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FGF and TGFbeta signalling in an in-vitro model of craniosynostosis

By K.M.A. Lee


Fibroblast Growth Factor (FGF) and Transforming Growth Factor beta (TGFbeta) are key regulators of bone development. Constitutively activating mutations of FGF Receptors (FGFR) 1-3 result in craniosynostosis, premature fusion of cranial sutures. The aim of this thesis was to determine how FGF signalling is impaired in osteoblasts with the mutation FGFR2-C278F, known to induce craniosnostosis and investigate possible interactions with TGFbeta signalling. To this purpose MC3T3-E1 osteoblasts (derived from newborn mouse calvaria) that had been stably transfected with human FGFR2 (wild type FGFR2-WT or mutated FGFR2-C278F) were used as an in-vitro model and these cell lines were named R2-WT and R2-C278F. These cell lines were characterised at the cellular and molecular level to define the craniosynostotic phenotype. Gene expression was assessed with real time PCR, proliferation using both fluorescence activated cell sorting (FACS) and the methylene blue assay and protein expression by FACS, immunocytochemistry and Western blotting. Cell proliferation was reduced and apoptosis increased in the R2-C278F mutant and differentiation increased, as shown by reduced expression of differentiation marker osteopontin and an increase in osteocalcin. The effect of FGF signalling on cell growth was demonstrated by using FGFR inhibitor SU5402. This study suggested that FGFR2-C278F decreases the level of FGFR signalling. FGFR2-C278F impairs TGFbeta signalling as shown by: i) reduced Tgfbeta1 and -3 expression in R2-C278F cells; ii) maximal reduction of cell growth only in R2-C278F cells following TGFbeta inhibition using SB431542 (1μM); iii) the inability of exogenous TGFbeta1 to induce proliferation in R2-C278F cells. This suggests that exogenous TGFbeta1 cannot rescue the impaired TGFbeta signalling caused by FGFR2-C278F mutation. Fgf and Tgfbeta signalling may converge to affect osteoblast proliferation via extracellular related kinase 1/2 (Erk1/2). Analysis of the Erk1/2 protein expression in R2-C278F cells showed that Erk1 isoform had increased relative to Erk2. This change has been associated with growth arrest in osteoblasts, fibroblasts and hepatocytes and therefore it is likely to underlie the defect in proliferative response to Fgf and Tgfbeta signalling in R2-C278F cells. In summary FGFR2-C278F in MC3T3 cells impairs Fgf and Tgfbeta signalling, resulting in a proliferation defect for which increased differentiation is implicated as a secondary effect. A key convergence between FGFR2-C278F and Tgfbeta appears to be via impaired Erk1/2 signal transduction. These findings provide a valuable basis for future investigations of other Erk1/2 upstream pathways and their contribution to the craniosynostotic osteoblast phenotype

Publisher: UCL (University College London)
Year: 2009
OAI identifier:
Provided by: UCL Discovery

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  1. (2004). A gain-offunction mutation of Fgfr2c demonstrates the roles of this receptor variant in osteogenesis.
  2. (2006). A model for the pharmacological treatment of crouzon syndrome.
  3. (1999). A new 34-kilodalton isoform of human fibroblast growth factor 2 is cap dependently synthesized by using a nonAUG start codon and behaves as a survival factor.
  4. (2008). A Runx2 Threshold for the Cleidocranial Dysplasia Phenotype.
  5. (2005). A syndrome of altered cardiovascular, craniofacial, neurocognitive and skeletal development caused by mutations in TGFBR1 or TGFBR2.
  6. (2004). A twist code determines the onset of osteoblast differentiation.
  7. (1997). A unique point mutation in the fibroblast growth factor receptor 3 gene (FGFR3) defines a new craniosynostosis syndrome.
  8. (2003). Activating (P253R, C278F) and dominant negative mutations of FGFR2: differential effects on calvarial bone cell proliferation, differentiation, and mineralization.
  9. (1998). Activating mutations in the extracellular domain of the fibroblast growth factor receptor 2 function by disruption of the disulfide bond in the third immunoglobulin-like domain.
  10. (2007). Activation of osteocalcin transcription involves interaction of protein kinase A- and protein kinase Cdependent pathways.
  11. (2004). Activation of the pro-survival phosphatidylinositol 3-kinase/AKT pathway by transforming growth factor-beta1 in mesenchymal cells is mediated by p38 MAPK-dependent induction of an autocrine growth factor.
