGFR3 K650T mutation
- Author
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Cossiez Cacard, M.A., primary, Coulombe, J., additional, Bernard, P., additional, Kaci, N., additional, Bressieux, J.M., additional, Souchon, P.F., additional, Motte, J., additional, Legeai-Mallet, L., additional, Hadj-Rabia, S., additional, and Eschard, C., additional
- Published
- 2015
- Full Text
- View/download PDF
17. Cranial and craniovertebral junction anomalies in FGFR3Y367C/+ mice: New insights in normal and pathological skull growth
- Author
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Di Rocco⁎, F., primary, Kaci, N., additional, Mugniery, E., additional, Benoist-Lasselin, C., additional, Munnich, A., additional, and Legeai-Mallet, L., additional
- Published
- 2012
- Full Text
- View/download PDF
18. Impact of activating fibroblast growth factor receptor 3 mutation in endochondral ossification
- Author
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Mugniery, E., primary, Dacquin, R., additional, Marty, C., additional, Benoist-Lasselin, C., additional, Munnich, A., additional, de Vernejoul, M.-C., additional, Jurdic, P., additional, Geoffroy, V., additional, and Legeai-Mallet, L., additional
- Published
- 2011
- Full Text
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19. EXT 1 gene mutation induces chondrocyte cytoskeletal abnormalities and defective collagen expression in the exostoses
- Author
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Legeai Mallet, L, Rossi, A, Benoist Lasselin, C, Piazza, R, Mallet, J, Delezoide, A, Munnich, A, Bonaventure, J, Zylberberg, L, PIAZZA, ROCCO GIOVANNI, Mallet, JF, Delezoide, AL, Zylberberg, L., Legeai Mallet, L, Rossi, A, Benoist Lasselin, C, Piazza, R, Mallet, J, Delezoide, A, Munnich, A, Bonaventure, J, Zylberberg, L, PIAZZA, ROCCO GIOVANNI, Mallet, JF, Delezoide, AL, and Zylberberg, L.
- Abstract
Hereditary multiple exostoses (HME), an autosomal skeletal disorder characterized by cartilage-capped excrescences, has been ascribed to mutations in EXT 1 and EXT 2, two tumor suppressor-related genes encoding glycosyltransferases involved in the heparan sulfate proteoglycan (HSPG) biosynthesis. Taking advantage of the availability of three different exostoses from a patient with HME harboring a premature termination codon in the EXT 1 gene, morphological, immunologic, and biochemical analyses of the samples were carried out. The cartilaginous exostosis, when compared with control cartilage, exhibited alterations in the distribution and morphology of chondrocytes with abundant bundles of actin filaments indicative of cytoskeletal defects. Chondrocytes in the exostosis were surrounded by an extracellular matrix containing abnormally high amounts of collagen type X. The unexpected presence of collagen type I unevenly distributed in the cartilage matrix further suggested that some of the hypertrophic chondrocytes detected in the cartilaginous caps of the exostoses underwent accelerated differentiation. The two mineralized exostoses presented lamellar bone arrangement undergoing intense remodeling as evidenced by the presence of numerous reversal lines. The increased electrophoretic mobility of chondroitin sulfate and dermatan sulfate proteoglycans (PGs) extracted from the two bony exostoses was ascribed to an absence of the decorin core protein. Altogether, these data indicate that EXT mutations might induce a defective endochondral ossification process in exostoses by altering actin distribution and chondrocyte differentiation and by promoting primary calcification through decorin removal
- Published
- 2000
20. Overexpression of FGFR3, Stat1, Stat5 and p21Cip1 correlates with phenotypic severity and defective chondrocyte differentiation in FGFR3-related chondrodysplasias
- Author
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Legeai-Mallet, L, primary, Benoist-Lasselin, C, additional, Munnich, A, additional, and Bonaventure, J, additional
- Published
- 2004
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- View/download PDF
21. Maladie des exostoses multiples après 40 ans d’évolution : à propos d’un cas
- Author
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Rambeloarisoa, J, primary, El Guedj, M, additional, Legeai-Mallet, L, additional, Zagdanski, A.M, additional, Délépine, G, additional, Le Merrer, M, additional, and Farge, D, additional
- Published
- 2002
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22. Abnormal FGFR 3 Expression in Cartilage of Thanatophoric Dysplasia Fetuses
- Author
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Delezoide, A.-L., primary, Lasselin-Benoist, C., additional, Legeai-Mallet, L., additional, Brice, P., additional, Senee, V., additional, Yayon, A., additional, Munnich, A., additional, Vekemans, M., additional, and Bonaventure, J., additional
- Published
- 1997
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23. Common Mutations in the Fibroblast Growth Factor Receptor 3 (FGFR 3) Gene Account for Achondroplasia, Hypochondroplasia and Thanatophoric Dwarfism
- Author
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Bonaventure, J., primary, Rousseau, F., additional, Legeai-Mallet, L., additional, Merrer, M. Le, additional, Munnich, A., additional, and Maroteaux, P., additional
- Published
- 1997
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24. Récepteurs des facteurs de croissance fibroblastique et anomalies héréditaires de la croissance osseuse
- Author
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Bonaventure, J, primary, Rousseau, F, additional, Legeai-Mallet, L, additional, Benoist-Lasselin, C, additional, Merrer, M Le, additional, and Munnich, A, additional
- Published
- 1997
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25. Common mutations in the gene encoding fibroblast growth factor receptor 3 account for achondroplasia, hypochondroplasia and thanatophoric dysplasia
- Author
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Bonaventure, J, primary, Rousseau, F, additional, Legeai-Mallet, L, additional, Merrer, M Le, additional, Munnich, A, additional, and Maroteaux, P, additional
- Published
- 1996
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26. Clinical and genetic heterogeneity of hypochondroplasia.
