FGFR3 targeting strategies for achondroplasia

Melanie B. Laederich; William A. Horton

doi:10.1017/erm.2012.4

FGFR3 targeting strategies for achondroplasia

Published online by Cambridge University Press: 23 April 2012

Melanie B. Laederich and

William A. Horton

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Melanie B. Laederich: Affiliation:
Shriners Hospital for Children, Research Center, Portland, OR, USA Departments of Cell & Developmental Biology and Molecular & Medical Genetics, Oregon Health & Science University, Portland, OR, USA
William A. Horton*: Affiliation:
Shriners Hospital for Children, Research Center, Portland, OR, USA Departments of Cell & Developmental Biology and Molecular & Medical Genetics, Oregon Health & Science University, Portland, OR, USA
*: *Corresponding author: William A. Horton, Research Center, Shriners Hospital for Children, 3101 SW Sam Jackson Park Road, Portland, OR 97239, USA. E-mail: wah@shcc.org

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Abstract

Mutations that exaggerate signalling of the receptor tyrosine kinase fibroblast growth factor receptor 3 (FGFR3) give rise to achondroplasia, the most common form of dwarfism in humans. Here we review the clinical features, genetic aspects and molecular pathogenesis of achondroplasia and examine several therapeutic strategies designed to target the mutant receptor or its signalling pathways, including the use of kinase inhibitors, blocking antibodies, physiologic antagonists, RNAi and chaperone inhibitors. We conclude by discussing the challenges of treating growth plate disorders in children.

Type: Review Article
Information: Expert Reviews in Molecular Medicine , Volume 14 , March 2012 , e11

DOI: https://doi.org/10.1017/erm.2012.4[Opens in a new window]
Copyright: Copyright © Cambridge University Press 2012

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1Horton, W.A., Hall, J.G. and Hecht, J.T. (2007) Achondroplasia. Lancet 370, 162-172CrossRef Google Scholar PubMed

2Kozma, C. (2006) Dwarfs in ancient Egypt. American Journal of Medical Genetics A 140, 303-311CrossRef Google Scholar PubMed

3Rimoin, D.L. (1975) The chondrodystrophies. Advances in Human Genetics 5, 1-118Google Scholar PubMed

4Shiang, R. et al. (1994) Mutations in the transmembrane domain of FGFR3 cause the most common genetic form of dwarfism, achondroplasia. Cell 78, 335-342CrossRef Google Scholar PubMed

5Rousseau, F. et al. (1994) Mutations in the gene encoding fibroblast growth factor receptor-3 in achondroplasia. Nature 371, 252-254CrossRef Google Scholar PubMed

6Bellus, G.A. et al. (1995) Achondroplasia is defined by recurrent G380R mutations of FGFR3. American Journal of Human Genetics 56, 368-373Google Scholar PubMed

7Wynn, J. et al. (2007) Mortality in achondroplasia study: a 42-year follow-up. American Journal of Medical Genetics Part A 143A, 2502-2511CrossRef Google Scholar PubMed

8Velinov, M. et al. (1994) The gene for achondroplasia maps to the telomeric region of chromosome 4p. Nature Genetics 6, 314-317CrossRef Google Scholar PubMed

9Bellus, G.A. et al. (1995) A recurrent mutation in the tyrosine kinase domain of fibroblast growth factor receptor 3 causes hypochondroplasia. Nature Genetics 10, 357-359CrossRef Google Scholar PubMed

10Tavormina, P.L. et al. (1995) Thanatophoric dysplasia (types I and II) caused by distinct mutations in fibroblast growth factor receptor 3. Nature Genetics 9, 321-328CrossRef Google Scholar PubMed

11Vajo, Z., Francomano, C.A. and Wilkin, D.J. (2000) 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. Endocrine Reviews 21, 23-39Google Scholar PubMed

12Dodurga, Y. et al. (2011) Incidence of fibroblast growth factor receptor 3 gene (FGFR3) A248C, S249C, G372C, and T375C mutations in bladder cancer. Genetics and Molecular Research: GMR 10, 86-95CrossRef Google Scholar PubMed

13Sonvilla, G. et al. (2010) Fibroblast growth factor receptor 3-IIIc mediates colorectal cancer growth and migration. British Journal of Cancer 102, 1145-1156CrossRef Google Scholar PubMed

