FGF18 represses noggin expression and is induced by calcineurin.
Fibroblast growth factors (FGFs) and bone morphogenetic proteins strongly regulate chondrogenesis and chondrocyte gene expression. The interactions of the signaling pathways initiated by these factors are central to the control of chondrocyte differentiation. Here we show that calcium-dependent signals induce expression of FGF18, an essential regulator of bone and cartilage differentiation. The induction of FGF18 expression required the calcium-dependent phosphatase, calcineurin. The activated forms of calcineurin or the calcineurin-dependent transcription factor, NFAT4 (nuclear factor of activated T-cell 4), induced FGF18 expression. FGF18 or a constitutive active FGF receptor suppressed noggin gene induction and thereby increased chondrocyte gene expression and chondrogenesis by facilitating bone morphogenetic protein-dependent signals. These findings reinforce the interdependence of bone morphogenetic protein and FGF signaling and provide a rational explanation for abnormal bone development occurring in humans or mice with constitutively active FGF receptors.
Reinhold
Martina I
MI
Department of Pathology, University of Texas Health Science Center, San Antonio, Texas 78229, USA.
Abe
Makoto
M
Kapadia
Ravi M
RM
Liao
Zhixiang
Z
Naski
Michael C
MC
D000256:Adenoviridae / Q000235:genetics; D053674:Aggrecans; D000818:Animals; D015152:Blotting, Northern; D015153:Blotting, Western; D055396:Bone Morphogenetic Protein 2; D019485:Bone Morphogenetic Proteins / Q000378:metabolism; D019703:Calcineurin / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism; D002352:Carrier Proteins; D002454:Cell Differentiation; D002467:Cell Nucleus / Q000378:metabolism; D002614:Chelating Agents / Q000494:pharmacology; D019902:Chondrocytes / Q000166:cytology; D004268:DNA-Binding Proteins / Q000378:metabolism; D016326:Extracellular Matrix Proteins / Q000378:metabolism; D005346:Fibroblast Growth Factors / Q000378:metabolism / Q000502:physiology*; D019084:Fluorescent Antibody Technique, Indirect; D005786:Gene Expression Regulation; D006801:Humans; D015759:Ionomycin / Q000494:pharmacology; D037181:Lectins, C-Type; D008024:Ligands; D051379:Mice; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D011233:Precipitin Tests; D011506:Proteins / Q000378:metabolism*; D011509:Proteoglycans / Q000378:metabolism; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D013997:Time Factors; D014157:Transcription Factors / Q000378:metabolism; D015533:Transcriptional Activation; D016212:Transforming Growth Factor beta / Q000378:metabolism; D053773:Transforming Growth Factor beta1; D025801:Ubiquitin / Q000378:metabolism; D000099176:Noggin Protein
D053674:Aggrecans; D055396:Bone Morphogenetic Protein 2; D019485:Bone Morphogenetic Proteins; D019703:Calcineurin; D002118:Calcium; D002352:Carrier Proteins; D002614:Chelating Agents; D004268:DNA-Binding Proteins; D016326:Extracellular Matrix Proteins; D005346:Fibroblast Growth Factors; D015759:Ionomycin; D037181:Lectins, C-Type; D008024:Ligands; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D011506:Proteins; D011509:Proteoglycans; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D025801:Ubiquitin; D000099176:Noggin Protein; C508320:Acan protein, mouse; C508321:Acan protein, rat; C525718:BMP2 protein, human; C525719:Bmp2 protein, mouse; C525720:Bmp2 protein, rat; C494008:NFATC3 protein, human; C494009:Nfatc3 protein, mouse; C508960:TGFB1 protein, human; C508961:Tgfb1 protein, mouse; C508962:Tgfb1 protein, rat; C113569:fibroblast growth factor 18