- Author
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Rousseau, F, primary, Bonaventure, J, additional, Legeai-Mallet, L, additional, Schmidt, H, additional, Weissenbach, J, additional, Maroteaux, P, additional, Munnich, A, additional, and Le Merrer, M, additional
- Published
- 1996
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- View/download PDF
27. Common mutations in the fibroblast growth factor receptor 3 (FGFR3) gene account for achondroplasia, hypochondroplasia, and thanatophoric dwarfism
- Author
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Bonaventure, J., primary, Rousseau, F., additional, Legeai-Mallet, L., additional, Le Merrer, M., additional, Munnich, A., additional, and Maroteaux, P., additional
- Published
- 1996
- Full Text
- View/download PDF
28. Overexpression of FGFR3, Stat1, Stat5 and p21Cip1 correlates with phenotypic severity and defective chondrocyte differentiation in FGFR3-related chondrodysplasias
- Author
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Legeai-Mallet, L., Benoist-Lasselin, C., Munnich, A., and Bonaventure, J.
- Subjects
- *
ACHONDROPLASIA , *DYSPLASIA , *FIBROBLAST growth factors , *GROWTH factors , *CARTILAGE cells , *PHOSPHORYLATION - Abstract
Achondroplasia (ACH) and thanatophoric dysplasia (TD) are human skeletal disorders of increasing severity accounted for by mutations in the fibroblast growth factor receptor 3 (FGFR3). Attempts to elucidate the molecular signaling pathways leading to these phenotypes through mouse model engineering have provided relevant information mostly in the postnatal period. The availability of a large series of human fetuses including 14 ACH and 26 TD enabled the consequences of FGFR3 mutations on endogenous receptor expression during the prenatal period to be assessed by analysis of primary cultured chondrocytes and cartilage growth plates. Overexpression and ligand-independent phosphorylation of the fully glycosylated isoform of FGFR3 were observed in ACH and TD cells. Immunohistochemical analysis of fetal growth plates showed a phenotype-related reduction of the collagen type X-positive hypertrophic zone. Abnormally high amounts of Stat1, Stat5 and p21Cip1 proteins were found in prehypertrophic–hypertrophic chondrocytes, the extent of overexpression being directly related to the severity of the disease. Double immunostaining procedures revealed an overlap of FGFR3 and Stat1 expression in the prehypertrophic–hypertrophic zone, suggesting that constitutive activation of the receptor accounts for Stat overexpression. By contrast, expression of Stat and p21Cip1 proteins in the proliferative zone differed only slightly from control cartilage and differences were restricted to the last arrays of proliferative cells. Our results indicate that FGFR3 mutations in the prenatal period upregulate FGFR3 and Stat–p21Cip1 expression, thus inducing premature exit of proliferative cells from the cell cycle and their differentiation into prehypertrophic chondrocytes. We conclude that defective differentiation of chondrocytes is the main cause of longitudinal bone growth retardation in FGFR3-related human chondrodysplasias. [Copyright &y& Elsevier]
- Published
- 2004
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29. Comprendre les anomalies de développement du crâne et de la charnière crâniovertébrale à l’aide de 3 modèles murins FGFR3
- Author
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Di Rocco, F., Kaci, N., Mugniery, E., Benoist-Lasselin, C., Litim, N., Munnich, A., and Legeai-Mallet, L.
- Published
- 2011
- Full Text
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30. Missense FGFR3 Mutations Create Cysteine Residues in Thanatophoric Dwarfism Type I (TD1).
- Author
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Rousseau, F., El Ghouzzi, V., Delezoide, A. L., Legeai-Mallet, L., Le Merrer, M., Munnich, A., and Bonaventure, J.
- Published
- 1996
- Full Text
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31. Fibroblast growth factor receptor 3 mutations promote apoptosis but do not alter chondrocyte proliferation in thanatophoric dysplasia.
- Author
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Legeai-Mallet, L, Benoist-Lasselin, C, Delezoide, A L, Munnich, A, and Bonaventure, J
- Abstract
Thanatophoric dysplasia (TD) is a lethal skeletal disorder caused by recurrent mutations in the fibroblast growth factor receptor 3 (FGFR 3) gene. The mitogenic response of fetal TD I chondrocytes in primary cultures upon stimulation by either FGF 2 or FGF 9 did not significantly differ from controls. Although the levels of FGFR 3 mRNAs in cultured TD chondrocytes were similar to controls, an abundant immunoreactive material was observed at the perinuclear level using an anti-FGFR 3 antibody in TD cells. Transduction signaling via the mitogen-activated protein kinase pathway was assessed by measuring extracellular signal-regulated kinase activity (ERK 1 and ERK 2). Early ERKs activation following FGF 9 supplementation was observed in TD chondrocytes (2 min) as compared with controls (5 min) but no signal was detected in the absence of ligand. By contrast ligand-independent activation of the STAT signaling pathway was demonstrated in cultured TD cells and confirmed by immunodetection of Stat 1 in the nuclei of hypertrophic TD chondrocytes. Moreover, the presence of an increased number of apoptotic chondrocytes in TD fetuses was associated with a higher expression of Bax and the simultaneous decrease of Bcl-2 levels. Taken together, these results indicate that FGFR 3 mutations in TD I fetuses do not hamper chondrocyte proliferation but rather alter their differentiation by triggering premature apoptosis through activation of the STAT signaling pathway.
- Published
- 1998
32. Spatio-temporal expression of FGFR 1, 2 and 3 genes during human embryo-fetal ossification
- Author
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Delezoide, A.-L., Benoist-Lasselin, C., Legeai-Mallet, L., Merrer, M. Le, Munnich, A., Vekemans, M., and Bonaventure, J.
- Published
- 1998
- Full Text
- View/download PDF
33. Hereditary multiple exostoses with 40 years follow-up: case report.
- Author
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Rambeloarisoa, J., El Guedj, M., Legeai-Mallet, L., Zagdanski, A.M., Délépine, G., Le Merrer, M., and Farge, D.