14Chesi, M. et al. (1997) Frequent translocation t(4;14)(p16.3;q32.3) in multiple myeloma is associated with increased expression and activating mutations of fibroblast growth factor receptor 3. Nature Genetics 16, 260-264CrossRef Google Scholar

15Goriely, A. et al. (2005) Gain-of-function amino acid substitutions drive positive selection of FGFR2 mutations in human spermatogonia. Proceedings of the National Academy Science of the United States of America 102, 6051-6056CrossRef Google Scholar PubMed

16Wilkie, A.O. (2005) Bad bones, absent smell, selfish testes: the pleiotropic consequences of human FGF receptor mutations. Cytokine and Growth Factor Reviews 16, 187-203CrossRef Google Scholar PubMed

17Eswarakumar, V.P., Lax, I. and Schlessinger, J. (2005) Cellular signaling by fibroblast growth factor receptors. Cytokine and Growth Factor Reviews 16, 139-149CrossRef Google Scholar PubMed

18Ornitz, D.M. (2005) FGF signaling in the developing endochondral skeleton. Cytokine and Growth Factor Reviews 16, 205-213CrossRef Google Scholar PubMed

19Chen, H. et al. (2007) A molecular brake in the kinase hinge region regulates the activity of receptor tyrosine kinases. Molecular Cell 27, 717-730CrossRef Google Scholar PubMed

20Colvin, J.S. et al. (1996) Skeletal overgrowth and deafness in mice lacking fibroblast growth factor receptor 3. Nature Genetics 12, 390-397CrossRef Google Scholar PubMed

21Deng, C. et al. (1996) Fibroblast growth factor receptor 3 is a negative regulator of bone growth. Cell 84, 911-921CrossRef Google Scholar PubMed

22Naski, M.C. et al. (1998) Repression of hedgehog signaling and BMP4 expression in growth plate cartilage by fibroblast growth factor receptor 3. Development 125, 4977-4988Google Scholar PubMed

23Garofalo, S. et al. (1999) Skeletal dysplasia and defective chondrocyte differentiation by targeted overexpression of fibroblast growth factor 9 in transgenic mice. Journal of Bone and Mineral Research: The Official Journal of the American Society for Bone and Mineral Research 14, 1909-1915CrossRef Google Scholar PubMed

24Itoh, N. and Ornitz, D.M. (2008) Functional evolutionary history of the mouse Fgf gene family. Developmental Dynamics: An Official Publication of the American Association of Anatomists 237, 18-27CrossRef Google Scholar PubMed

25Ornitz, D.M. et al. (1996) Receptor specificity of the fibroblast growth factor family. Journal of Biological Chemistry 271, 15292-15297CrossRef Google Scholar PubMed

26Liu, Z. et al. (2002) Coordination of chondrogenesis and osteogenesis by fibroblast growth factor 18. Genes and Development 16, 859-869CrossRef Google Scholar PubMed

27Ohbayashi, N. et al. (2002) FGF18 is required for normal cell proliferation and differentiation during osteogenesis and chondrogenesis. Genes and Development 16, 870-879CrossRef Google Scholar PubMed

28Liu, Z. et al. (2007) FGF18 is required for early chondrocyte proliferation, hypertrophy and vascular invasion of the growth plate. Developmental Biology 302, 80-91CrossRef Google Scholar PubMed

29Krejci, P. et al. (2007) Fibroblast growth factors 1, 2, 17, and 19 are the predominant FGF ligands expressed in human fetal growth plate cartilage. Pediatric Research 61, 267-272CrossRef Google Scholar

30Chuang, C.Y. et al. (2010) Heparan sulfate-dependent signaling of fibroblast growth factor 18 by chondrocyte-derived perlecan. Biochemistry 49, 5524-5532CrossRef Google Scholar PubMed

31Plotnikov, A.N. et al. (1999) Structural basis for FGF receptor dimerization and activation. Cell 98, 641-650CrossRef Google Scholar PubMed

32Hart, K.C., Robertson, S.C. and Donoghue, D.J. (2001) Identification of tyrosine residues in constitutively activated fibroblast growth factor receptor 3 involved in mitogenesis, Stat activation, and phosphatidylinositol 3-kinase activation. Molecular Biology of the Cell 12, 931-942CrossRef Google Scholar PubMed