  12. (2002). Activations of ERK1/2 and JNK by transforming growth factor beta negatively regulate Smad3-induced alkaline phosphatase activity and mineralization in mouse osteoblastic cells.
  13. (2004). Akt interacts directly with Smad3 to regulate the sensitivity to TGF-beta induced apoptosis.
  14. (2007). Akt1 in osteoblasts and osteoclasts controls bone remodeling.
  15. (2003). An SP1-like transcription factor Spr2 acts downstream of Fgf signaling to mediate mesoderm induction.
  16. (1998). Analysis of patients with craniosynostosis syndromes for a pro246Arg mutation of FGFR4.
  17. (2005). Apert and Crouzon Syndromes: Clinical Findings, Genes and Extracellular Matrix.
  18. (1995). Apert syndrome results from localized mutations of FGFR2 and is allelic with Crouzon syndrome.
  19. (2005). Apoptosis in membranous bone formation: role of fibroblast growth factor and bone morphogenetic protein signaling. Crit Rev.
  20. (2005). Assembly of TbetaRI:TbetaRII:TGFbeta ternary complex in vitro with receptor extracellular domains is cooperative and isoform-dependent.
  21. (2006). Attenuation of signaling pathways stimulated by pathologically activated FGFreceptor 2 mutants prevents craniosynostosis.
  22. (2005). Bad bones, absent smell, selfish testes: the pleiotropic consequences of human FGF receptor mutations.
  23. (2007). Basic fibroblast growth factor (FGF-2): the high molecular weight forms come of age.
  24. (1999). Basic fibroblast growth factor and transforming growth factor beta-1 expression in the developing dura mater correlates with calvarial bone formation.
  25. (2007). Basic fibroblast growth factor stimulates fibronectin expression through phospholipase C gamma, protein kinase C alpha, c-Src, NF-kappaB, and p300 pathway in osteoblasts.
  26. (1992). Basic fibroblast growth factor, a protein devoid of secretory signal sequence, is released by cells via a pathway independent of the endoplasmic reticulumGolgi complex.
  27. (2002). Blocking endogenous FGF-2 activity prevents cranial osteogenesis.
  28. (1994). Bone sialoprotein mRNA expression and ultrastructural localization in fetal porcine calvarial bone: comparisons with osteopontin.
  29. (2002). Both the Smad and p38 MAPK pathways play a crucial role in Runx2 expression following induction by transforming growth factor-beta and bone morphogenetic protein.
  30. (2007). Brain malformation in syndromic craniosynostoses, a primary disorder of white matter: a review.
  31. (1996). Caenorhabditis elegans genes sma-2, sma-3, and sma-4 define a conserved family of transforming growth factor beta pathway components.
  32. (1999). Cbfa1 as a regulator of osteoblast differentiation and function.
  33. (1999). Cbfa1 isoforms exert functional differences in osteoblast differentiation.
  34. (1997). Cbfa1, a candidate gene for cleidocranial dysplasia syndrome, is essential for osteoblast differentiation and bone development.
  35. (2005). Cell death independent of caspases: a review.
  36. (2007). Cell fate specification during calvarial bone and suture development.
  37. (2005). Cellular signaling by fibroblast growth factor receptors.
  38. (1993). Characterization of porcine bone sialoprotein: primary structure and cellular expression.
  39. (2004). Clinical Management of Craniosynostosis.,
  40. (1984). Closing and non-closing sutures in 256 crania of known age and sex from Amsterdam.
  41. (2005). Co-ordination of TGF-beta and FGF signaling pathways in bone organ cultures.
  42. (2001). Common regulation of growth arrest and differentiation of osteoblasts by helix-loop-helix factors.
  43. (2005). Comparative genomics on FGF7, FGF10, FGF22 orthologs, and identification of fgf25.
  44. (1996). Comparison of glyceraldehyde-3-phosphate dehydrogenase and 28s-ribosomal RNA gene expression in human hepatocellular carcinoma.
  45. (1994). Competition between nuclear localization and secretory signals determines the subcellular fate of a single CUG-initiated form of FGF3.
  46. (2003). Conditional inactivation of FGF receptor 2 reveals an essential role for FGF signaling in the regulation of osteoblast function and bone growth.
  47. (2002). Coordinate gene expression patterns during osteoblast maturation and retinoic acid treatment of MC3T3-E1 cells.
