Recent research on the growth plate: Advances in fibroblast growth factor signaling in growth plate development and disorders.

Skeletons are formed through two distinct developmental actions, intramembranous ossification and endochondral ossification. During embryonic development, most bone is formed by endochondral ossification. The growth plate is the developmental center for endochondral ossification. Multiple signaling pathways participate in the regulation of endochondral ossification. Fibroblast growth factor (FGF)/FGF receptor (FGFR) signaling has been found to play a vital role in the development and maintenance of growth plates. Missense mutations in FGFs and FGFRs can cause multiple genetic skeletal diseases with disordered endochondral ossification. Clarifying the molecular mechanisms of FGFs/FGFRs signaling in skeletal development and genetic skeletal diseases will have implications for the development of therapies for FGF-signaling-related skeletal dysplasias and growth plate injuries. In this review, we summarize the recent advances in elucidating the role of FGFs/FGFRs signaling in growth plate development, genetic skeletal disorders, and the promising therapies for those genetic skeletal diseases resulting from FGFs/FGFRs dysfunction. Finally, we also examine the potential important research in this field in the future.

[1]  C. Deng,et al.  FGFR3 induces degradation of BMP type I receptor to regulate skeletal development. , 2014, Biochimica et biophysica acta.

[2]  H. Kocher,et al.  The ins and outs of fibroblast growth factor receptor signalling. , 2014, Clinical science.

[3]  C. Deng,et al.  Soluble form of FGFR2 with S252W partially prevents craniosynostosis of the apert mouse model , 2014, Developmental dynamics : an official publication of the American Association of Anatomists.

[4]  M. Baum,et al.  Regulation of renal phosphate transport by FGF23 is mediated by FGFR1 and FGFR4. , 2014, American journal of physiology. Renal physiology.

[5]  C. Little,et al.  Modulation of endochondral ossification by MEK inhibitors PD0325901 and AZD6244 (Selumetinib). , 2014, Bone.

[6]  R. Pettinato,et al.  Increased FGF3 and FGF4 gene dosage is a risk factor for craniosynostosis. , 2014, Gene.

[7]  Isabel B. Lokody.  Genetic therapies: Correcting genetic defects with CRISPR–Cas9 , 2013, Nature Reviews Genetics.

[8]  S. Matsuura,et al.  TALEN-mediated single-base-pair editing identification of an intergenic mutation upstream of BUB1B as causative of PCS (MVA) syndrome , 2013, Proceedings of the National Academy of Sciences.

[9]  A. Masuda,et al.  Meclozine Facilitates Proliferation and Differentiation of Chondrocytes by Attenuating Abnormally Activated FGFR3 Signaling in Achondroplasia , 2013, PloS one.

[10]  Marc Muller,et al.  Fgf receptors Fgfr1a and Fgfr2 control the function of pharyngeal endoderm in late cranial cartilage development. , 2013, Differentiation; research in biological diversity.

[11]  Hui Zhang,et al.  Transcription Activator-like Effector Nuclease (TALEN)-mediated Gene Correction in Integration-free β-Thalassemia Induced Pluripotent Stem Cells* , 2013, The Journal of Biological Chemistry.

[12]  Y. Le Marchand-Brustel,et al.  Postnatal Soluble FGFR3 Therapy Rescues Achondroplasia Symptoms and Restores Bone Growth in Mice , 2013, Science Translational Medicine.

[13]  J. Boulanger,et al.  New evidence for positive selection helps explain the paternal age effect observed in achondroplasia , 2013, Human molecular genetics.

[14]  T. Michigami.  Regulatory mechanisms for the development of growth plate cartilage , 2013, Cellular and Molecular Life Sciences.

[15]  W. Sellers,et al.  Pharmacological inhibition of fibroblast growth factor (FGF) receptor signaling ameliorates FGF23‐mediated hypophosphatemic rickets , 2013, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[16]  R. Shroff.  Phosphate is a vascular toxin , 2013, Pediatric Nephrology.

[17]  L. Bonewald,et al.  FGF23 production by osteocytes , 2013, Pediatric Nephrology.

[18]  D. Haudenschild,et al.  Interactions between FGF21 and BMP-2 in osteogenesis. , 2013, Biochemical and biophysical research communications.

[19]  M. Iino,et al.  β-catenin regulates parathyroid hormone/parathyroid hormone-related protein receptor signals and chondrocyte hypertrophy through binding to the intracellular C-terminal region of the receptor. , 2013, Arthritis and rheumatism.

[20]  M. Egerbacher,et al.  Fibroblast Growth Factor 23 and Klotho Are Present in the Growth Plate , 2013, Connective tissue research.

[21]  Liping Xiao,et al.  Nuclear fibroblast growth factor 2 (FGF2) isoforms inhibit bone marrow stromal cell mineralization through FGF23/FGFR/MAPK in vitro , 2013, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[22]  C. Deng,et al.  A novel FGFR3-binding peptide inhibits FGFR3 signaling and reverses the lethal phenotype of mice mimicking human thanatophoric dysplasia. , 2012, Human molecular genetics.

[23]  K. Ozono,et al.  FGF23 Suppresses Chondrocyte Proliferation in the Presence of Soluble α-Klotho both in Vitro and in Vivo* , 2012, The Journal of Biological Chemistry.

[24]  A. Munnich,et al.  Evaluation of the therapeutic potential of a CNP analog in a Fgfr3 mouse model recapitulating achondroplasia. , 2012, American journal of human genetics.

[25]  S. Wołczyński,et al.  Evidence that FGFR1 loss-of-function mutations may cause variable skeletal malformations in patients with Kallmann syndrome. , 2012, Advances in medical sciences.

[26]  J. Hirschhorn,et al.  Synthesizing genome-wide association studies and expression microarray reveals novel genes that act in the human growth plate to modulate height. , 2012, Human molecular genetics.

[27]  J. Larrick,et al.  Fibroblast growth factor-21 is a promising dietary restriction mimetic. , 2012, Rejuvenation research.

[28]  Di Chen,et al.  Genetic inhibition of fibroblast growth factor receptor 1 in knee cartilage attenuates the degeneration of articular cartilage in adult mice. , 2012, Arthritis and rheumatism.