- Subjects
- *
EXOSTOSIS , *GENETIC disorders , *DISEASES in men - Abstract
Introduction. – Hereditary multiple exostoses is an autosomal dominant skeletal disorder with genetic heterogeneity and an estimated prevalence of 1/50 000 in western countries. Malignant degeneration is a rare (about 2%) but classical complication in patients with hereditary multiple exostoses. At least 3 loci identified as EXT 1, EXT 2 and EXT 3 are involved in this skeletal disease.Exegesis. – The case of a 45-year old man is described with 15 years follow-up after resection of a well-differentiated chondrosarcoma (grade I), which arose from a right posterior pelvic exostosis. The observed radiological lesions remained relatively stable until now. The genetic mutation which is responsible for the disease was determined at the locus EXT 1.Conclusion. – The present case report illustrates the natural history of hereditary multiple exostoses, especially since the patient underwent a malignant degeneration which could be resected without recurrence. The results of the genetic analysis contributed to the understanding of the pathophysiology of the disease. [ABSTRACT FROM AUTHOR]
- Published
- 2002
- Full Text
- View/download PDF
34. EXT 1 Gene Mutation Induces Chondrocyte Cytoskeletal Abnormalities and Defective Collagen Expression in the Exostoses
- Author
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Antonio Rossi, Arnold Munnich, Rocco Piazza, Laurence Legeai-Mallet, Louise Zylberberg, Jean-Francois Mallet, Catherine Benoist-Lasselin, Anne-Lise Delezoide, J. Bonaventure, Legeai Mallet, L, Rossi, A, Benoist Lasselin, C, Piazza, R, Mallet, J, Delezoide, A, Munnich, A, Bonaventure, J, and Zylberberg, L
- Subjects
Male ,Adolescent ,Decorin ,Endocrinology, Diabetes and Metabolism ,Hereditary multiple exostoses ,Biology ,Gene mutation ,N-Acetylglucosaminyltransferases ,EXT1, chondrocyte, collagen, exostoses ,Chondrocyte ,Cell Line ,Extracellular matrix ,Chondrocytes ,Skeletal disorder ,medicine ,Humans ,Orthopedics and Sports Medicine ,Child ,Endochondral ossification ,Cytoskeleton ,Genetics ,Cartilage ,Hand ,medicine.disease ,Pedigree ,Cell biology ,Radiography ,carbohydrates (lipids) ,medicine.anatomical_structure ,Mutation ,RNA ,Female ,Proteoglycans ,Collagen ,Hand Deformities, Congenital ,Exostoses, Multiple Hereditary - Abstract
Hereditary multiple exostoses (HME), an autosomal skeletal disorder characterized by cartilage-capped excrescences, has been ascribed to mutations in EXT 1 and EXT 2, two tumor suppressor-related genes encoding glycosyltransferases involved in the heparan sulfate proteoglycan (HSPG) biosynthesis. Taking advantage of the availability of three different exostoses from a patient with HME harboring a premature termination codon in the EXT 1 gene, morphological, immunologic, and biochemical analyses of the samples were carried out. The cartilaginous exostosis, when compared with control cartilage, exhibited alterations in the distribution and morphology of chondrocytes with abundant bundles of actin filaments indicative of cytoskeletal defects. Chondrocytes in the exostosis were surrounded by an extracellular matrix containing abnormally high amounts of collagen type X. The unexpected presence of collagen type I unevenly distributed in the cartilage matrix further suggested that some of the hypertrophic chondrocytes detected in the cartilaginous caps of the exostoses underwent accelerated differentiation. The two mineralized exostoses presented lamellar bone arrangement undergoing intense remodeling as evidenced by the presence of numerous reversal lines. The increased electrophoretic mobility of chondroitin sulfate and dermatan sulfate proteoglycans (PGs) extracted from the two bony exostoses was ascribed to an absence of the decorin core protein. Altogether, these data indicate that EXT mutations might induce a defective endochondral ossification process in exostoses by altering actin distribution and chondrocyte differentiation and by promoting primary calcification through decorin removal.
- Published
- 2000
35. Cranial and craniovertebral junction anomalies in FGFR3Y367C/+ mice: New insights in normal and pathological skull growth
- Author
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⁎, F., Kaci, N., Mugniery, E., Benoist-Lasselin, C., Munnich, A., and Legeai-Mallet, L.
- Published
- 2012
- Full Text
- View/download PDF
36. Low-dose infigratinib increases bone growth and corrects growth plate abnormalities in an achondroplasia mouse model.
- Author
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Demuynck B, Flipo J, Kaci N, Dambkowski C, Paull M, Muslimova E, Shah BP, and Legeai-Mallet L
- Subjects
- Animals, Mice, Phenylurea Compounds pharmacology, Phenylurea Compounds administration & dosage, Bone Development drug effects, Receptor, Fibroblast Growth Factor, Type 3 metabolism, Receptor, Fibroblast Growth Factor, Type 3 genetics, Dose-Response Relationship, Drug, Chondrocytes drug effects, Chondrocytes pathology, Chondrocytes metabolism, Achondroplasia drug therapy, Achondroplasia pathology, Growth Plate drug effects, Growth Plate pathology, Growth Plate metabolism, Disease Models, Animal, Pyrimidines pharmacology, Pyrimidines administration & dosage
- Abstract
Achondroplasia (ACH), the most common form of disproportionate short stature, is caused by gain-of-function point mutations in fibroblast growth factor receptor 3 (FGFR3). Abnormally elevated activation of FGFR3 modulates chondrocyte proliferation and differentiation via multiple signaling pathways, such as the MAPK pathway. Using a mouse model mimicking ACH (Fgfr3Y367C/+), we have previously shown that daily treatment with infigratinib (BGJ398), a selective and orally bioavailable FGFR1-3 inhibitor, at a dose of 2 mg/kg, significantly increased bone growth. In this study, we investigated the activity of infigratinib administered at substantially lower doses (0.2 and 0.5 mg/kg, given once daily) and using an intermittent dosing regimen (1 mg/kg every 3 days). Following a 15-day treatment period, these low dosages were sufficient to observe significant improvement of clinical hallmarks of ACH such as growth of the axial and appendicular skeleton and skull development. Immunohistological labeling demonstrated the positive impact of infigratinib on chondrocyte differentiation in the cartilage growth plate and the cartilage end plate of the vertebrae. Macroscopic and microcomputed analyses showed enlargement of the foramen magnum area at the skull base, thus improving foramen magnum stenosis, a well-recognized complication in ACH. No changes in FGF23 or phosphorus levels were observed, indicating that the treatment did not modify phosphate homeostasis. This proof-of-concept study demonstrates that infigratinib administered at low doses has the potential to be a safe and effective therapeutic option for children with ACH., (© The Author(s) 2024. Published by Oxford University Press on behalf of the American Society for Bone and Mineral Research.)
