Molecular basis for the treatment of achondroplasia.
Achondroplasia (ACH), the most common form of short-limbed dwarfism, and its related disorders are caused by constitutively activated point-mutated fibroblast growth factor receptor 3 (FGFR3). Recent studies have provided a large body of evidence to prove chondrocyte proliferation and differentiation in these disorders. However, little is known about the possible effects of the FGFR3 mutants on apoptosis of chondrocytes. In the present study, we analyzed apoptosis using a chondrogenic cell line, ATDC5, expressing the FGFR3 mutants causing ACH and thanatophoric dysplasia, which is a more severe neonatal lethal form comprising type I and type II. We found that the introduction of these mutated FGFR3s into ATDC5 cells decreased mRNA expression of parathyroid hormone-related peptide (PTHrP) and induced apoptosis. Importantly, replacement of PTHrP prevented the apoptotic changes in ATDC5 cells expressing ACH mutant. Insulin-like growth factor (IGF)-I, which is an important mediator of growth hormone (GH), also reduced apoptosis in ATDC5 cells expressing ACH mutant. IGF-I prevented apoptosis through the phosphatidylinositol 3-kinase and mitogen-activated protein kinase pathways, indicating the mechanisms by which GH treatment improves disturbed bone growth in ACH.
Yamanaka
Yoshitaka
Y
Department of Pediatrics, Okayama University Graduate School of Medicine and Dentistry, Okayama, Japan. yamanaka@cc.okayama-u.ac.jp
Ueda
Koso
K
Seino
Yoshiki
Y
Tanaka
Hiroyuki
H
D000130:Achondroplasia / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D002460:Cell Line; D019902:Chondrocytes / Q000166:cytology / Q000378:metabolism; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology; D020935:MAP Kinase Signaling System / Q000187:drug effects; D051379:Mice; D009154:Mutation; D044162:Parathyroid Hormone-Related Protein / Q000378:metabolism / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000235:genetics* / Q000378:metabolism*; D051498:Receptor, Fibroblast Growth Factor, Type 3; D017468:Receptors, Fibroblast Growth Factor / Q000235:genetics* / Q000378:metabolism*
D044162:Parathyroid Hormone-Related Protein; D017468:Receptors, Fibroblast Growth Factor; D007334:Insulin-Like Growth Factor I; D019869:Phosphatidylinositol 3-Kinases; C496365:FGFR3 protein, human; C496366:Fgfr3 protein, mouse; D011505:Protein-Tyrosine Kinases; D051498:Receptor, Fibroblast Growth Factor, Type 3