[29]  C. Xian,et al.  Role of FGFs/FGFRs in skeletal development and bone regeneration , 2012, Journal of cellular physiology.

[30]  M. Hurley,et al.  Role of fibroblast growth factor 2 and wnt signaling in anabolic effects of parathyroid hormone on bone formation , 2012, Journal of cellular physiology.

[31]  P. Hurlin,et al.  Disruption of a Sox9-β-catenin circuit by mutant Fgfr3 in thanatophoric dysplasia type II. , 2012, Human molecular genetics.

[32]  A. Gropman,et al.  Epilepsy in Muenke syndrome: FGFR3-related craniosynostosis. , 2012, Pediatric neurology.

[33]  C. Deng,et al.  Intermittent PTH (1-34) injection rescues the retarded skeletal development and postnatal lethality of mice mimicking human achondroplasia and thanatophoric dysplasia. , 2012, Human molecular genetics.

[34]  S. Iseki,et al.  Apert syndrome mutant FGFR2 and its soluble form reciprocally alter osteogenesis of primary calvarial osteoblasts , 2012, Journal of cellular physiology.

[35]  S. Gong.  The Fgfr2W290R mouse model of Crouzon syndrome , 2012, Child's Nervous System.

[36]  M. Jin,et al.  Cross‐talk between FGF and other cytokine signalling pathways during endochondral bone development , 2012, Cell biology international.

[37]  F. De Luca,et al.  Fibroblast Growth Factor 21 (FGF21) Inhibits Chondrocyte Function and Growth Hormone Action Directly at the Growth Plate , 2012, The Journal of Biological Chemistry.

[38]  K. Winston,et al.  Syndromic craniosynostosis, fibroblast growth factor receptor 2 (FGFR2) mutations, and sacrococcygeal eversion presenting as human tails , 2012, Child's Nervous System.

[39]  A. Munnich,et al.  An activating Fgfr3 mutation affects trabecular bone formation via a paracrine mechanism during growth. , 2012, Human molecular genetics.

[40]  J. Richtsmeier,et al.  p38 Inhibition ameliorates skin and skull abnormalities in Fgfr2 Beare-Stevenson mice. , 2012, The Journal of clinical investigation.

[41]  A. Wilkie,et al.  Atypical Crouzon Syndrome with a Novel Cys62Arg Mutation in FGFR2 Presenting with Sagittal Synostosis , 2012, The Cleft palate-craniofacial journal : official publication of the American Cleft Palate-Craniofacial Association.

[42]  J. Toppari,et al.  Fibroblast Growth Factor 8b Causes Progressive Stromal and Epithelial Changes in the Epididymis and Degeneration of the Seminiferous Epithelium in the Testis of Transgenic Mice1 , 2012, Biology of reproduction.

[43]  Liesbet Geris,et al.  Relating the Chondrocyte Gene Network to Growth Plate Morphology: From Genes to Phenotype , 2012, PloS one.

[44]  Lukas Balek,et al.  Receptor Tyrosine Kinases Activate Canonical WNT/β-Catenin Signaling via MAP Kinase/LRP6 Pathway and Direct β-Catenin Phosphorylation , 2012, PloS one.

[45]  Z. Ren,et al.  Rapid detection of G1138A and G1138C mutations of the FGFR3 gene in patients with achondroplasia using high-resolution melting analysis. , 2012, Genetic testing and molecular biomarkers.

[46]  A. Kamath,et al.  Preclinical pharmacokinetics of MFGR1877A, a human monoclonal antibody to FGFR3, and prediction of its efficacious clinical dose for the treatment of t(4;14)-positive multiple myeloma , 2012, Cancer Chemotherapy and Pharmacology.

[47]  P. Marie,et al.  FGF/FGFR signaling in bone formation: Progress and perspectives , 2012, Growth factors.

[48]  K. Lyons,et al.  Bent bone dysplasia-FGFR2 type, a distinct skeletal disorder, has deficient canonical FGF signaling. , 2012, American journal of human genetics.

[49]  Ruei-Zeng Lin,et al.  Fibroblast growth factor-2 facilitates rapid anastomosis formation between bioengineered human vascular networks and living vasculature. , 2012, Methods.

[50]  Arnold Munnich,et al.  A novel tyrosine kinase inhibitor restores chondrocyte differentiation and promotes bone growth in a gain-of-function Fgfr3 mouse model. , 2012, Human molecular genetics.

[51]  H. Ryoo,et al.  Functional characterization of a novel FGFR2 mutation, E731K, in craniosynostosis , 2012, Journal of cellular biochemistry.

[52]  J. Navarro-González,et al.  FGF23/Klotho axis: phosphorus, mineral metabolism and beyond. , 2012, Cytokine & growth factor reviews.

[53]  W. Wilcox,et al.  Sixteen years and counting: The current understanding of fibroblast growth factor receptor 3 (FGFR3) signaling in skeletal dysplasias , 2012, Human mutation.

[54]  A. Wilkie,et al.  Mild isolated craniosynostosis due to a novel FGFR3 mutation, p.Ala334Thr , 2011, American journal of medical genetics. Part A.

[55]  D. Chan,et al.  SOX9 Governs Differentiation Stage-Specific Gene Expression in Growth Plate Chondrocytes via Direct Concomitant Transactivation and Repression , 2011, PLoS genetics.

[56]  W. Sellers,et al.  FGF receptors control vitamin D and phosphate homeostasis by mediating renal FGF‐23 signaling and regulating FGF‐23 expression in bone , 2011, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[57]  Liping Xiao,et al.  The impaired bone anabolic effect of PTH in the absence of endogenous FGF2 is partially due to reduced ATF4 expression. , 2011, Biochemical and biophysical research communications.

[58]  M. Mohammadi,et al.  Regulation of serum 1,25(OH)2 vitamin D3 levels by fibroblast growth factor 23 is mediated by FGF receptors 3 and 4. , 2011, American journal of physiology. Renal physiology.

[59]  J. Bernheim,et al.  The potential roles of FGF23 and Klotho in the prognosis of renal and cardiovascular diseases. , 2011, Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association.

[60]  Hojun Li,et al.  In vivo genome editing restores hemostasis in a mouse model of hemophilia , 2011, Nature.