- Published
- 2024
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37. Embryonic cranial cartilage defects in the Fgfr3 Y367C /+ mouse model of achondroplasia.
- Author
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Motch Perrine SM, Sapkota N, Kawasaki K, Zhang Y, Chen DZ, Kawasaki M, Durham EL, Heuzé Y, Legeai-Mallet L, and Richtsmeier JT
- Abstract
Achondroplasia, the most common chondrodysplasia in humans, is caused by one of two gain of function mutations localized in the transmembrane domain of fibroblast growth factor receptor 3 (FGFR3) leading to constitutive activation of FGFR3 and subsequent growth plate cartilage and bone defects. Phenotypic features of achondroplasia include macrocephaly with frontal bossing, midface hypoplasia, disproportionate shortening of the extremities, brachydactyly with trident configuration of the hand, and bowed legs. The condition is defined primarily on postnatal effects on bone and cartilage, and embryonic development of tissues in affected individuals is not well studied. Using the Fgfr3
Y367C/+ mouse model of achondroplasia, we investigated the developing chondrocranium and Meckel's cartilage (MC) at embryonic days (E)14.5 and E16.5. Sparse hand annotations of chondrocranial and MC cartilages visualized in phosphotungstic acid enhanced three-dimensional (3D) micro-computed tomography (microCT) images were used to train our automatic deep learning-based 3D segmentation model and produce 3D isosurfaces of the chondrocranium and MC. Using 3D coordinates of landmarks measured on the 3D isosurfaces, we quantified differences in the chondrocranium and MC of Fgfr3Y367C/+ mice relative to those of their unaffected littermates. Statistically significant differences in morphology and growth of the chondrocranium and MC were found, indicating direct effects of this Fgfr3 mutation on embryonic cranial and pharyngeal cartilages, which in turn can secondarily affect cranial dermal bone development. Our results support the suggestion that early therapeutic intervention during cartilage formation may lessen the effects of this condition., (© 2023 The Authors. The Anatomical Record published by Wiley Periodicals LLC on behalf of American Association for Anatomy.)- Published
- 2023
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38. Hypochondroplasia gain-of-function mutation in FGFR3 causes defective bone mineralization in mice.
- Author
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Loisay L, Komla-Ebri D, Morice A, Heuzé Y, Viaut C, de La Seiglière A, Kaci N, Chan D, Lamouroux A, Baujat G, Bassett JHD, Williams GR, and Legeai-Mallet L
- Subjects
- Animals, Mice, Calcification, Physiologic, Gain of Function Mutation, Dwarfism genetics, Osteoporosis, Receptor, Fibroblast Growth Factor, Type 3 genetics
- Abstract
Hypochondroplasia (HCH) is a mild dwarfism caused by missense mutations in fibroblast growth factor receptor 3 (FGFR3), with the majority of cases resulting from a heterozygous p.Asn540Lys gain-of-function mutation. Here, we report the generation and characterization of the first mouse model (Fgfr3Asn534Lys/+) of HCH to our knowledge. Fgfr3Asn534Lys/+ mice exhibited progressive dwarfism and impairment of the synchondroses of the cranial base, resulting in defective formation of the foramen magnum. The appendicular and axial skeletons were both severely affected and we demonstrated an important role of FGFR3 in regulation of cortical and trabecular bone structure. Trabecular bone mineral density (BMD) of long bones and vertebral bodies was decreased, but cortical BMD increased with age in both tibiae and femurs. These results demonstrate that bones in Fgfr3Asn534Lys/+ mice, due to FGFR3 activation, exhibit some characteristics of osteoporosis. The present findings emphasize the detrimental effect of gain-of-function mutations in the Fgfr3 gene on long bone modeling during both developmental and aging processes, with potential implications for the management of elderly patients with hypochondroplasia and osteoporosis.
- Published
- 2023
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39. Craniofacial growth and function in achondroplasia: a multimodal 3D study on 15 patients.
- Author
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Morice A, Taverne M, Eché S, Griffon L, Fauroux B, Leboulanger N, Couloigner V, Baujat G, Cormier-Daire V, Picard A, Legeai-Mallet L, Kadlub N, and Khonsari RH
- Subjects
- Humans, Cephalometry, Retrognathia, Sleep Apnea Syndromes, Sleep Apnea, Obstructive, Achondroplasia genetics
- Abstract
Background: Achondroplasia is the most frequent FGFR3-related chondrodysplasia, leading to rhizomelic dwarfism, craniofacial anomalies, stenosis of the foramen magnum, and sleep apnea. Craniofacial growth and its correlation with obstructive sleep apnea syndrome has not been assessed in achondroplasia. In this study, we provide a multimodal analysis of craniofacial growth and anatomo-functional correlations between craniofacial features and the severity of obstructive sleep apnea syndrome., Methods: A multimodal study was performed based on a paediatric cohort of 15 achondroplasia patients (mean age, 7.8 ± 3.3 years), including clinical and sleep study data, 2D cephalometrics, and 3D geometric morphometry analyses, based on CT-scans (mean age at CT-scan: patients, 4.9 ± 4.9 years; controls, 3.7 ± 4.2 years)., Results: Craniofacial phenotype was characterized by maxillo-zygomatic retrusion, deep nasal root, and prominent forehead. 2D cephalometric studies showed constant maxillo-mandibular retrusion, with excessive vertical dimensions of the lower third of the face, and modifications of cranial base angles. All patients with available CT-scan had premature fusion of skull base synchondroses. 3D morphometric analyses showed more severe craniofacial phenotypes associated with increasing patient age, predominantly regarding the midface-with increased maxillary retrusion in older patients-and the skull base-with closure of the spheno-occipital angle. At the mandibular level, both the corpus and ramus showed shape modifications with age, with shortened anteroposterior mandibular length, as well as ramus and condylar region lengths. We report a significant correlation between the severity of maxillo-mandibular retrusion and obstructive sleep apnea syndrome (p < 0.01)., Conclusions: Our study shows more severe craniofacial phenotypes at older ages, with increased maxillomandibular retrusion, and demonstrates a significant anatomo-functional correlation between the severity of midface and mandible craniofacial features and obstructive sleep apnea syndrome., (© 2023. The Author(s).)