  48. (2006). Coordinated fibroblast growth factor and heparan sulfate regulation of osteogenesis.
  49. (2002). Coordination of chondrogenesis and osteogenesis by fibroblast growth factor 18. Genes Dev.
  50. (1999). Cranial suture obliteration is induced by removal of transforming growth factor (TGF)-beta 3 activity and prevented by removal of TGF-beta 2 activity from fetal rat calvaria in vitro.
  51. (2000). Cranial sutures as intramembranous bone growth sites.
  52. (1986). Craniosynostosis: diagnosis, evaluation and
  53. (2008). Craniosynostotic variations in syndromic, identical twins.
  54. (2001). Critical role for the dockingprotein FRS2 alpha in FGF receptor-mediated signal transduction pathways.
  55. (2004). Crouzon syndrome: phenotypic signs and symptoms of the postnatally expressed subtype.
  56. (2008). Current treatment of craniosynostosis and future therapeutic directions.
  57. (2008). Decoding the quantitative nature of TGF-beta/Smad signaling.
  58. (1999). Decreased proliferation and altered differentiation in osteoblasts from genetically and clinically distinct craniosynostotic disorders.
  59. (2004). Defective bone mineralization and osteopenia in young adult FGFR3-/- mice.
  60. (1998). Description of a new mutation and characterization of FGFR1, FGFR2, and FGFR3 mutations among Brazilian patients with syndromic craniosynostoses.
  61. (2006). Design, synthesis and antitumor evaluation of a new series of N-substituted-thiourea derivatives.
  62. (1983). Development of the frontal bone and cranial meninges in the embryonic chick: an experimental study of tissue interactions.
  63. (1988). Developmental expression of 44-kDa bone phosphoprotein (osteopontin) and bone gamma-carboxyglutamic acid (Gla)-containing protein (osteocalcin) in calcifying tissues of rat.
  64. (1993). Developmental localization of the splicing alternatives of fibroblast growth factor receptor-2 (FGFR2).
  65. Different abilities of the four FGFRs to mediate FGF-1 translocation are linked to differences in the receptor Cterminal tail.
  66. (2007). Differential effects of TGF-beta isoforms on murine fetal dural cells and calvarial osteoblasts.
  67. (2002). Differential regulation of Cbfa1/Runx2 and osteocalcin gene expression by vitamin-D3, dexamethasone, and local growth factors in primary human osteoblasts.
  68. (2006). Dimethyl sulfoxide as an inducer of differentiation in preosteoblast MC3T3-E1 cells.
  69. (2007). Direct interactions of Runx2 and canonical Wnt signaling induce FGF18.
  70. (2007). Dura mater-derived FGF-2 mediates mitogenic signaling in calvarial osteoblasts.
  71. (2008). Effect of progesterone on apoptosis of murine MC3T3-E1 osteoblastic cells.
  72. (1996). Effects of parathyroid hormone and agonists of the adenylyl cyclase and protein kinase C pathways on bone cell proliferation.
  73. (2003). EGFR and FGFR signaling through FRS2 is subject to negative feedback control by ERK1/2.
  74. (1993). Endogenous protein kinase-C activation in osteoblast-like cells modulates responsiveness to estrogen and estrogen receptor levels.
  75. (2006). ERK activity facilitates activation of the S-phase DNA damage checkpoint by modulating ATR function.
  76. (2007). ERK implication in cell cycle regulation.
  77. (2001). Erk is essential for growth, differentiation, integrin expression, and cell function in human osteoblastic cells.
  78. (2006). Erk pathways negatively regulate matrix mineralization.
  79. (2006). ERK1 and ERK2 mitogen-activated protein kinases affect Ras-dependent cell signaling differentially.
  80. (2006). Erk1/2 signaling is required for Tgfbeta2-induced suture closure.
  81. (2007). ERK2 but not ERK1 plays a key role in hepatocyte replication: An RNAi-mediated ERK2 knockdown approach in wild-type and ERK1 null hepatocytes.
  82. (1981). Establishment of a clonal osteogenic cell line from newborn mouse calvaria.
  83. Evidence for a role of p38 MAP kinase in expression of alkaline phosphatase during osteoblastic cell differentiation.
  84. (1997). Evidence for MEK-independent pathways regulating the prolonged activation of the ERK-MAP kinases.