[61]  D. Coutu,et al.  Inhibition of cellular senescence by developmentally regulated FGF receptors in mesenchymal stem cells. , 2011, Blood.

[62]  W. Richards,et al.  Fibroblast Growth Factor 23 (FGF23) and Alpha-Klotho Stimulate Osteoblastic MC3T3.E1 Cell Proliferation and Inhibit Mineralization , 2011, Calcified Tissue International.

[63]  T. Shimada,et al.  Anti‐FGF‐23 neutralizing antibodies ameliorate muscle weakness and decreased spontaneous movement of Hyp mice , 2011, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[64]  Jian Q. Feng,et al.  FGF23 in Skeletal Modeling and Remodeling , 2011, Current osteoporosis reports.

[65]  L. Quarles,et al.  Compound deletion of Fgfr3 and Fgfr4 partially rescues the Hyp mouse phenotype. , 2011, American journal of physiology. Endocrinology and metabolism.

[66]  A. Kawanami,et al.  Genetic inactivation of ERK1 and ERK2 in chondrocytes promotes bone growth and enlarges the spinal canal , 2011, Journal of orthopaedic research : official publication of the Orthopaedic Research Society.

[67]  N. Hirokawa,et al.  KIF16B/Rab14 molecular motor complex is critical for early embryonic development by transporting FGF receptor. , 2011, Developmental cell.

[68]  N. Malats,et al.  Multiple oncogenic mutations and clonal relationship in spatially distinct benign human epidermal tumors , 2010, Proceedings of the National Academy of Sciences.

[69]  Geert Carmeliet,et al.  Osteoblast precursors, but not mature osteoblasts, move into developing and fractured bones along with invading blood vessels. , 2010, Developmental cell.

[70]  Ayellet V. Segrè,et al.  Hundreds of variants clustered in genomic loci and biological pathways affect human height , 2010, Nature.

[71]  K. Nakao,et al.  Translational research of C-type natriuretic peptide (CNP) into skeletal dysplasias. , 2010, Endocrine journal.

[72]  M. Sabbieti,et al.  Signaling pathways implicated in PGF2α effects on Fgf2+/+ and Fgf2−/− osteoblasts , 2010, Journal of cellular physiology.

[73]  A. Kozubík,et al.  FGFR3 signaling induces a reversible senescence phenotype in chondrocytes similar to oncogene-induced premature senescence. , 2010, Bone.

[74]  M. Nagata,et al.  FGFR3 down-regulates PTH/PTHrP receptor gene expression by mediating JAK/STAT signaling in chondrocytic cell line. , 2010, Journal of electron microscopy.

[75]  Di Chen,et al.  Gain-of-function mutation in FGFR3 in mice leads to decreased bone mass by affecting both osteoblastogenesis and osteoclastogenesis. , 2010, Human molecular genetics.

[76]  M. Wuelling,et al.  Transcriptional networks controlling chondrocyte proliferation and differentiation during endochondral ossification , 2010, Pediatric Nephrology.

[77]  K. Ohshima,et al.  Phase I study of KW-0761, a defucosylated humanized anti-CCR4 antibody, in relapsed patients with adult T-cell leukemia-lymphoma and peripheral T-cell lymphoma. , 2010, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[78]  A. Hess,et al.  SOX9 is a major negative regulator of cartilage vascularization, bone marrow formation and endochondral ossification , 2010, Development.

[79]  E. Bermejo,et al.  Review of the recently defined molecular mechanisms underlying thanatophoric dysplasia and their potential therapeutic implications for achondroplasia , 2010, American journal of medical genetics. Part A.

[80]  Yue Shen,et al.  Fibroblast growth factor receptor 1 regulates the differentiation and activation of osteoclasts through Erk1/2 pathway. , 2009, Biochemical and biophysical research communications.

[81]  Liping Xiao,et al.  Nuclear Isoforms of Fibroblast Growth Factor 2 Are Novel Inducers of Hypophosphatemia via Modulation of FGF23 and KLOTHO* , 2009, The Journal of Biological Chemistry.

[82]  T. Shimada,et al.  Therapeutic Effects of Anti‐FGF23 Antibodies in Hypophosphatemic Rickets/Osteomalacia , 2009, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[83]  G. Karsenty,et al.  Genetic control of bone formation. , 2009, Annual review of cell and developmental biology.

[84]  D. Barisani,et al.  Increased p21 expression in chondrocytes of achondroplasic children independently from the presence of the G380R FGFR3 mutation , 2009, Journal of orthopaedic science : official journal of the Japanese Orthopaedic Association.

[85]  Wei Huang,et al.  Multiple synostoses syndrome is due to a missense mutation in exon 2 of FGF9 gene. , 2009, American journal of human genetics.

[86]  I. Reid,et al.  Actions of fibroblast growth factor-8 in bone cells in vitro. , 2009, American journal of physiology. Endocrinology and metabolism.

[87]  T. Sturgill,et al.  Fibroblast growth factor receptor-3 regulates Paneth cell lineage allocation and accrual of epithelial stem cells during murine intestinal development. , 2009, American journal of physiology. Gastrointestinal and liver physiology.

[88]  M. Taketo,et al.  The Wnt/β-Catenin Pathway Interacts Differentially with PTHrP Signaling to Control Chondrocyte Hypertrophy and Final Maturation , 2009, PloS one.

[89]  M. Mohammadi,et al.  FGF23 decreases renal NaPi-2a and NaPi-2c expression and induces hypophosphatemia in vivo predominantly via FGF receptor 1. , 2009, American journal of physiology. Renal physiology.

[90]  J. Szumiło,et al.  Morphology and physiology of the epiphyseal growth plate. , 2009, Folia histochemica et cytobiologica.

[91]  Christian Wiesmann,et al.  Antibody-based targeting of FGFR3 in bladder carcinoma and t(4;14)-positive multiple myeloma in mice. , 2009, The Journal of clinical investigation.

[92]  Joseph Schlessinger,et al.  FGFR3-targeted mAb therapy for bladder cancer and multiple myeloma. , 2009, The Journal of clinical investigation.

[93]  K. Retting,et al.  BMP canonical Smad signaling through Smad1 and Smad5 is required for endochondral bone formation , 2009, Development.

