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¥3,100,000 (Direct Cost: ¥3,100,000)
Fiscal Year 2003: ¥1,000,000 (Direct Cost: ¥1,000,000)
Fiscal Year 2002: ¥800,000 (Direct Cost: ¥800,000)
Fiscal Year 2001: ¥1,300,000 (Direct Cost: ¥1,300,000)
Achondroplasia and chondrodysplaisa, both of which are congenital deformities, are caused by constitutively-active forms of FGFR3 and PTH/PTHrP receptor, respectively. We have attempted to clarify which of FGFR3 and PTHrP show predominant function on chondrocyte differentiation. Furthermore, PTHrP has a nucleolar targeting signal in the internal region., without mediating the common receptor with PTH. Thus, we examined the biological action of PTHrPand FGFR3 in cartilage development.
(1)The 18-day-old fetus with null mutation of FGFR3/PTHrP genes revealed shorted limbs, consistent with the abnormalities of the PTHrP^<-/-> fetuses. The FGFR3^<-/->/PTHrP^<-/-> compound mutant fetuses showed reduced numbers of epiphyseal chondrocytes and a form of chondrodysplasia, which are characteristic features of the PTHrP^<-/-> fetus. Therefore, PTHrP appeared to function predominantly to FGFR3, or to lie down-stream of PTHrP on chondrocyte proliferation. However, the numbers of apoptotic chondrocytes were significantly reduced in FGFR3^<-/->/PTHrP^<-/-> fetuses, compared with that of PTHrP^<-/-> fetus. In addition, the FGFR3^<-/-> and the compound fetuses revealed the markedly reduced expression of VEGF in the hypertrophic zone, whereas the PTHrP deficient fetus displayed the abundant mRNA of VEGF in the matched region. Thus, FGFR3 appears to act functionally in the upstream to PTHrP signaling on proliferating chondrocytes, as well as to act independently on hypertrophic chondrocytes.
(2)The majority of the biological activity of PTHrP is mediated through the binding to the common receptor with PTH. However, PTHrP shows a nucleolar targeting signal in the internal region. Chondrocytic cell line transfected with truncated forms of PTHrP cDNA showed this peptide in the nucleoli mediated by translation initiating from AUG-codon and alternatively initiating from CUG codons.