  85. (2003). Evidence for selective advantage of pathogenic FGFR2 mutations in the male germ line.
  86. (2008). Evidence that Fgf10 contributes to the skeletal and visceral defects of an apert syndrome mouse
  87. (2004). Evolution of the Fgf and Fgfr gene families.
  88. (2001). Expression and regulation of Runx2/Cbfa1 and osteoblast phenotypic markers during the growth and differentiation of human osteoblasts.
  89. (2000). Expression patterns of Twist and Fgfr1, -2 and -3 in the developing mouse coronal suture suggest a key role for twist in suture initiation and biogenesis.
  90. (1995). Extracellular signal-regulated protein kinases (ERKs) and ERK kinase (MEK) in brain: regional distribution and regulation by chronic morphine.
  91. (2005). FGF and FGFR signaling in chondrodysplasias and craniosynostosis.
  92. (2008). FGF induces oscillations of Hes1 expression and Ras/ERK activation.
  93. (2005). FGF signal regulates gastrulation cell movements and morphology through its target NRH.
  94. (1999). FGF signaling inhibits chondrocyte proliferation and regulates bone development through the STAT-1 pathway.
  95. (2002). FGF signaling pathways in endochondral and intramembranous bone development and human genetic disease.
  96. (2007). FGF signalling pathways in development of the midbrain and anterior hindbrain.
  97. (2005). FGF-2 acts through an ERK1/2 intracellular pathway to affect osteoblast differentiation.
  98. (2003). FGF-2 stimulation affects calvarial osteoblast biology: quantitative analysis of nine genes important for cranial suture biology by real-time reverse transcription polymerase chain reaction.
  99. (1995). FGF-8 isoforms activate receptor splice forms that are expressed in mesenchymal regions of mouse development.
  100. (2003). FGF17b and FGF18 have different midbrain regulatory properties from FGF8b or activated FGF receptors.
  101. (2002). FGF18 is required for normal cell proliferation and differentiation during osteogenesis and chondrogenesis.
  102. (2006). FGF9 can induce endochondral ossification in cranial mesenchyme.
  103. (1997). FGFR activation in skeletal disorders: too much of a good thing.
  104. (2003). Fgfr mRNA isoforms in craniofacial bone development.
  105. (1999). Fgfr1 and Fgfr2 have distinct differentiation- and proliferation-related roles in the developing mouse skull vault.
  106. (1997). Fgfr2 and osteopontin domains in the developing skull vault are mutually exclusive and can be altered by locally applied FGF2.
  107. (2003). FGFR2 mutations among Thai children with Crouzon and Apert syndromes.
  108. (2003). Fibroblast growth factor (FGF) homologous factors share structural but not functional homology with FGFs.
  109. (1989). Fibroblast growth factor enhances type beta 1 transforming growth factor gene expression in osteoblast-like cells.
  110. (2001). Fibroblast growth factor homologous factors are intracellular signaling proteins.
  111. (1996). Fibroblast growth factor receptor 2 mutations in Beare-Stevenson cutis gyrata syndrome.
  112. (1995). Fibroblast growth factor receptor 3 (FGFR3) transmembrane mutation in Crouzon syndrome with acanthosis nigricans.
  113. (2002). Fibroblast growth factor receptor 4 (FGFR4) expression in newborn murine calvaria and primary osteoblast cultures.
  114. (1999). Fibroblast growth factor receptor signalling is dictated by specific heparan sulphate saccharides.
  115. (2004). Fibroblast growth factor-2 induces osteoblast survival through a phosphatidylinositol 3-kinase-dependent, -beta-catenin-independent signaling pathway.
  116. (2001). Fibroblast growth factors and skeletogenesis.
  117. (2003). Fibroblast growth factors and their receptors in the central nervous system. Cell Tissue Res.
  118. (2003). Fibroblast growth factors lead to increased Msx2 expression and fusion in calvarial sutures.
  119. (2000). Fibroblast growth factors, their receptors and signaling.
  120. (2001). Fibroblast growth factors.
  121. (2003). Fidelity and spatio-temporal control in MAP kinase (ERKs) signalling.
  122. (2000). FIF [fibroblast growth factor-2 (FGF-2)-interacting-factor], a nuclear putatively antiapoptotic factor, interacts specifically with FGF-2.
  123. (2003). Fluid flow shear stress stimulates human osteoblast proliferation and differentiation through multiple interacting and competing signal transduction pathways.