[94]  T. Doetschman,et al.  Endogenous FGF‐2 is critically important in PTH anabolic effects on bone , 2009, Journal of cellular physiology.

[95]  M. Takagi,et al.  FGF8 regulates myogenesis and induces Runx2 expression and osteoblast differentiation in cultured cells , 2009, Journal of cellular biochemistry.

[96]  A. Munnich,et al.  Activating Fgfr3 Y367C mutation causes hearing loss and inner ear defect in a mouse model of chondrodysplasia. , 2009, Biochimica et biophysica acta.

[97]  Gillian M Morriss-Kay,et al.  Skeletal analysis of the Fgfr3P244R mouse, a genetic model for the Muenke craniosynostosis syndrome , 2009, Developmental dynamics : an official publication of the American Association of Anatomists.

[98]  T. Doetschman,et al.  Exported 18-kDa Isoform of Fibroblast Growth Factor-2 Is a Critical Determinant of Bone Mass in Mice* , 2009, Journal of Biological Chemistry.

[99]  Makoto Taiji,et al.  FGF9 monomer/dimer equilibrium regulates extracellular matrix affinity and tissue diffusion , 2009, Nature Genetics.

[100]  A. Kawanami,et al.  FGFR3 promotes synchondrosis closure and fusion of ossification centers through the MAPK pathway. , 2008, Human molecular genetics.

[101]  L. Liaw,et al.  Overexpression of Spry1 in chondrocytes causes attenuated FGFR ubiquitination and sustained ERK activation resulting in chondrodysplasia. , 2008, Developmental biology.

[102]  T. Suda,et al.  Role of fibroblast growth factor 8 (FGF8) in animal models of osteoarthritis , 2008, Arthritis research & therapy.

[103]  Xin Sun,et al.  An Fgf/Gremlin inhibitory feedback loop triggers termination of limb bud outgrowth , 2008, Nature.

[104]  T. Akizawa,et al.  [Role of kidney in calcium homeostasis and premature aging]. , 2008, Clinical calcium.

[105]  G. Duester,et al.  Retinoic acid controls heart anteroposterior patterning by down‐regulating Isl1 through the Fgf8 pathway , 2008, Developmental dynamics : an official publication of the American Association of Anatomists.

[106]  D. Ambrosetti,et al.  Fibroblast Growth Factor Signaling Uses Multiple Mechanisms To Inhibit Wnt-Induced Transcription in Osteoblasts , 2008, Molecular and Cellular Biology.

[107]  G. Martin,et al.  Genetic evidence that FGFs have an instructive role in limb proximal–distal patterning , 2008, Nature.

[108]  Xiaoling Xu,et al.  A Pro253Arg mutation in fibroblast growth factor receptor 2 (Fgfr2) causes skeleton malformation mimicking human Apert syndrome by affecting both chondrogenesis and osteogenesis. , 2008, Bone.

[109]  D. Ornitz,et al.  FGF signaling regulates mesenchymal differentiation and skeletal patterning along the limb bud proximodistal axis , 2008, Development.

[110]  C. Mathieu,et al.  Vitamin D and human health: lessons from vitamin D receptor null mice. , 2008, Endocrine reviews.

[111]  N. Itoh,et al.  Functional evolutionary history of the mouse Fgf gene family , 2008, Developmental dynamics : an official publication of the American Association of Anatomists.

[112]  Miguel Manzanares,et al.  Snail1 is a transcriptional effector of FGFR3 signaling during chondrogenesis and achondroplasias. , 2007, Developmental cell.

[113]  G. Gillard,et al.  FGFR2IIIb signaling regulates thymic epithelial differentiation , 2007, Developmental dynamics : an official publication of the American Association of Anatomists.

[114]  E. Rieger-Fackeldey,et al.  Altered Expressions of Fibroblast Growth Factor Receptors and Alveolarization in Neonatal Mice Exposed to 85% Oxygen , 2007, Pediatric Research.

[115]  P. Barros-Núñez,et al.  Crouzon with acanthosis nigricans. Further delineation of the syndrome , 2007, Clinical genetics.

[116]  Kenneth P. Roos,et al.  Autocrine VEGF Signaling Is Required for Vascular Homeostasis , 2007, Cell.

[117]  X. Coumoul,et al.  RNA interference and inhibition of MEK-ERK signaling prevent abnormal skeletal phenotypes in a mouse model of craniosynostosis , 2007, Nature Genetics.

[118]  V. P. Eswarakumar,et al.  Lacrimo-Auriculo-Dento-Digital Syndrome Is Caused by Reduced Activity of the Fibroblast Growth Factor 10 (FGF10)-FGF Receptor 2 Signaling Pathway , 2007, Molecular and Cellular Biology.

[119]  Hiroyuki Tanaka,et al.  Sustained phosphorylation of mutated FGFR3 is a crucial feature of genetic dwarfism and induces apoptosis in the ATDC5 chondrogenic cell line via PLCgamma-activated STAT1. , 2007, Bone.

[120]  D. Ornitz,et al.  FGF9 regulates early hypertrophic chondrocyte differentiation and skeletal vascularization in the developing stylopod. , 2007, Developmental biology.

[121]  Hiroyuki Tanaka,et al.  PTH has the potential to rescue disturbed bone growth in achondroplasia. , 2007, Bone.

[122]  J. Aubin,et al.  Mineralized tissue cells are a principal source of FGF23. , 2007, Bone.

[123]  S. Fukumoto,et al.  FGF23 is a hormone-regulating phosphate metabolism--unique biological characteristics of FGF23. , 2007, Bone.

[124]  C. Heike,et al.  Syndromic craniosynostosis: from history to hydrogen bonds. , 2007, Orthodontics & craniofacial research.

[125]  B. Maher,et al.  Impaired FGF signaling contributes to cleft lip and palate , 2007, Proceedings of the National Academy of Sciences.

[126]  J. Baron,et al.  Fibroblast growth factor expression in the postnatal growth plate. , 2007, Bone.

[127]  W. Wilcox,et al.  Fibroblast Growth Factors 1, 2, 17, and 19 Are the Predominant FGF Ligands Expressed in Human Fetal Growth Plate Cartilage , 2007, Pediatric Research.

