title: PTH has the potential to rescue disturbed bone growth in achondroplasia.
abstract: BACKGROUND
  Achondroplasia (Ach), the most common form of short-limb short stature, and related disorders are caused by constitutively active point mutations in the fibroblast growth factor receptor 3 (FGFR3) gene. Recent studies have provided a large body of evidence for the role of the proliferation and differentiation of chondrocytes in these disorders. Furthermore, a G380R mutation in FGFR3 (FGFR3(Ach)), which results in achondroplasia, induces apoptosis in the chondrogenic cell line ATDC5. This is associated with a decrease in the expression of PTHrP, which shares the same receptor with PTH, and it is significant that PTHrP rescues these cells from apoptosis.
  
  
  METHODS
  Fetuses derived from transgenic mice expressing FGFR3(Ach) under the control of the type II collagen promoter (AchTG) or from wild-type mice were obtained on the 15th day of pregnancy. The femurs were collected from these specimens and cultured for 4 days with PTH. The effects of PTH treatment were then determined by morphometric and histological analyses, in situ hybridization of type X collagen mRNA, and the TUNEL assay.
  
  
  RESULTS
  AchTG femurs showed suppressed growth compared with wild type (0.29+/-0.10 mm vs. 0.46+/-0.06 mm, respectively; p<0.05), particularly in cartilage. PTH treatments improved the growth velocity in the femurs of the AchTG (0.50+/-0.06 mm; p<0.01 vs. control). This was associated with the inhibition of both differentiation and apoptosis in chondrocytes.
  
  
  CONCLUSIONS
  Our data suggest that PTH inhibits differentiation and apoptosis in chondrocytes and improves bone growth. These effects thus counterbalance the effects of FGFR3 mutations. PTH therefore is a potential therapeutic agent for achondroplasia.
authors.affiliation: Department of Pediatrics, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan. ueda-endo@umin.ac.jp
authors.forename: Koso
authors.initials: K
authors.lastname: Ueda
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Yamanaka
authors.forename: Daisuke
authors.initials: D
authors.lastname: Harada
authors.forename: Emi
authors.initials: E
authors.lastname: Yamagami
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Tanaka
authors.forename: Yoshiki
authors.initials: Y
authors.lastname: Seino
mesh_terms: D000130:Achondroplasia / Q000188:drug therapy* / Q000196:embryology / Q000235:genetics; D000818:Animals; D001846:Bone Development / Q000187:drug effects*; D024121:Collagen Type X / Q000235:genetics; D046149:Embryo Culture Techniques; D005260:Female; D005269:Femur / Q000187:drug effects / Q000196:embryology; D006801:Humans; D017403:In Situ Hybridization; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D017354:Point Mutation; D011247:Pregnancy; D012333:RNA, Messenger / Q000235:genetics; D051498:Receptor, Fibroblast Growth Factor, Type 3 / Q000235:genetics; D019379:Teriparatide / Q000494:pharmacology*
chemical_list: D024121:Collagen Type X; D012333:RNA, Messenger; D019379:Teriparatide; C496366:Fgfr3 protein, mouse; D051498:Receptor, Fibroblast Growth Factor, Type 3