- Published
- 2023
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40. FGFR3 overactivation in the brain is responsible for memory impairments in Crouzon syndrome mouse model.
- Author
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Cornille M, Moriceau S, Khonsari RH, Heuzé Y, Loisay L, Boitez V, Morice A, Arnaud E, Collet C, Bensidhoum M, Kaci N, Boddaert N, Paternoster G, Rauschendorfer T, Werner S, Mansour SL, Di Rocco F, Oury F, and Legeai-Mallet L
- Subjects
- Animals, Brain, Disease Models, Animal, Memory Disorders genetics, Mice, Receptor, Fibroblast Growth Factor, Type 3 genetics, Acanthosis Nigricans complications, Acanthosis Nigricans genetics, Craniofacial Dysostosis complications, Craniofacial Dysostosis genetics, Craniosynostoses genetics
- Abstract
Crouzon syndrome with acanthosis nigricans (CAN, a rare type of craniosynostosis characterized by premature suture fusion and neurological impairments) has been linked to a gain-of-function mutation (p.Ala391Glu) in fibroblast growth factor receptor 3 (FGFR3). To characterize the CAN mutation's impact on the skull and on brain functions, we developed the first mouse model (Fgfr3A385E/+) of this syndrome. Surprisingly, Fgfr3A385E/+ mice did not exhibit craniosynostosis but did show severe memory impairments, a structurally abnormal hippocampus, low activity-dependent synaptic plasticity, and overactivation of MAPK/ERK and Akt signaling pathways in the hippocampus. Systemic or brain-specific pharmacological inhibition of FGFR3 overactivation by BGJ398 injections rescued the memory impairments observed in Fgfr3A385E/+ mice. The present study is the first to have demonstrated cognitive impairments associated with brain FGFR3 overactivation, independently of skull abnormalities. Our results provide a better understanding of FGFR3's functional role and the impact of its gain-of-function mutation on brain functions. The modulation of FGFR3 signaling might be of value for treating the neurological disorders associated with craniosynostosis., Competing Interests: Disclosures: L. Legeai-Mallet and F. Oury reported a patent to BIO19248 pending. No other disclosures were reported., (© 2022 Cornille et al.)
- Published
- 2022
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41. Growth charts in FGFR2 - and FGFR3 -related faciocraniosynostoses.
- Author
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Ea C, Hennocq Q, Picard A, Polak M, Collet C, Legeai-Mallet L, Arnaud É, Paternoster G, and Khonsari RH
- Abstract
Objective: Faciocraniosynostoses (FCS) are malformations affecting the development of the bones of the skull and face, due to the premature closure of one or more craniofacial sutures, mostly secondary to activating Fibroblast Growth Factor Receptor ( FGFR ) 1-3 mutations. Gain-of-function FGFR3 mutations are also responsible for various conditions referred to as osteochondrodysplasia (OCD), characterized by structural and functional abnormalities of growth plate cartilages. We hypothesized that patients with FGFR -related faciocraniosynostoses may present extra-cranial growth anomalies., Study Design: We retrospectively collected height and weight data from a cohort of 70 patients. Included patients were admitted for FGFR -related FCS between 2000 and 2021 at the Craniofacial Unit of Necker - Enfants Malades University Hospital in Paris, France., Results: We showed that FGFR -related faciocraniosynostoses had significantly reduced heights and weights relative to controls, and that two specific time periods (1-3 years and > 8 years of age) were associated with lower height and weight values. Four patients had received growth hormone treatment but remained below normal values for growth in height and weight., Conclusions: Patients with FGFR -related faciocraniosynostoses have clinically significant extra-cranial anomalies which are not currently investigated and managed in usual protocols; these patients could benefit from a systematic pre-pubertal endocrine assessment. More generally, our results extend the scope of extracranial anomalies in FGFR -related faciocraniosynostoses and support the hypothesis that all conditions with activating FGFR mutations affect both membranous ossification and long bones., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2022 Published by Elsevier Inc.)
- Published
- 2022
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42. Theobroma cacao improves bone growth by modulating defective ciliogenesis in a mouse model of achondroplasia.
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Martin L, Kaci N, Benoist-Lasselin C, Mondoloni M, Decaudaveine S, Estibals V, Cornille M, Loisay L, Flipo J, Demuynck B, de la Luz Cádiz-Gurrea M, Barbault F, Fernández-Arroyo S, Schibler L, Segura-Carretero A, Dambroise E, and Legeai-Mallet L
- Abstract
A gain-of-function mutation in the fibroblast growth factor receptor 3 gene (FGFR3) results in achondroplasia (ACH), the most frequent form of dwarfism. Constitutive activation of FGFR3 impairs bone formation and elongation and many signal transduction pathways. Identification of new and relevant compounds targeting the FGFR3 signaling pathway is of broad importance for the treatment of ACH, and natural plant compounds are prime drug candidate sources. Here, we found that the phenolic compound (-)-epicatechin, isolated from Theobroma cacao, effectively inhibited FGFR3's downstream signaling pathways. Transcriptomic analysis in an Fgfr3 mouse model showed that ciliary mRNA expression was modified and influenced significantly by the Indian hedgehog and PKA pathways. (-)-Epicatechin is able to rescue mRNA expression impairments that control both the structural organization of the primary cilium and ciliogenesis-related genes. In femurs isolated from a mouse model (Fgfr3
Y367C/+ ) of ACH, we showed that (-)-epicatechin eliminated bone growth impairment during 6 days of ex vivo culture. In vivo, we confirmed that daily subcutaneous injections of (-)-epicatechin to Fgfr3Y367C/+ mice increased bone elongation and rescued the primary cilium defects observed in chondrocytes. This modification to the primary cilia promoted the typical columnar arrangement of flat proliferative chondrocytes and thus enhanced bone elongation. The results of the present proof-of-principle study support (-)-epicatechin as a potential drug for the treatment of ACH., (© 2022. The Author(s).)- Published
- 2022
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43. Phosphatase inhibition by LB-100 enhances BMN-111 stimulation of bone growth.