[128]  D. Ornitz,et al.  FGF18 is required for early chondrocyte proliferation, hypertrophy and vascular invasion of the growth plate. , 2007, Developmental biology.

[129]  M. Bamshad,et al.  A novel mutation in FGFR3 causes camptodactyly, tall stature, and hearing loss (CATSHL) syndrome. , 2006, American journal of human genetics.

[130]  J. Partanen,et al.  Fibroblast growth factor receptor 1 signaling in the osteo-chondrogenic cell lineage regulates sequential steps of osteoblast maturation. , 2006, Developmental biology.

[131]  Xi Jiang,et al.  Pathogenic role of Fgf23 in Hyp mice. , 2006, American journal of physiology. Endocrinology and metabolism.

[132]  Riccardo Priore,et al.  Downregulation of Akt activity contributes to the growth arrest induced by FGF in chondrocytes , 2006, Journal of cellular physiology.

[133]  E. Quenneville,et al.  Defects in articular cartilage metabolism and early arthritis in fibroblast growth factor receptor 3 deficient mice. , 2006, Human molecular genetics.

[134]  S. Trudel,et al.  The inhibitory anti-FGFR3 antibody, PRO-001, is cytotoxic to t(4;14) multiple myeloma cells. , 2006, Blood.

[135]  P. Härkönen,et al.  Regulation of osteoblast differentiation: a novel function for fibroblast growth factor 8. , 2006, Endocrinology.

[136]  J. Milunsky,et al.  LADD syndrome is caused by FGF10 mutations , 2006, Clinical genetics.

[137]  E. Tanaka,et al.  Fibroblast Growth Factor-2 Augments Recombinant Human Bone Morphogenetic Protein-2-Induced Osteoinductive Activity , 2006, Annals of Biomedical Engineering.

[138]  M. Ito,et al.  Impaired bone anabolic response to parathyroid hormone in Fgf2-/- and Fgf2+/- mice. , 2006, Biochemical and biophysical research communications.

[139]  C. Cremers,et al.  Mutations in different components of FGF signaling in LADD syndrome , 2006, Nature Genetics.

[140]  I. Shapiro,et al.  Fate of the hypertrophic chondrocyte: microenvironmental perspectives on apoptosis and survival in the epiphyseal growth plate. , 2005, Birth defects research. Part C, Embryo today : reviews.

[141]  M. Hurley,et al.  FGF and FGFR signaling in chondrodysplasias and craniosynostosis , 2005, Journal of cellular biochemistry.

[142]  R. Lauster,et al.  Expression of Fgf and Tgfbeta signaling related genes during embryonic endochondral ossification. , 2005, Gene expression patterns : GEP.

[143]  K. White,et al.  Analysis of the biochemical mechanisms for the endocrine actions of fibroblast growth factor-23. , 2005, Endocrinology.

[144]  H. Prats,et al.  Interaction of fibroblast growth factor and C-natriuretic peptide signaling in regulation of chondrocyte proliferation and extracellular matrix homeostasis , 2005, Journal of Cell Science.

[145]  D. Fortin,et al.  Distinct Fibroblast Growth Factor (FGF)/FGF Receptor Signaling Pairs Initiate Diverse Cellular Responses in the Oligodendrocyte Lineage , 2005, The Journal of Neuroscience.

[146]  Fan Yang,et al.  Abnormalities in cartilage and bone development in the Apert syndrome FGFR2+/S252W mouse , 2005, Development.

[147]  K. Nakao,et al.  Complementary antagonistic actions between C-type natriuretic peptide and the MAPK pathway through FGFR-3 in ATDC5 cells. , 2005, Bone.

[148]  L. Thompson,et al.  Sustained ERK1/2 but not STAT1 or 3 activation is required for thanatophoric dysplasia phenotypes in PC12 cells. , 2005, Human molecular genetics.

[149]  M. Ito,et al.  Over‐expression of fibroblast growth factor‐2 causes defective bone mineralization and osteopenia in transgenic mice , 2005, Journal of cellular biochemistry.

[150]  A. van Daal,et al.  Linkage disequilibrium analysis identifies an FGFR1 haplotype-tag SNP associated with normal variation in craniofacial shape. , 2005, Genomics.

[151]  D. Ornitz,et al.  FGF signaling in the developing endochondral skeleton. , 2005, Cytokine & growth factor reviews.

[152]  V. P. Eswarakumar,et al.  Cellular signaling by fibroblast growth factor receptors. , 2005, Cytokine & growth factor reviews.

[153]  M. Knowles,et al.  Cell responses to FGFR3 signalling: growth, differentiation and apoptosis. , 2005, Experimental cell research.

[154]  K. White,et al.  FGF23 and disorders of phosphate homeostasis. , 2005, Cytokine & growth factor reviews.

[155]  A. Wilkie.  Bad bones, absent smell, selfish testes: the pleiotropic consequences of human FGF receptor mutations. , 2005, Cytokine & growth factor reviews.

[156]  D. Ambrosetti,et al.  Mechanisms underlying differential responses to FGF signaling. , 2005, Cytokine & growth factor reviews.

[157]  D. Ambrosetti,et al.  Sox2 induction by FGF and FGFR2 activating mutations inhibits Wnt signaling and osteoblast differentiation , 2005, The Journal of cell biology.

[158]  E. Schipani,et al.  Molecular mechanisms of endochondral bone development. , 2005, Biochemical and biophysical research communications.

[159]  K. White,et al.  Mutations that cause osteoglophonic dysplasia define novel roles for FGFR1 in bone elongation. , 2005, American journal of human genetics.

[160]  C. Deng,et al.  [Gly374Arg mutation in Fgfr3 causes achondroplasia in mice]. , 2004, Zhonghua yi xue yi chuan xue za zhi = Zhonghua yixue yichuanxue zazhi = Chinese journal of medical genetics.

[161]  D. Miao,et al.  Transgenic mice overexpressing human fibroblast growth factor 23 (R176Q) delineate a putative role for parathyroid hormone in renal phosphate wasting disorders. , 2004, Endocrinology.

