Abstract
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.
Publication types
-
Research Support, Non-U.S. Gov't
-
Research Support, U.S. Gov't, P.H.S.
MeSH terms
-
Adenoviridae / genetics
-
Aggrecans
-
Animals
-
Blotting, Northern
-
Blotting, Western
-
Bone Morphogenetic Protein 2
-
Bone Morphogenetic Proteins / metabolism
-
Calcineurin / metabolism*
-
Calcium / metabolism
-
Carrier Proteins
-
Cell Differentiation
-
Cell Nucleus / metabolism
-
Chelating Agents / pharmacology
-
Chondrocytes / cytology
-
DNA-Binding Proteins / metabolism
-
Extracellular Matrix Proteins / metabolism
-
Fibroblast Growth Factors / metabolism
-
Fibroblast Growth Factors / physiology*
-
Fluorescent Antibody Technique, Indirect
-
Gene Expression Regulation
-
Humans
-
Ionomycin / pharmacology
-
Lectins, C-Type
-
Ligands
-
Mice
-
Mice, Inbred C57BL
-
Models, Biological
-
NFATC Transcription Factors
-
Nuclear Proteins*
-
Precipitin Tests
-
Proteins / metabolism*
-
Proteoglycans / metabolism
-
Rats
-
Reverse Transcriptase Polymerase Chain Reaction
-
Signal Transduction
-
Time Factors
-
Transcription Factors / metabolism
-
Transcriptional Activation
-
Transforming Growth Factor beta / metabolism
-
Transforming Growth Factor beta1
-
Ubiquitin / metabolism
Substances
-
Acan protein, mouse
-
Acan protein, rat
-
Aggrecans
-
BMP2 protein, human
-
Bmp2 protein, mouse
-
Bmp2 protein, rat
-
Bone Morphogenetic Protein 2
-
Bone Morphogenetic Proteins
-
Carrier Proteins
-
Chelating Agents
-
DNA-Binding Proteins
-
Extracellular Matrix Proteins
-
Lectins, C-Type
-
Ligands
-
NFATC Transcription Factors
-
NFATC3 protein, human
-
Nfatc3 protein, mouse
-
Nuclear Proteins
-
Proteins
-
Proteoglycans
-
TGFB1 protein, human
-
Tgfb1 protein, mouse
-
Tgfb1 protein, rat
-
Transcription Factors
-
Transforming Growth Factor beta
-
Transforming Growth Factor beta1
-
Ubiquitin
-
fibroblast growth factor 18
-
noggin protein
-
Ionomycin
-
Fibroblast Growth Factors
-
Calcineurin
-
Calcium