FGF upregulates osteopontin in epiphyseal growth plate chondrocytes: implications for endochondral ossification.
Fibroblast growth factor receptor 3 (FGFR3) signaling pathways are essential for normal longitudinal bone growth. Mutations in this receptor lead to various human growth disorders, including Achondroplasia, disproportionately short-limbed dwarfism, characterized by narrowing of the hypertrophic region of the epiphyseal growth plates. Here we find that FGF9, a preferred ligand for FGFR3 rapidly induces the upregulation and secretion of the matrix resident phosphoprotein, osteopontin (OPN) in cultured chicken chondrocytes. This effect was observed as early as two hours post stimulation and at FGF9 concentrations as low as 1.25 ng/ml at both mRNA and protein levels. OPN expression is known to be associated with chondrocyte and osteoblast differentiation and osteoclast activation. Unexpectedly, FGF9 induced OPN was accompanied by inhibition of differentiation and increased proliferation of the treated chondrocytes. Moreover, FGF9 stimulated OPN expression irrespective of the differentiation stage of the cells or culture conditions. In situ hybridization analysis of epiphyseal growth plates from chicken or mice homozygous for the Achondroplasia, G369C/mFGFR3 mutation demonstrated co-localization of OPN expression and osteoclast activity, as evidenced by tartarate resistant acid phosphatase positive cells in the osteochondral junction. We propose that FGF signaling directly activates OPN expression independent of chondrocytes differentiation. This may enhance the recruitment and activation of osteoclasts, and increase in cartilage resorption and remodeling in the chondro-osseus border.
Weizmann
S
S
Institute of Animal Science, the Volcani Center, Bet Dagan 50250, Israel.
Tong
A
A
Reich
A
A
Genina
O
O
Yayon
A
A
Monsonego-Ornan
E
E
D000130:Achondroplasia / Q000235:genetics / Q000378:metabolism; D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D002645:Chickens; D019902:Chondrocytes / Q000187:drug effects* / Q000378:metabolism; D005109:Extracellular Matrix / Q000378:metabolism; D051525:Fibroblast Growth Factor 9 / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects; D005998:Glycine / Q000235:genetics / Q000378:metabolism; D006132:Growth Plate / Q000166:cytology* / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D009154:Mutation / Q000235:genetics; D010012:Osteogenesis / Q000187:drug effects*; D053495:Osteopontin; D051381:Rats; D051498:Receptor, Fibroblast Growth Factor, Type 3 / Q000235:genetics / Q000378:metabolism; D012795:Sialoglycoproteins / Q000378:metabolism*; D015854:Up-Regulation / Q000187:drug effects*
D051525:Fibroblast Growth Factor 9; C506895:SPP1 protein, human; D012795:Sialoglycoproteins; C506896:Spp1 protein, mouse; C506897:Spp1 protein, rat; D053495:Osteopontin; D051498:Receptor, Fibroblast Growth Factor, Type 3; D005998:Glycine