[162]  K. Moriyama,et al.  A Soluble Form of Fibroblast Growth Factor Receptor 2 (FGFR2) with S252W Mutation Acts as an Efficient Inhibitor for the Enhanced Osteoblastic Differentiation Caused by FGFR2 Activation in Apert Syndrome* , 2004, Journal of Biological Chemistry.

[163]  Gillian M Morriss-Kay,et al.  A gain-of-function mutation of Fgfr2c demonstrates the roles of this receptor variant in osteogenesis. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[164]  A. Hampl,et al.  FGF2 inhibits proliferation and alters the cartilage-like phenotype of RCS cells. , 2004, Experimental cell research.

[165]  C. Ohlsson,et al.  Transgenic mice expressing fibroblast growth factor 23 under the control of the alpha1(I) collagen promoter exhibit growth retardation, osteomalacia, and disturbed phosphate homeostasis. , 2004, Endocrinology.

[166]  Liping Xiao,et al.  Stat1 Controls Postnatal Bone Formation by Regulating Fibroblast Growth Factor Signaling in Osteoblasts* , 2004, Journal of Biological Chemistry.

[167]  C. Whitehead,et al.  High vitamin D3 requirements in broilers for bone quality and prevention of tibial dyschondroplasia and interactions with dietary calcium, available phosphorus and vitamin A , 2004, British poultry science.

[168]  Hong Chang,et al.  Detection of Chromosome 13q Deletions and IgH Translocations in Patients with Multiple Myeloma by FISH: Comparison with Karyotype Analysis , 2004, Leukemia & lymphoma.

[169]  T. Yoneya,et al.  FGF-23 transgenic mice demonstrate hypophosphatemic rickets with reduced expression of sodium phosphate cotransporter type IIa. , 2004, Biochemical and biophysical research communications.

[170]  S. Murakami,et al.  Constitutive activation of MEK1 in chondrocytes causes Stat1-independent achondroplasia-like dwarfism and rescues the Fgfr3-deficient mouse phenotype. , 2004, Genes & development.

[171]  Z. Werb,et al.  Matrix remodeling during endochondral ossification. , 2004, Trends in cell biology.

[172]  E. Laplantine,et al.  Activation of the ERK1/2 and p38 Mitogen-activated Protein Kinase Pathways Mediates Fibroblast Growth Factor-induced Growth Arrest of Chondrocytes* , 2004, Journal of Biological Chemistry.

[173]  J. Heath,et al.  Skeletal development is regulated by fibroblast growth factor receptor 1 signalling dynamics , 2003, Development.

[174]  D. Goltzman,et al.  Defective bone mineralization and osteopenia in young adult FGFR3-/- mice. , 2003, Human molecular genetics.

[175]  Hiroyuki Tanaka,et al.  PTHrP Rescues ATDC5 Cells From Apoptosis Induced by FGF Receptor 3 Mutation , 2003, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[176]  C. Deng,et al.  A Ser250Trp substitution in mouse fibroblast growth factor receptor 2 (Fgfr2) results in craniosynostosis , 2003 .

[177]  D. Rice,et al.  Fgfr mRNA isoforms in craniofacial bone development. , 2003, Bone.

[178]  T. Jessell,et al.  Specification of dorsal telencephalic character by sequential Wnt and FGF signaling , 2003, Nature Neuroscience.

[179]  E. Olson,et al.  Conditional inactivation of FGF receptor 2 reveals an essential role for FGF signaling in the regulation of osteoblast function and bone growth , 2003, Development.

[180]  E. Laplantine,et al.  A network of transcriptional and signaling events is activated by FGF to induce chondrocyte growth arrest and differentiation , 2003, The Journal of cell biology.

[181]  T. Doetschman,et al.  Impaired Osteoclast Formation in Bone Marrow Cultures of Fgf2 Null Mice in Response to Parathyroid Hormone* , 2003, Journal of Biological Chemistry.

[182]  Stephen M Warren,et al.  Age-related Changes in the Biomolecular Mechanisms of Clvarial Osteoblast Biology Affect Fibroblast Growth Factor-2 Signaling and Osteogenesis* , 2003, Journal of Biological Chemistry.

[183]  I. Mason.  Fibroblast growth factors , 2003, Current Biology.

[184]  K. White,et al.  Fibroblast growth factor 23 in oncogenic osteomalacia and X-linked hypophosphatemia. , 2003, The New England journal of medicine.

[185]  W. Puhl,et al.  PTHrP, PTHr, and FGFR3 are involved in the process of endochondral ossification in human osteophytes , 2003, Histochemistry and Cell Biology.

[186]  Tony Reiman,et al.  In multiple myeloma, t(4;14)(p16;q32) is an adverse prognostic factor irrespective of FGFR3 expression. , 2003, Blood.

[187]  D. Robinson,et al.  The short-lived exostosis induced surgically versus the lasting genetic hereditary multiple exostoses. , 2003, Experimental and molecular pathology.

[188]  J. Thiery,et al.  Novel fibroblast growth factor receptor 3 (FGFR3) mutations in bladder cancer previously identified in non-lethal skeletal disorders , 2002, European Journal of Human Genetics.

[189]  Andrea Vortkamp,et al.  Interaction of FGF, Ihh/Pthlh, and BMP signaling integrates chondrocyte proliferation and hypertrophic differentiation. , 2002, Developmental cell.

[190]  M. Pines,et al.  The IIIc alternative of Fgfr2 is a positive regulator of bone formation. , 2002, Development.

[191]  S. Nishikawa,et al.  Elbow knee synostosis (Eks): a new mutation on mouse Chromosome 14 , 2002, Mammalian Genome.

[192]  B. Lanske,et al.  PTHrP and Indian hedgehog control differentiation of growth plate chondrocytes at multiple steps. , 2002, Development.

[193]  P. Marie,et al.  FGF signaling pathways in endochondral and intramembranous bone development and human genetic disease. , 2002, Genes & development.

[194]  D. Ornitz,et al.  Coordination of chondrogenesis and osteogenesis by fibroblast growth factor 18. , 2002, Genes & development.

[195]  N. Itoh,et al.  FGF18 is required for normal cell proliferation and differentiation during osteogenesis and chondrogenesis. , 2002, Genes & development.

[196]  E. Wagner,et al.  Reaching a genetic and molecular understanding of skeletal development. , 2002, Developmental cell.