33Mohammadi, M., Olsen, S.K. and Ibrahimi, O.A. (2005) Structural basis for fibroblast growth factor receptor activation. Cytokine and Growth Factor Reviews 16, 107-137CrossRef Google Scholar PubMed

34Horton, W.A. and Degnin, C.R. (2009) FGFs in endochondral skeletal development. Trends in Endocrinology and Metabolism 20, 341-348CrossRef Google Scholar PubMed

35Bae, J.H. and Schlessinger, J. (2010) Asymmetric tyrosine kinase arrangements in activation or autophosphorylation of receptor tyrosine kinases. Molecules and Cells 29, 443-448CrossRef Google Scholar PubMed

36Su, W.C. et al. (1997) Activation of Stat1 by mutant fibroblast growth-factor receptor in thanatophoric dysplasia type II dwarfism. Nature 386, 288-292CrossRef Google Scholar PubMed

37Legeai-Mallet, L. et al. (1998) Fibroblast growth factor receptor 3 mutations promote apoptosis but do not alter chondrocyte proliferation in thanatophoric dysplasia. Journal of Biological Chemistry 273, 13007-13014CrossRef Google Scholar

38Sahni, M. et al. (1999) FGF signaling inhibits chondrocyte proliferation and regulates bone development through the STAT-1 pathway. Genes and Development 13, 1361-1366CrossRef Google Scholar PubMed

39Hart, K.C. et al. (2000) Transformation and Stat activation by derivatives of FGFR1, FGFR3, and FGFR4. Oncogene 19, 3309-3320CrossRef Google Scholar PubMed

40Choi, D.Y. et al. (2001) Fibroblast growth factor receptor 3 induces gene expression primarily through Ras-independent signal transduction pathways. Journal of Biological Chemistry 276, 5116-5122CrossRef Google Scholar PubMed

41Murakami, S. et al. (2004) Constitutive activation of MEK1 in chondrocytes causes Stat1-independent achondroplasia-like dwarfism and rescues the Fgfr3-deficient mouse phenotype. Genes and Development 18, 290-305CrossRef Google Scholar PubMed

42Zhang, R. et al. (2006) Constitutive activation of MKK6 in chondrocytes of transgenic mice inhibits proliferation and delays endochondral bone formation. Proceedings of the National Academy Science of the United States of America 103, 365-370CrossRef Google Scholar PubMed

43Minina, E. et al. (2002) Interaction of FGF, Ihh/Pthlh, and BMP signaling integrates chondrocyte proliferation and hypertrophic differentiation. Developmental Cell 3, 439-449CrossRef Google Scholar PubMed

44Dailey, L. et al. (2003) A network of transcriptional and signaling events is activated by FGF to induce chondrocyte growth arrest and differentiation. Journal of Cell Biology 161, 1053-1066CrossRef Google Scholar

45Schibler, L. et al. (2009) New insight on FGFR3-related chondrodysplasias molecular physiopathology revealed by human chondrocyte gene expression profiling. PLoS ONE 4, e7633CrossRef Google Scholar PubMed

46Degnin, C.R., Laederich, M.B. and Horton, W.A. (2011) Ligand activation leads to regulated intramembrane proteolysis (RIP) of Fibroblast Growth Factor Receptor 3. Molecular Biology of the Cell 22, 3861-3873CrossRef Google Scholar PubMed

47Lyu, J., Yamamoto, V. and Lu, W. (2008) Cleavage of the Wnt receptor Ryk regulates neuronal differentiation during cortical neurogenesis. Developmental Cell 15, 773-780CrossRef Google Scholar PubMed

48Carpenter, G. and Liao, H.J. (2009) Trafficking of receptor tyrosine kinases to the nucleus. Experimental Cell Research 315, 1556-1566CrossRef Google Scholar PubMed

49Parkhurst, C.N., Zampieri, N. and Chao, M.V. (2010) Nuclear localization of the p75 neurotrophin receptor intracellular domain. Journal of Biological Chemistry 285, 5361-5368CrossRef Google Scholar PubMed