  124. Functional diversity of FGF-2 isoforms by intracellular sorting.
  125. (1958). Fusion of the frontal suture in the rat.
  126. (2007). GAPDH and autophagy preserve survival after apoptotic cytochrome c release in the absence of caspase activation.
  127. (1998). gene expression and suppresses CBFA1 gene expression in osteoblastic osteosarcoma ROS17/2.8 cells and primary rat calvaria cells.
  128. (1995). Genetic characterization and cloning of mothers against dpp, a gene required for decapentaplegic function in Drosophila melanogaster. Genetics 139, 1347-1358. Reference List Selvamurugan,N., Kwok,S., Alliston,T., Reiss,M., and Partridge,N.C.
  129. (2008). Genetics of craniosynostosis: genes, syndromes, mutations and genotype-phenotype correlations.
  130. (1999). Grant's Atlas of Anatomy. Lippincott Williams
  131. (2005). Growth of the normal skull vault and its alteration in craniosynostosis: insights from human genetics and experimental studies.
  132. (1992). Heat shock induces the release of fibroblast growth factor 1 from NIH 3T3 cells.
  133. (1994). Heparin-induced oligomerization of FGF molecules is responsible for FGF receptor dimerization, activation, and cell proliferation.
  134. (2003). Human osteoblast-like cell proliferation induced by calcitonin-related peptides involves PKC activity.
  135. (2008). Hyaluronan facilitates transforming growth factor-beta1-mediated fibroblast proliferation.
  136. (2002). Identification of an additional hypoxia responsive element in the glyceraldehyde-3-phosphate dehydrogenase gene promoter.
  137. (2006). Identification of G2/M targets for the MAP kinase pathway by functional proteomics.
  138. (1996). Increased expression of TGF-beta 2 in osteoblasts results in an osteoporosis-like phenotype.
  139. Increased osteoblast apoptosis in apert craniosynostosis: role of protein kinase C and interleukin-1.
  140. (2004). Inhibition of human bladder tumour cell growth by fibroblast growth factor receptor 2b is independent of its kinase activity. Involvement of the carboxy-terminal region of the receptor.
  141. (2002). Inhibition of transforming growth factor (TGF)-beta1-induced extracellular matrix with a novel inhibitor of the TGF-beta type I receptor kinase activity: SB-431542.
  142. (2006). Insights into the role of heparan sulphate in fibroblast growth factor signalling.
  143. Integration of FGF and TWIST in calvarial bone and suture development.
  144. (2003). Integrative nuclear FGFR1 signaling (INFS) as a part of a universal "feed-forward-and-gate" signaling module that controls cell growth and differentiation.
  145. (2006). Intracellular retention, degradation and signaling of glycosylation deficient FGFR2 and craniosynostosis syndrome associated FGFR2C278F.
  146. (2005). Intracranial pressure monitoring in children with single suture and complex craniosynostosis: a review. Childs Nerv.
  147. (2006). Intracranial volume changes in craniosynostotic rabbits: effects of age and surgical correction.
  148. (2003). Involvement of SAPK/JNK in basic fibroblast growth factor-induced vascular endothelial growth factor release in osteoblasts.
  149. (1994). Jackson-Weiss and Crouzon syndromes are allelic with mutations in fibroblast growth factor receptor 2.
  150. (2004). Langman's Medical Embryology. Lippincott Williams
  151. (2004). Ligand dependent and independent internalization and nuclear translocation of fibroblast growth factor (FGF) receptor 1.
  152. (2006). Limitations of commonly used internal controls for real-time RT-PCR analysis of renal epithelial-mesenchymal cell transition.
  153. (1995). Localization of craniosynostosis Adelaide type to 4p16.
  154. (2007). Loeys-Dietz syndrome: MDCT angiography findings.
  155. (2000). Loss of fibroblast growth factor receptor 2 ligand-binding specificity in Apert syndrome.
  156. (2005). Low proliferation and high apoptosis of osteoblastic cells on hydrophobic surface are associated with defective Ras signaling.
  157. (2000). Management of craniosynostoses.
  158. (1974). Mathematical analysis of DNA distributions derived from flow microfluorometry.
  159. (2003). Mechanisms of TGF-beta signaling from cell membrane to the nucleus.
  160. (2005). Mechanisms underlying differential responses to FGF signaling.