[197]  W Gaffield,et al.  BMP and Ihh/PTHrP signaling interact to coordinate chondrocyte proliferation and differentiation. , 2001, Development.

[198]  F. Luyten,et al.  Molecular markers predictive of the capacity of expanded human articular chondrocytes to form stable cartilage in vivo. , 2001, Arthritis and rheumatism.

[199]  C. Deng,et al.  Highly activated Fgfr3 with the K644M mutation causes prolonged survival in severe dwarf mice. , 2001, Human molecular genetics.

[200]  S. Takeda,et al.  Cloning and characterization of FGF23 as a causative factor of tumor-induced osteomalacia , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[201]  J. Lemonnier,et al.  Increased osteoblast apoptosis in apert craniosynostosis: role of protein kinase C and interleukin-1. , 2001, The American journal of pathology.

[202]  J. Lemonnier,et al.  Increased Expression of Protein Kinase Cα, Interleukin‐1α, and RhoA Guanosine 5′‐Triphosphatase in Osteoblasts Expressing the Ser252Trp Fibroblast Growth Factor 2 Apert Mutation: Identification by Analysis of Complementary DNA Microarray , 2001 .

[203]  C. Dickson,et al.  A splicing switch and gain-of-function mutation in FgfR2-IIIc hemizygotes causes Apert/Pfeiffer-syndrome-like phenotypes , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[204]  C. Deng,et al.  A Ser(365)-->Cys mutation of fibroblast growth factor receptor 3 in mouse downregulates Ihh/PTHrP signals and causes severe achondroplasia. , 2001, Human molecular genetics.

[205]  A. McMahon,et al.  Indian hedgehog couples chondrogenesis to osteogenesis in endochondral bone development. , 2001, The Journal of clinical investigation.

[206]  E. Schwarz,et al.  BMP signaling stimulates chondrocyte maturation and the expression of Indian hedgehog , 2001, Journal of orthopaedic research : official publication of the Orthopaedic Research Society.

[207]  M. Capecchi,et al.  Fgf8 is required for outgrowth and patterning of the limbs , 2000, Nature Genetics.

[208]  T. Meitinger,et al.  Autosomal dominant hypophosphataemic rickets is associated with mutations in FGF23 , 2000, Nature Genetics.

[209]  N. Amizuka,et al.  The biological action of parathyroid hormone-related peptide (PTHrP) and fibroblast growth factor receptor 3 (FGFR3) on bone and cartilage. , 2000, Kaibogaku zasshi. Journal of anatomy.

[210]  C. Powers,et al.  Fibroblast growth factors, their receptors and signaling. , 2000, Endocrine-related cancer.

[211]  C. Deng,et al.  A Pro250Arg substitution in mouse Fgfr1 causes increased expression of Cbfa1 and premature fusion of calvarial sutures. , 2000, Human molecular genetics.

[212]  C. Deng,et al.  A neonatal lethal mutation in FGFR3 uncouples proliferation and differentiation of growth plate chondrocytes in embryos. , 2000, Human molecular genetics.

[213]  C. Basilico,et al.  Signaling by Fibroblast Growth Factors (Fgf) and Fibroblast Growth Factor Receptor 2 (Fgfr2)–Activating Mutations Blocks Mineralization and Induces Apoptosis in Osteoblasts , 2000, The Journal of cell biology.

[214]  D. Rice,et al.  Integration of FGF and TWIST in calvarial bone and suture development. , 2000, Development.

[215]  M. Ito,et al.  Disruption of the fibroblast growth factor-2 gene results in decreased bone mass and bone formation. , 2000, The Journal of clinical investigation.

[216]  M. Capecchi,et al.  Normal limb development in conditional mutants of Fgf4. , 2000, Development.

[217]  D. Givol,et al.  Restrained chondrocyte proliferation and maturation with abnormal growth plate vascularization and ossification in human FGFR-3(G380R) transgenic mice. , 2000, Human molecular genetics.

[218]  L. Cheng,et al.  Expression of FGFR3 with the G380R Achondroplasia Mutation Inhibits Proliferation and Maturation of CFK2 Chondrocytic Cells , 2000, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[219]  A. Wilkie,et al.  Fgfr1 and Fgfr2 have distinct differentiation- and proliferation-related roles in the developing mouse skull vault. , 1999, Development.

[220]  C. Deng,et al.  Gly369Cys mutation in mouse FGFR3 causes achondroplasia by affecting both chondrogenesis and osteogenesis. , 1999, The Journal of clinical investigation.

[221]  A. Yayon,et al.  Skeletal Dysplasia and Defective Chondrocyte Differentiation by Targeted Overexpression of Fibroblast Growth Factor 9 in Transgenic Mice , 1999, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[222]  A. Sigurdsson,et al.  The gene for cherubism maps to chromosome 4p16.3. , 1999, American journal of human genetics.

[223]  D. Levy,et al.  FGF signaling inhibits chondrocyte proliferation and regulates bone development through the STAT-1 pathway. , 1999, Genes & development.

[224]  D. Givol,et al.  A mouse model for achondroplasia produced by targeting fibroblast growth factor receptor 3. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[225]  D. Ornitz,et al.  Repression of hedgehog signaling and BMP4 expression in growth plate cartilage by fibroblast growth factor receptor 3. , 1998, Development.

[226]  B. Lanske,et al.  The parathyroid hormone/parathyroid hormone-related peptide receptor coordinates endochondral bone development by directly controlling chondrocyte differentiation. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[227]  C. Deng,et al.  FGFR-3 and FGFR-4 function cooperatively to direct alveogenesis in the murine lung. , 1998, Development.

[228]  A. Munnich,et al.  Spatio-temporal expression of FGFR 1, 2 and 3 genes during human embryo-fetal ossification , 1998, Mechanisms of Development.

[229]  G. Martin,et al.  The roles of FGFs in the early development of vertebrate limbs. , 1998, Genes & development.

[230]  M. Evans,et al.  Crouzon‐like craniofacial dysmorphology in the mouse is caused by an insertional mutation at the Fgf3/Fgf4 locus , 1998, Developmental dynamics : an official publication of the American Association of Anatomists.