50Ben-Zvi, T. et al. (2006) Suppressors of cytokine signaling (SOCS) 1 and SOCS3 interact with and modulate fibroblast growth factor receptor signaling. Journal of Cell Science 119(Pt 2), 380-387CrossRef Google Scholar PubMed

51de Frutos, C.A. et al. (2007) Snail1 is a transcriptional effector of FGFR3 signaling during chondrogenesis and achondroplasias. Developmental Cell 13, 872-883CrossRef Google Scholar PubMed

52Potter, L.R., Abbey-Hosch, S. and Dickey, D.M. (2006) Natriuretic peptides, their receptors, and cyclic guanosine monophosphate-dependent signaling functions. Endocrine Reviews 27, 47-72CrossRef Google Scholar PubMed

53Yasoda, A. et al. (2004) Overexpression of CNP in chondrocytes rescues achondroplasia through a MAPK-dependent pathway. Nature Medicine 10, 80-86CrossRef Google Scholar PubMed

54Pejchalova, K., Krejci, P. and Wilcox, W.R. (2007) C-natriuretic peptide: an important regulator of cartilage. Molecular Genetics and Metabolism 92, 210-215CrossRef Google Scholar PubMed

55Sellitti, D.F., Koles, N. and Mendonca, M.C. (2011) Regulation of C-type natriuretic peptide expression. Peptides 32, 1964-1971CrossRef Google Scholar PubMed

56Bartels, C.F. et al. (2004) Mutations in the transmembrane natriuretic peptide receptor NPR-B impair skeletal growth and cause acromesomelic dysplasia, type Maroteaux. American Journal of Human Genetics 75, 27-34CrossRef Google Scholar PubMed

57Yasoda, A. et al. (1998) Natriuretic peptide regulation of endochondral ossification. Evidence for possible roles of the C-type natriuretic peptide/guanylyl cyclase-B pathway. Journal of Biological Chemistry 273, 11695-11700CrossRef Google Scholar PubMed

58Miyazawa, T. et al. (2002) Cyclic GMP-dependent protein kinase II plays a critical role in C-type natriuretic peptide-mediated endochondral ossification. Endocrinology 143, 3604-3610CrossRef Google Scholar

59Krejci, P. et al. (2005) Interaction of fibroblast growth factor and C-natriuretic peptide signaling in regulation of chondrocyte proliferation and extracellular matrix homeostasis. Journal of Cell Science 118(Pt 21), 5089-5100CrossRef Google Scholar PubMed

60Chusho, H. et al. (2001) Dwarfism and early death in mice lacking C-type natriuretic peptide. Proceedings of the National Academy of Sciences of the United States of America 98, 4016-4021CrossRef Google Scholar PubMed

61Horton, W.A. (2006) Skeletal development. In Cell Signaling and Growth Factors in Development (Unsicker, K. and Krieglstein, K., eds), pp. 619-640, Wiley-VCH VerlagGmbH & Co., WeinheimGoogle Scholar

62Laederich, M.B. and Horton, W.A. (2010) Achondroplasia: pathogenesis and implications for future treatment. Current Opinion in Pediatrics 22, 516-523CrossRef Google Scholar PubMed

63Webster, M.K. and Donoghue, D.J. (1996) Constitutive activation of fibroblast growth factor receptor 3 by the transmembrane domain point mutation found in achondroplasia. EMBO Journal 15, 520-527Google Scholar PubMed

64You, M., Li, E. and Hristova, K. (2006) The achondroplasia mutation does not alter the dimerization energetics of the fibroblast growth factor receptor 3 transmembrane domain. Biochemistry 45, 5551-5556CrossRef Google Scholar

65Monsonego-Ornan, E. et al. (2000) The transmembrane mutation G380R in fibroblast growth factor receptor 3 uncouples ligand-mediated receptor activation from down-regulation. Molecular and Cellular Biology 20, 516-522CrossRef Google Scholar PubMed

66Cho, J.Y. et al. (2004) Defective lysosomal targeting of activated fibroblast growth factor receptor 3 in achondroplasia. Proceedings of the National Academy of Sciences of the United States of America 101, 609-614CrossRef Google Scholar PubMed

67Guo, C. et al. (2008) Sprouty 2 disturbs FGFR3 degradation in thanatophoric dysplasia type II: a severe form of human achondroplasia. Cellular Signalling 20, 1471-1477CrossRef Google Scholar PubMed