- Author
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Shuhaibar LC, Kaci N, Egbert JR, Horville T, Loisay L, Vigone G, Uliasz TF, Dambroise E, Swingle MR, Honkanen RE, Biosse Duplan M, Jaffe LA, and Legeai-Mallet L
- Subjects
- Animals, Bone Diseases, Developmental genetics, Cartilage drug effects, Cartilage growth & development, Cell Differentiation drug effects, Chondrocytes drug effects, Drug Synergism, Growth Plate drug effects, Growth Plate growth & development, Mice, Natriuretic Peptide, C-Type pharmacology, Organ Size, Phosphorylation, Primary Cell Culture, Receptors, Atrial Natriuretic Factor genetics, Tibia drug effects, Tibia growth & development, Achondroplasia genetics, Bone Development drug effects, Enzyme Inhibitors pharmacology, Natriuretic Peptide, C-Type analogs & derivatives, Phosphoric Monoester Hydrolases antagonists & inhibitors, Piperazines pharmacology, Receptor, Fibroblast Growth Factor, Type 3 genetics, Receptors, Atrial Natriuretic Factor agonists
- Abstract
Activating mutations in fibroblast growth factor receptor 3 (FGFR3) and inactivating mutations in the natriuretic peptide receptor 2 (NPR2) guanylyl cyclase both result in decreased production of cyclic GMP in chondrocytes and severe short stature, causing achondroplasia (ACH) and acromesomelic dysplasia, type Maroteaux, respectively. Previously, we showed that an NPR2 agonist BMN-111 (vosoritide) increases bone growth in mice mimicking ACH (Fgfr3Y367C/+). Here, because FGFR3 signaling decreases NPR2 activity by dephosphorylating the NPR2 protein, we tested whether a phosphatase inhibitor (LB-100) could enhance BMN-111-stimulated bone growth in ACH. Measurements of cGMP production in chondrocytes of living tibias, and of NPR2 phosphorylation in primary chondrocytes, showed that LB-100 counteracted FGF-induced dephosphorylation and inactivation of NPR2. In ex vivo experiments with Fgfr3Y367C/+ mice, the combination of BMN-111 and LB-100 increased bone length and cartilage area, restored chondrocyte terminal differentiation, and increased the proliferative growth plate area, more than BMN-111 alone. The combination treatment also reduced the abnormal elevation of MAP kinase activity in the growth plate of Fgfr3Y367C/+ mice and improved the skull base anomalies. Our results provide a proof of concept that a phosphatase inhibitor could be used together with an NPR2 agonist to enhance cGMP production as a therapy for ACH.
- Published
- 2021
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44. Prevention of guanylyl cyclase-B dephosphorylation rescues achondroplastic dwarfism.
- Author
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Wagner BM, Robinson JW, Lin YW, Lee YC, Kaci N, Legeai-Mallet L, and Potter LR
- Subjects
- Animals, Body Size genetics, Femur growth & development, Growth Plate growth & development, Growth Plate pathology, Mice, Mice, Transgenic, Organ Size, Phosphorylation, Receptors, Atrial Natriuretic Factor metabolism, Skull growth & development, Tibia growth & development, Achondroplasia genetics, Bone Development genetics, Receptor, Fibroblast Growth Factor, Type 3 genetics, Receptors, Atrial Natriuretic Factor genetics
- Abstract
Activating mutations in the fibroblast growth factor receptor 3 (FGFR3) or inactivating mutations in guanylyl cyclase-B (GC-B), also known as NPR-B or Npr2, cause short-limbed dwarfism. FGFR3 activation causes dephosphorylation and inactivation of GC-B, but the contribution of GC-B dephosphorylation to achondroplasia (ACH) is unknown. GC-B7E/7E mice that express a glutamate-substituted version of GC-B that cannot be inactivated by dephosphorylation were bred with mice expressing FGFR3-G380R, the most common human ACH mutation, to determine if GC-B dephosphorylation is required for ACH. Crossing GC-B7E/7E mice with FGFR3G380R/G380R mice increased naso-anal and long (tibia and femur), but not cranial, bone length twice as much as crossing GC-B7E/7E mice with FGFR3WT/WT mice from 4 to 16 weeks of age. Consistent with increased GC-B activity rescuing ACH, long bones from the GC-B7E/7E/FGFR3G380R/G380R mice were not shorter than those from GC-BWT/WT/FGFR3WT/WT mice. At 2 weeks of age, male but not female FGFR3G380R/G380R mice had shorter long bones and smaller growth plate hypertrophic zones, whereas female but not male GC-B7E/7E mice had longer bones and larger hypertrophic zones. In 2-week-old males, crossing FGFR3G380R/G380R mice with GC-B7E/7E mice increased long bone length and hypertrophic zone area to levels observed in mice expressing WT versions of both receptors. We conclude that preventing GC-B dephosphorylation rescues reduced axial and appendicular skeleton growth in a mouse model of achondroplasia.
- Published
- 2021
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45. An Fgfr3-activating mutation in immature murine osteoblasts affects the appendicular and craniofacial skeleton.