[231]  M. Kool,et al.  Drug export activity of the human canalicular multispecific organic anion transporter in polarized kidney MDCK cells expressing cMOAT (MRP2) cDNA. , 1998, The Journal of clinical investigation.

[232]  P. Leder,et al.  Fibroblast growth factor receptor 2 (FGFR2)-mediated reciprocal regulation loop between FGF8 and FGF10 is essential for limb induction. , 1998, Development.

[233]  J. Heath,et al.  Fgfr2 and osteopontin domains in the developing skull vault are mutually exclusive and can be altered by locally applied FGF2. , 1997, Development.

[234]  T. Kuwana,et al.  The mesenchymal factor, FGF10, initiates and maintains the outgrowth of the chick limb bud through interaction with FGF8, an apical ectodermal factor. , 1997, Development.

[235]  Xin-Yuan Fu,et al.  Activation of Statl by mutant fibroblast growth-factor receptor in thanatophoric dysplasia type II dwarfism , 1997, Nature.

[236]  E. Haan,et al.  A unique point mutation in the fibroblast growth factor receptor 3 gene (FGFR3) defines a new craniosynostosis syndrome. , 1997, American journal of human genetics.

[237]  W. Reardon,et al.  A recurrent mutation, ala391glu, in the transmembrane region of FGFR3 causes Crouzon syndrome and acanthosis nigricans. , 1996, Journal of medical genetics.

[238]  Gary W. Harding,et al.  Skeletal overgrowth and deafness in mice lacking fibroblast growth factor receptor 3 , 1996, Nature Genetics.

[239]  P. Leder,et al.  Fibroblast Growth Factor Receptor 3 Is a Negative Regulator of Bone Growth , 1996, Cell.

[240]  B. Olwin,et al.  Changes in the expression of fibroblast growth factor receptors mark distinct stages of chondrogenesis in vitro and during chick limb skeletal patterning , 1995, Developmental dynamics : an official publication of the American Association of Anatomists.

[241]  I. Munro,et al.  Fibroblast growth factor receptor 3 (FGFR3) transmembrane mutation in Crouzon syndrome with acanthosis nigricans , 1995, Nature Genetics.

[242]  G. Dorn,et al.  Abnormal bone growth and selective translational regulation in basic fibroblast growth factor (FGF-2) transgenic mice. , 1995, Molecular biology of the cell.

[243]  D. Rimoin,et al.  Thanatophoric dysplasia (types I and II) caused by distinct mutations in fibroblast growth factor receptor 3 , 1995, Nature Genetics.

[244]  T. Nakamura,et al.  Stimulation of endosteal bone formation by systemic injections of recombinant basic fibroblast growth factor in rats. , 1995, Endocrinology.

[245]  P. Leder,et al.  Murine FGFR-1 is required for early postimplantation growth and axial organization. , 1994, Genes & development.

[246]  J. Rossant,et al.  fgfr-1 is required for embryonic growth and mesodermal patterning during mouse gastrulation. , 1994, Genes & development.

[247]  W. Reardon,et al.  A common mutation in the fibroblast growth factor receptor 1 gene in Pfeiffer syndrome , 1994, Nature Genetics.

[248]  B. Olwin,et al.  FGF-2: apical ectodermal ridge growth signal for chick limb development. , 1994, Science.

[249]  D. Givol,et al.  Developmental localization of the splicing alternatives of fibroblast growth factor receptor-2 (FGFR2). , 1993, Developmental biology.

[250]  S. Werner,et al.  Unique expression pattern of the FGF receptor 3 gene during mouse organogenesis. , 1993, Developmental biology.

[251]  B. Boyan,et al.  Regulation of prostaglandin E2 production by vitamin D metabolites in growth zone and resting zone chondrocyte cultures is dependent on cell maturation. , 1992, Bone.

[252]  T. W. Odom,et al.  The effect ofin ovo boron supplementation on bone mineralization of the vitamin D-deficient chicken embryo , 1991, Biological Trace Element Research.

[253]  R. W. Perry,et al.  Pathology of experimental vitamin D deficiency in turkeys and the effects of various vitamin D supplements. , 1991, Avian diseases.

[254]  J. Partanen,et al.  FGFR‐4, a novel acidic fibroblast growth factor receptor with a distinct expression pattern. , 1991, The EMBO journal.

[255]  J. Lian,et al.  Effect of sodium warfarin on vitamin K‐dependent proteins and skeletal development in the rat fetus , 1990, Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.

[256]  P. Krejcí.  The paradox of FGFR3 signaling in skeletal dysplasia: why chondrocytes growth arrest while other cells over proliferate. , 2014, Mutation research. Reviews in mutation research.

[257]  D. Ornitz,et al.  Development of the endochondral skeleton. , 2013, Cold Spring Harbor perspectives in biology.

[258]  T. Shimada,et al.  FGF23 as a novel therapeutic target. , 2012, Advances in experimental medicine and biology.

[259]  S. Murakami,et al.  FGF and ERK signaling coordinately regulate mineralization-related genes and play essential roles in osteocyte differentiation , 2011, Journal of Bone and Mineral Metabolism.

[260]  N. Amizuka,et al.  Signalling by fibroblast growth factor receptor 3 and parathyroid hormone-related peptide coordinate cartilage and bone development. , 2004, Bone.

[261]  V. Nurcombe,et al.  Fibroblast growth factor receptor 4 (FGFR4) expression in newborn murine calvaria and primary osteoblast cultures. , 2002, The International journal of developmental biology.

[262]  C. Deng,et al.  A Lys644Glu substitution in fibroblast growth factor receptor 3 (FGFR3) causes dwarfism in mice by activation of STATs and ink4 cell cycle inhibitors. , 1999, Human molecular genetics.

[263]  K. Kato,et al.  In vivo stimulation of endosteal bone formation by basic fibroblast growth factor in rats. , 1993, Growth factors.

[264]  S. Werner,et al.  Two FGF receptor genes are differentially expressed in epithelial and mesenchymal tissues during limb formation and organogenesis in the mouse. , 1992, Development.

[265]  Z. Schwartz,et al.  Effects of 1 alpha(OH)-vitamin D3 and 24,25(OH)2-vitamin D3 on long bones of glucocorticoid-treated rats. , 1992, Acta anatomica.