68Degnin, C.R., Laederich, M.B. and Horton, W.A. (2011) Ligand activation leads to regulated intramembrane proteolysis of fibroblast growth factor receptor 3. Molecular Biology of the Cell 22, 3861-3873CrossRef Google Scholar PubMed

69Kim, Y.S. et al. (2009) Update on Hsp90 inhibitors in clinical trial. Current Topics in Medicinal Chemistry 9, 1479-1492CrossRef Google Scholar

70Trepel, J. et al. (2010) Targeting the dynamic HSP90 complex in cancer. Nature Reviews. Cancer 10, 537-549Google Scholar

71Horton, W.A. (2003) Skeletal development: insights from targeting the mouse genome. Lancet 362, 560-569CrossRef Google Scholar PubMed

72Kronenberg, H.M. (2003) Developmental regulation of the growth plate. Nature 423, 332-336CrossRef Google Scholar PubMed

73Dailey, L. et al. (2005) Mechanisms underlying differential responses to FGF signaling. Cytokine and Growth Factor Reviews 16, 233-247CrossRef Google Scholar PubMed

74Murakami, S. et al. (2000) Up-regulation of the chondrogenic Sox9 gene by fibroblast growth factors is mediated by the mitogen-activated protein kinase pathway. Proceedings of the National Academy of Sciences of the United States of America 97, 1113-1118CrossRef Google Scholar PubMed

75Hartmann, J.T. et al. (2009) Tyrosine kinase inhibitors – a review on pharmacology, metabolism and side effects. Current Drug Metabolism 10, 470-481CrossRef Google Scholar PubMed

76Collins, I. and Workman, P. (2006) Design and development of signal transduction inhibitors for cancer treatment:experience and challenges with kinase targets. Current Signal Transduction Therapy 1, 13-23CrossRef Google Scholar

77Aviezer, D., Golembo, M. and Yayon, A. (2003) Fibroblast growth factor receptor-3 as a therapeutic target for Achondroplasia–genetic short limbed dwarfism. Current Drug Targets 4, 353-365CrossRef Google Scholar PubMed

78Novartis (2011) Dovitinib (TKI258) and BGJ398. In http://www.novartisoncology.us/research/pipeline/tki258.jsp Google Scholar

79Hall, P.S. and Cameron, D.A. (2009) Current perspective – trastuzumab. European Journal of Cancer 45, 12-18CrossRef Google Scholar PubMed

80Rauchenberger, R. et al. (2003) Human combinatorial Fab library yielding specific and functional antibodies against the human fibroblast growth factor receptor 3. Journal of Biological Chemistry 278, 38194-38205CrossRef Google Scholar PubMed

81Cappellen, D. et al. (1999) Frequent activating mutations of FGFR3 in human bladder and cervix carcinomas. Nature Genetics 23, 18-20Google Scholar PubMed

82Martinez-Torrecuadrada, J. et al. (2005) Targeting the extracellular domain of fibroblast growth factor receptor 3 with human single-chain Fv antibodies inhibits bladder carcinoma cell line proliferation. Clinical Cancer Research 11, 6280-6290CrossRef Google Scholar PubMed

83Qing, J. et al. (2009) Antibody-based targeting of FGFR3 in bladder carcinoma and t(4;14)-positive multiple myeloma in mice. Journal of Clinical Investigation 119, 1216-1229CrossRef Google Scholar

84Hadari, Y. and Schlessinger, J. (2009) FGFR3-targeted mAb therapy for bladder cancer and multiple myeloma. Journal of Clinical Investigation 119, 1077-1079CrossRef Google Scholar PubMed

85Suda, M. et al. (1998) Skeletal overgrowth in transgenic mice that overexpress brain natriuretic peptide. Proceedings of the National Academy of Sciences of the United States of America 95, 2337-2342CrossRef Google Scholar PubMed

86Kake, T. et al. (2009) Chronically elevated plasma C-type natriuretic peptide level stimulates skeletal growth in transgenic mice. American Journal of Physiology. Endocrinology and Metabolism 297, E1339-E1348Google Scholar