- Author
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Biosse Duplan M, Dambroise E, Estibals V, Veziers J, Guicheux J, and Legeai-Mallet L
- Subjects
- Animals, Bone Diseases, Metabolic complications, Bone Diseases, Metabolic pathology, Chondrocytes pathology, Disease Models, Animal, Dwarfism complications, Dwarfism pathology, Face, Growth Plate abnormalities, Hypertrophy, Mice, Transgenic, Osteogenesis, Cell Differentiation genetics, Mutation genetics, Osteoblasts pathology, Receptor, Fibroblast Growth Factor, Type 3 genetics, Skull pathology
- Abstract
Achondroplasia (ACH), the most common form of dwarfism, is caused by a missense mutation in the gene coding for fibroblast growth factor receptor 3 (FGFR3). The resulting increase in FGFR3 signaling perturbs the proliferation and differentiation of chondrocytes (CCs), alters the process of endochondral ossification and thus reduces bone elongation. Increased FGFR3 signaling in osteoblasts (OBs) might also contribute to bone anomalies in ACH. In the present study of a mouse model of ACH, we sought to determine whether FGFR3 overactivation in OBs leads to bone modifications. The model carries an Fgfr3-activating mutation (Fgfr3Y367C/+) that accurately mimics ACH; we targeted the mutation to either immature OBs and hypertrophic CCs or to mature OBs by using the Osx-cre and collagen 1α1 (2.3 kb Col1a1)-cre mouse strains, respectively. We observed that Fgfr3 activation in immature OBs and hypertrophic CCs (Osx-Fgfr3) not only perturbed the hypertrophic cells of the growth plate (thus affecting long bone growth) but also led to osteopenia and low cortical thickness in long bones in adult (3-month-old) mice but not growing (3-week-old) mice. Importantly, craniofacial membranous bone defects were present in the adult mice. In contrast, activation of Fgfr3 in mature OBs (Col1-Fgfr3) had very limited effects on skeletal shape, size and micro-architecture. In vitro, we observed that Fgfr3 activation in immature OBs was associated with low mineralization activity. In conclusion, immature OBs appear to be affected by Fgfr3 overactivation, which might contribute to the bone modifications observed in ACH independently of CCs., Competing Interests: Competing interests The authors declare no competing or financial interests., (© 2021. Published by The Company of Biologists Ltd.)
- Published
- 2021
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46. Novel therapeutic approaches for the treatment of achondroplasia.
- Author
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Legeai-Mallet L and Savarirayan R
- Subjects
- Animals, Chondrogenesis, Growth Plate, Mice, Mutation, Osteogenesis, Receptors, Fibroblast Growth Factor genetics, Signal Transduction, Achondroplasia drug therapy, Achondroplasia genetics
- Abstract
Achondroplasia is the most common form of human dwarfism. The molecular basis of achondroplasia was elucidated in 1994 with the identification of the fibroblast growth factor receptor 3 (FGFR3) as the causative gene. Missense mutations causing achondroplasia result in activation of FGFR3 and its downstream signaling pathways, disturbing chondrogenesis, osteogenesis, and long bone elongation. A more accurate understanding of the clinical and molecular aspects of achondroplasia has allowed new therapeutic approaches to be developed. These are based on: clear understanding of the natural history of the disease; proof-of-concept preclinical studies in mouse models; and the current state of knowledge regarding FGFR3 and related growth plate homeostatic pathways. This review provides a brief overview of the preclinical mouse models of achondroplasia that have led to new, non-surgical therapeutic strategies being assessed and applied to children with achondroplasia through pioneering clinical trials., (Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.)
- Published
- 2020
- Full Text
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47. FGFR3 in Periosteal Cells Drives Cartilage-to-Bone Transformation in Bone Repair.
- Author
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Julien A, Perrin S, Duchamp de Lageneste O, Carvalho C, Bensidhoum M, Legeai-Mallet L, and Colnot C
- Subjects
- Animals, Bony Callus pathology, Cell Differentiation, Fracture Healing, Homeodomain Proteins metabolism, Integrases metabolism, Mice, Inbred C57BL, Phenotype, Tibia pathology, Bone Regeneration, Bone and Bones pathology, Cartilage pathology, Periosteum metabolism, Pseudarthrosis pathology, Receptor, Fibroblast Growth Factor, Type 3 metabolism
- Abstract
Most organs and tissues in the body, including bone, can repair after an injury due to the activation of endogenous adult stem/progenitor cells to replace the damaged tissue. Inherent dysfunctions of the endogenous stem/progenitor cells in skeletal repair disorders are still poorly understood. Here, we report that Fgfr3
Y637C/+ over-activating mutation in Prx1-derived skeletal stem/progenitor cells leads to failure of fracture consolidation. We show that periosteal cells (PCs) carrying the Fgfr3Y637C/+ mutation can engage in osteogenic and chondrogenic lineages, but following transplantation do not undergo terminal chondrocyte hypertrophy and transformation into bone causing pseudarthrosis. Instead, Prx1Cre ;Fgfr3Y637C/+ PCs give rise to fibrocartilage and fibrosis. Conversely, wild-type PCs transplanted at the fracture site of Prx1Cre ;Fgfr3Y637C/+ mice allow hypertrophic cartilage transition to bone and permit fracture consolidation. The results thus highlight cartilage-to-bone transformation as a necessary step for bone repair and FGFR3 signaling within PCs as a key regulator of this transformation., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)- Published
- 2020
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48. Fgfr3 Is a Positive Regulator of Osteoblast Expansion and Differentiation During Zebrafish Skull Vault Development.