  161. (2007). MEK1 activation by PAK: A novel mechanism.
  162. (1997). Mutation associated with Crouzon syndrome causes ligand-independent dimerization and activation of FGF receptor-2.
  163. (2006). Mutation screening in patients with syndromic craniosynostoses indicates that a limited number of recurrent FGFR2 mutations accounts for severe forms of Pfeiffer syndrome.
  164. (1994). Mutations in the fibroblast growth factor receptor 2 gene cause Crouzon syndrome.
  165. (2004). Mutations of the ephrin-B1 gene cause craniofrontonasal syndrome.
  166. (2005). Neelam, and Sanjeev
  167. (2001). Negative autoregulation of fibroblast growth factor receptor 2 expression characterizing cranial development in cases of Apert (P253R mutation) and Pfeiffer (C278F mutation) syndromes and suggesting a basis for differences in their cranial phenotypes.
  168. (2003). Negative feedback regulation of FGF signaling levels by Pyst1/MKP3 in chick embryos.
  169. (2004). New insights into TGF-beta-Smad signalling.
  170. (2006). Nitric Oxide-GAPDH-Siah: A Novel Cell Death Cascade. Cell
  171. (2006). Novel roles of Akt and mTOR in suppressing TGF-beta/ALK5-mediated Smad3 activation.
  172. (2001). Opposite effects of bone morphogenetic protein-2 and transforming growth factor-beta1 on osteoblast differentiation.
  173. (1997). Osf2/Cbfa1: a transcriptional activator of osteoblast differentiation.
  174. (2008). Osteoblast proliferation or differentiation is regulated by relative strengths of opposing signaling pathways.
  175. (1998). Osteoblastic responses to TGF-beta during bone remodeling.
  176. (2005). Osteopetrosis-like phenotype in latent TGF-beta binding protein 3 deficient mice.
  177. (2002). Osteopontin deficiency increases mineral content and mineral crystallinity in mouse bone.
  178. (2004). Osteopontin is a negative regulator of proliferation and differentiation in MC3T3-E1 pre-osteoblastic cells.
  179. (2003). Osteopontin regulation by inorganic phosphate is ERK1/2-, protein kinase C-, and proteasome-dependent.
  180. (2005). Overexpression of Smad2 in Tgf-beta3-null mutant mice rescues cleft palate.
  181. (2008). Palatal bone formation is regulated by palatal shelf fusion.
  182. (2008). Papilledema in patients with Apert, Crouzon, and Pfeiffer syndrome: prevalence, efficacy of treatment, and risk factors.
  183. (2006). Pfeiffer syndrome.
  184. Phosphorylation of three regulatory serines of Tob by Erk1 and Erk2 is required for Ras-mediated cell proliferation and transformation.
  185. (1999). Pleiotropic features of syndromic craniosynostoses correlate with differential expression of fibroblast growth factor receptors 1 and 2 during human craniofacial development.
  186. (1989). Possible involvement of protein kinase C in proliferation and differentiation of osteoblast-like cells.
  187. (2001). Potential role of nuclear translocation of glyceraldehyde-3-phosphate dehydrogenase in apoptosis and oxidative stress.
  188. (2007). Potential use of craniosynostotic osteoprogenitors and bioactive scaffolds for bone engineering.
  189. (2004). Preclinical studies of fibroblast growth factor receptor 3 as a therapeutic target in multiple myeloma.
  190. (2002). Pregnancy following preimplantation genetic diagnosis for Crouzon syndrome.
  191. (1992). Proliferative dependent regulation of the glyceraldehyde-3-phosphate dehydrogenase/uracil DNA glycosylase gene in human cells.
  192. (2005). Prostaglandin-dependent activation of ERK mediates cell proliferation induced by transforming growth factor beta in mouse osteoblastic cells.
  193. (1963). Quantitative studies of the growth of mouse embryo cells in culture and their development into established lines.
  194. (2007). RAB23 mutations in Carpenter syndrome imply an unexpected role for hedgehog signaling in cranial-suture development and obesity.
  195. (2008). Raised intracranial pressure in Apert syndrome.
  196. (2005). Raman imaging demonstrates FGF2-induced craniosynostosis in mouse calvaria.
  197. (1996). Receptor specificity of the fibroblast growth factor family.
  198. (2007). Reconstitution of Runx2/Cbfa1-null cells identifies a requirement for BMP2 signaling through a Runx2 functional domain during osteoblast differentiation.