87Yasoda, A. et al. (2009) Systemic administration of C-type natriuretic peptide as a novel therapeutic strategy for skeletal dysplasias. Endocrinology 150, 3138-3144CrossRef Google Scholar PubMed

88Hunt, P.J. et al. (1994) Bioactivity and metabolism of C-type natriuretic peptide in normal man. Journal of Clinical Endocrinology and Metabolism 78, 1428-1435Google Scholar PubMed

89Lorget, F. et al. BMN 111, a CNP analogue promotes skeletal growth and rescues dwarfism in two transgenic mouse models of Fgfr3-related chondrodysplasia. International Congress of Human Genetics (2011; Montreal)Google Scholar

90Olney, R.C. et al. (2006) Heterozygous mutations in natriuretic peptide receptor-B (NPR2) are associated with short stature. Journal of Clinical Endocrinology and Metabolism 91, 1229-1232CrossRef Google Scholar PubMed

91Bocciardi, R. et al. (2007) Overexpression of the C-type natriuretic peptide (CNP) is associated with overgrowth and bone anomalies in an individual with balanced t(2;7) translocation. Human Mutation 28, 724-731CrossRef Google Scholar

92Suga, S. et al. (1992) Receptor selectivity of natriuretic peptide family, atrial natriuretic peptide, brain natriuretic peptide, and C-type natriuretic peptide. Endocrinology 130, 229-239CrossRef Google Scholar PubMed

93Davidson, B.L. and McCray, P.B. Jr (2011) Current prospects for RNA interference-based therapies. Nature Reviews. Genetics 12, 329-340Google Scholar

94Boudreau, R.L., Rodriguez-Lebron, E. and Davidson, B.L. (2011) RNAi medicine for the brain: progresses and challenges. Human Molecular Genetics 20(R1), R21-R27CrossRef Google Scholar PubMed

95Lochmatter, D. and Mullis, P.E. (2011) RNA interference in mammalian cell systems. Hormone Research in Paediatrics 75, 63-69CrossRef Google Scholar PubMed

96Hartl, F.U., Bracher, A. and Hayer-Hartl, M. (2011) Molecular chaperones in protein folding and proteostasis. Nature 475, 324-332CrossRef Google Scholar PubMed

97Laederich, M.B. et al. (2011) Fibroblast growth factor receptor 3 (FGFR3) is a strong heat shock protein 90 (Hsp90) client: implications for therapeutic manipulation. Journal of Biological Chemistry 286, 19597-19604CrossRef Google Scholar PubMed

98Calamia, V. et al. (2011) Hsp90beta inhibition modulates nitric oxide production and nitric oxide-induced apoptosis in human chondrocytes. BMC Musculoskeletal Disorders 12, 237CrossRef Google Scholar PubMed

99Herzog, A. et al. (2011) Hsp90 and angiogenesis in bone disorders–lessons from the avian growth plate. American Journal of Physiology. Regulatory, Integrative and Comparative Physiology 301, R140-R147CrossRef Google Scholar

100Pandit, S.G. et al. (2002) The fibroblast growth factor receptor, FGFR3, forms gradients of intact and degraded protein across the growth plate of developing bovine ribs. Biochemical Journal 361(Pt 2), 231-241CrossRef Google Scholar PubMed

101Wolfe, M.S. (2009) gamma-Secretase in biology and medicine. Seminars in Cell and Developmental Biology 20, 219-224CrossRef Google Scholar PubMed

102Mulla, H. (2010) Understanding developmental pharmacodynamics: importance for drug development and clinical practice. Paediatric Drugs 12, 223-233CrossRef Google Scholar PubMed

103Goldberg, M., Langer, R. and Jia, X. (2007) Nanostructured materials for applications in drug delivery and tissue engineering. Journal of Biomaterials Science. Polymer Edition 18, 241-268Google Scholar

104Alexis, F. et al. (2008) Factors affecting the clearance and biodistribution of polymeric nanoparticles. Molecular Pharmaceutics 5, 505-515CrossRef Google Scholar PubMed

105Rothenfluh, D.A. et al. (2008) Biofunctional polymer nanoparticles for intra-articular targeting and retention in cartilage. Nature Materials 7, 248-254CrossRef Google Scholar PubMed

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FGFR3 targeting strategies for achondroplasia

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