- Author
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Dambroise E, Ktorza I, Brombin A, Abdessalem G, Edouard J, Luka M, Fiedler I, Binder O, Pelle O, Patton EE, Busse B, Menager M, Sohm F, and Legeai-Mallet L
- Subjects
- Animals, Cell Differentiation, Osteoblasts, Osteogenesis, Receptor, Fibroblast Growth Factor, Type 3 genetics, Skull, Zebrafish Proteins genetics, Zebrafish
- Abstract
Gain or loss-of-function mutations in fibroblast growth factor receptor 3 (FGFR3) result in cranial vault defects highlighting the protein's role in membranous ossification. Zebrafish express high levels of fgfr3 during skull development; in order to study FGFR3's role in cranial vault development, we generated the first fgfr3 loss-of-function zebrafish (fgfr3
lof/lof ). The mutant fish exhibited major changes in the craniofacial skeleton, with a lack of sutures, abnormal frontal and parietal bones, and the presence of ectopic bones. Integrated analyses (in vivo imaging and single-cell RNA sequencing of the osteoblast lineage) of zebrafish fgfr3lof/lof revealed a delay in osteoblast expansion and differentiation, together with changes in the extracellular matrix. These findings demonstrate that fgfr3 is a positive regulator of osteogenesis. We conclude that changes in the extracellular matrix within growing bone might impair cell-cell communication, mineralization, and new osteoblast recruitment. © 2020 American Society for Bone and Mineral Research., (© 2020 American Society for Bone and Mineral Research.)- Published
- 2020
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49. Mutations in the Kinesin-2 Motor KIF3B Cause an Autosomal-Dominant Ciliopathy.
- Author
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Cogné B, Latypova X, Senaratne LDS, Martin L, Koboldt DC, Kellaris G, Fievet L, Le Meur G, Caldari D, Debray D, Nizon M, Frengen E, Bowne SJ, Cadena EL, Daiger SP, Bujakowska KM, Pierce EA, Gorin M, Katsanis N, Bézieau S, Petersen-Jones SM, Occelli LM, Lyons LA, Legeai-Mallet L, Sullivan LS, Davis EE, and Isidor B
- Subjects
- Amino Acid Sequence, Animals, Cats, Child, Preschool, Cilia pathology, Female, Genome-Wide Association Study, Heterozygote, Humans, Kinesins chemistry, Kinesins metabolism, Larva, Male, Middle Aged, Pedigree, Phenotype, Photoreceptor Cells metabolism, Retina cytology, Retina growth & development, Retina metabolism, Rhodopsin metabolism, Young Adult, Zebrafish genetics, Zebrafish growth & development, Ciliopathies genetics, Ciliopathies pathology, Genes, Dominant genetics, Kinesins genetics, Mutation, Retina pathology
- Abstract
Kinesin-2 enables ciliary assembly and maintenance as an anterograde intraflagellar transport (IFT) motor. Molecular motor activity is driven by a heterotrimeric complex comprised of KIF3A and KIF3B or KIF3C plus one non-motor subunit, KIFAP3. Using exome sequencing, we identified heterozygous KIF3B variants in two unrelated families with hallmark ciliopathy phenotypes. In the first family, the proband presents with hepatic fibrosis, retinitis pigmentosa, and postaxial polydactyly; he harbors a de novo c.748G>C (p.Glu250Gln) variant affecting the kinesin motor domain encoded by KIF3B. The second family is a six-generation pedigree affected predominantly by retinitis pigmentosa. Affected individuals carry a heterozygous c.1568T>C (p.Leu523Pro) KIF3B variant segregating in an autosomal-dominant pattern. We observed a significant increase in primary cilia length in vitro in the context of either of the two mutations while variant KIF3B proteins retained stability indistinguishable from wild type. Furthermore, we tested the effects of KIF3B mutant mRNA expression in the developing zebrafish retina. In the presence of either missense variant, rhodopsin was sequestered to the photoreceptor rod inner segment layer with a concomitant increase in photoreceptor cilia length. Notably, impaired rhodopsin trafficking is also characteristic of recessive KIF3B models as exemplified by an early-onset, autosomal-recessive, progressive retinal degeneration in Bengal cats; we identified a c.1000G>A (p.Ala334Thr) KIF3B variant by genome-wide association study and whole-genome sequencing. Together, our genetic, cell-based, and in vivo modeling data delineate an autosomal-dominant syndromic retinal ciliopathy in humans and suggest that multiple KIF3B pathomechanisms can impair kinesin-driven ciliary transport in the photoreceptor., (Copyright © 2020 American Society of Human Genetics. All rights reserved.)
- Published
- 2020
- Full Text
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50. The influence of fronto-facial monobloc advancement on obstructive sleep apnea: An assessment of 109 syndromic craniosynostoses cases.
- Author
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Khonsari RH, Haber S, Paternoster G, Fauroux B, Morisseau-Durand MP, Cormier-Daire V, Legeai-Mallet L, James S, Hennocq Q, and Arnaud E
- Subjects
- Aged, Child, Humans, Middle Aged, Syndrome, Craniosynostoses, Sleep Apnea, Obstructive
- Abstract
Obstructive sleep apnea syndrome is prevalent in children with syndromic craniosynostoses. Here we assessed the effects of fronto-facial monobloc advancement with internal distraction on obstructive sleep apnea in syndromic craniosynostoses. All patients managed for syndromic craniosynostosis over a period of 14 years were assessed based on apnea-hyponea index (AHI) before and after fronto-facial surgery. AHI values were analyzed using multivariate models with focuses on (1) absolute decrease in AHI values after fronto-facial surgery and (2) AHI normalization (AHI < 5) after fronto-facial surgery. One hundred and nine patients were included with 407 polysomnographic studies. Higher pre-operative AHI (p < 0.001) and pre-operative vault expansion (p = 0.008) were associated with more AHI decrease. Early airways surgery (p = 0.002) and fronto-facial surgery at older ages (p < 0.001) were associated with more AHI normalization. Our results indicate that fronto-facial surgery is specifically efficient in reducing severe (AHI > 20) obstructive sleep apnea in syndromic craniosynostoses. Early airways surgery, early vault expansion and fronto-facial surgery at older ages are recommended for better respiratory results. We provide support for a protocol involving (1) early posterior vault expansion and airways surgery and (2) fronto-facial advancement performed as late as possible (>2.5 years)., (Copyright © 2020 European Association for Cranio-Maxillo-Facial Surgery. Published by Elsevier Ltd. All rights reserved.)
- Published
- 2020
- Full Text
- View/download PDF
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