  199. (2002). Ref Type: Thesis/Dissertation Reference List Petiot,A., Ferretti,P., Copp,A.J., and Chan,C.T.
  200. (1999). Regulation of alkaline phosphatase activity by p38 MAP kinase in response to activation of Gi protein-coupled receptors by epinephrine in osteoblast-like cells.
  201. (2004). Regulation of cranial suture morphogenesis. Cells Tissues.
  202. (2007). Regulation of ephexin1, a guanine nucleotide exchange factor of Rho family GTPases, by fibroblast growth factor receptormediated tyrosine phosphorylation.
  203. (2006). Regulation of osteoblast differentiation: a novel function for fibroblast growth factor 8.
  204. (2001). Regulation of osteoblast formation and function.
  205. (1995). Regulation of osteopontin expression in osteoblasts.
  206. (2000). Regulation of the gene promoter for extracellular signal-regulated protein kinase 2 by transcription factors NF-Y and Sp3.
  207. (1990). Relationship of cell growth to the regulation of tissuespecific gene expression during osteoblast differentiation.
  208. (1995). Relationships between cellular condensation, preosteoblast formation and epithelial-mesenchymal interactions in initiation of osteogenesis.
  209. (1997). Role of the glycolytic protein, glyceraldehyde-3-phosphate dehydrogenase, in normal cell function and in cell pathology.
  210. (2003). RUNX transcription factors as key targets of TGF-beta superfamily signaling.
  211. (2004). Runx2 induces osteoblast and chondrocyte differentiation and enhances their migration by coupling with PI3K-Akt signaling.
  212. (2006). Runx2 phosphorylation induced by fibroblast growth factor-2/protein kinase C pathways.
  213. (2002). SB-431542 is a potent and specific inhibitor of transforming growth factor-beta superfamily type I activin receptor-like kinase (ALK) receptors ALK4, ALK5, and ALK7.
  214. (2003). Sef inhibits fibroblast growth factor signaling by inhibiting FGFR1 tyrosine phosphorylation and subsequent ERK activation.
  215. (1999). Serial passage of MC3T3-E1 cells alters osteoblastic function and responsiveness to transforming growth factor-beta1 and bone morphogenetic protein-2.
  216. (2004). Serial passage of MC3T3-E1 cells downregulates proliferation during osteogenesis in vitro.
  217. (1999). Signal transduction by fibroblast growth factor receptors.
  218. (2002). Signal transductions induced by bone morphogenetic protein-2 and transforming growth factor-beta in normal human osteoblastic cells.
  219. (2000). Signaling by fibroblast growth factors (FGF) and fibroblast growth factor receptor 2 (FGFR2)-activating mutations blocks mineralization and induces apoptosis in osteoblasts.
  220. (2008). Single and combined silencing of ERK1 and ERK2 reveals their positive contribution to growth signaling depending on their expression levels.
  221. (2000). Smad1 domains interacting with Hoxc-8 induce osteoblast differentiation.
  222. (2005). Specification of neural crest cell formation and migration in mouse embryos.
  223. (2006). Sprouty genes are expressed in osteoblasts and inhibit fibroblast growth factor-mediated osteoblast responses.
  224. (1997). Structures of the tyrosine kinase domain of fibroblast growth factor receptor in complex with inhibitors.
  225. (1996). Studies in cranial suture biology: IV. Temporal sequence of posterior frontal cranial suture fusion in the mouse.
  226. (1996). Studies in cranial suture biology: part II. Role of the dura in cranial suture fusion.
  227. (1998). Studies in cranial suture biology: regional dura mater determines overlying suture biology.
  228. (1993). Sutural biology and the correlates of craniosynostosis.
  229. (2005). TGF-{beta}1 to the bone.
  230. TGF-beta 1 induces bone closure of skull defects.
  231. (1997). TGF-beta 1, TGF-beta 2, and TGF-beta 3 exhibit distinct patterns of expression during cranial suture formation and obliteration in vivo and in
  232. (2007). TGF-beta activates Erk MAP kinase signalling through direct phosphorylation of ShcA.
  233. (2007). TGF-beta mediated Msx2 expression controls occipital somites-derived caudal region of skull development.
  234. (2008). Tgf-beta regulation of suture morphogenesis and growth.
  235. (2003). TGF-beta signaling and its functional significance in regulating the fate of cranial neural crest cells. Crit Rev.
  236. (2001). TGF-beta-induced repression of CBFA1 by Smad3 decreases cbfa1 and osteocalcin expression and inhibits osteoblast differentiation.
  237. (2004). TGF-beta1, FGF-2, and receptor mRNA expression in suture mesenchyme and dura versus underlying brain in fusing and nonfusing mouse cranial sutures.
  238. (2006). TGF{beta}-mediated FGF signaling is crucial for regulating cranial neural crest cell proliferation during frontal bone development.
  239. (2007). TGFbeta-SMAD signal transduction: molecular specificity and functional flexibility.
  240. TGFbeta1/Smad3 counteracts BRCA1-dependent repair of DNA damage.
  241. (1997). TGFbeta2 knockout mice have multiple developmental defects that are nonoverlapping with other TGFbeta knockout phenotypes.
  242. (1995). Thanatophoric dysplasia (types I and II) caused by distinct mutations in fibroblast growth factor receptor 3.
  243. (1997). The 27-kDa heat shock protein facilitates basic fibroblast growth factor release from endothelial cells.
  244. (2001). The cell survival signal Akt is differentially activated by PDGF-BB, EGF, and FGF-2 in osteoblastic cells.
  245. (1996). The effectiveness of papilledema as an indicator of raised intracranial pressure in children with craniosynostosis.
  246. (1998). The effects of fibroblast growth factor-2 on human neonatal calvaria osteoblastic cells are differentiation stage specific.
  247. (2006). The expression profile of PKC isoforms during MC3T3-E1 differentiation.
  248. (1989). The heparin-binding (fibroblast) growth factor family of proteins.
  249. (2002). The IIIc alternative of Fgfr2 is a positive regulator of bone formation.
  250. (1997). The mouse extracellular signalregulated kinase 2 gene. Gene structure and characterization of the promoter.
  251. (2006). The origin of EFNB1 mutations in craniofrontonasal syndrome: frequent somatic mosaicism and explanation of the paucity of carrier males.
  252. (2007). The physiological and pharmacological role of basic fibroblast growth factor in the dopaminergic nigrostriatal system.
  253. (2003). The protein kinase C pathway plays a central role in the fibroblast growth factor-stimulated expression and transactivation activity of Runx2.
  254. (2006). The protein kinase C-eta isoform induces proliferation in glioblastoma cell lines through an ERK/Elk-1 pathway.
  255. (1993). Tissue interactions with underlying dura mater inhibit osseous obliteration of developing cranial sutures.
  256. (2002). Tissue origins and interactions in the mammalian skull vault.
  257. (1987). Tissue specificity and developmental expression of rat osteopontin.
  258. (1989). Transcriptional regulation of osteocalcin production by transforming growth factor-beta in rat osteoblast-like cells.
  259. (1988). Transcriptional regulation of osteopontin production in rat osteosarcoma cells by type beta transforming growth factor.
  260. (1987). Transforming growth factor beta is a bifunctional regulator of replication and collagen synthesis in osteoblast-enriched cell cultures from fetal rat bone.
  261. (2000). Transforming growth factor-beta 2 and TGF-beta 3 regulate fetal rat cranial suture morphogenesis by regulating rates of cell proliferation and apoptosis.
  262. (1994). Transforming growth factor-beta gene family members and bone.
  263. (2004). Transforming growth factor-beta isoform expression in the perisutural tissues of craniosynostotic rabbits. Cleft Palate Craniofac.
  264. (2008). Transforming growth factor-beta prevents osteoblast apoptosis induced by skeletal unloading via PI3K/Akt, Bcl-2, and phospho-Bad signaling.
  265. (2001). Transforming growth factor-beta-induced osteoblast elongation regulates osteoclastic bone resorption through a p38 mitogenactivated protein kinase- and matrix metalloproteinase-dependent pathway.
  266. Transforming growth factor-beta3 (Tgf-beta3) down-regulates Tgf-beta3 receptor type I (Tbetar-I) during rescue of cranial sutures from osseous obliteration.
  267. Transforming growth factorbeta 3(Tgf-beta3) in a collagen gel delays fusion of the rat posterior interfrontal suture in vivo.
  268. (1999). TWIST, a basic helix-loophelix transcription factor, can regulate the human osteogenic lineage.
  269. (2002). Two major Smad pathways in TGF-beta superfamily signalling.

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