Functional analyses of TRPS1 in bone morphogenesis

2003 Fiscal Year Final Research Report Summary

• Project/Area Number: 14570199
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Experimental pathology
• Research Institution: Wakayama Medical University
• Principal Investigator: MURAGAKI Yasuteru Wakayama Medical University, Dept of Pathology, Associate Professor, 医学部, 助教授 (40190904)
• Project Period (FY): 2002 – 2003
• Keywords: TRPS1 / knockout mouse / cartilage / cell proliferation / apoptosis

Research Abstract

Tricho-rhino-phalangeal syndromes (TRPSs) are human inherited skeletal disorders and its responsible gene, TRPS1, was cloned by positional cloning. TRPS1 is thought to be a transcriptional repressor with 9 zinc-finger domains including a GATA DNA binding domain and a C-terminus Ikaros-like zinc finger domain. To investigate the pathophysiological function of Trps1, we generated the Trps1-deficient mice by gene targeting. Homozygote mutant mice die soon after birth due to respiratory failure. The long bones in the limbs are shorter than in wild-type mice. However, the length of the epiphyseal cartilage is longer in Trps1-deficient mice as compared to wild-type mice. Histological examination of the mutant growth plate showed that the length of proliferation, prehypertrophic, and hyperti-ophic chondrocyte zones is extended and the shape of chondrocytes is abnormal. BrdU incorporation into chondrocytes was significantly decreased in mutant epiphyseal cartilage. Also, the number of apoptotic hypertrophic chondrocytes was dramatically decreased as detected by a TUNEL method. In in situ hybridization, the localization of Trps1 mRNA in E14.5 limbs has been found to be very much overlapped with that of Gdf5 mRNA. Since Gdf5-/-mice have joint fusion in the digit, we examined the phalangeal joints of Trps1-deficient mice. Interestingly, phalanges are still fused with interzone cells in E18.5 mutant mice, while the joint spaces are completely formed in wild-type mice. A TUNEL staining demonstrated that virtually no positive cells are detected in E15.5 mutant interzone, while some positive cells are seen in wild-type mice, suggesting that Trps1 is closely associated with apoptosis of interzone cells in phalangeal joint formation. Altogether, we concluded that Trps1 regulates proliferation and apoptosis of chondrocytes.

Research Products

• [Publications] Sato, M., Muragaki, Y., Saika, S., Roberts, A.B., Ooshima, A.: "Targeted disruption of TGF-β1/Smad3 signaling protects against renal tubulointerstitial fibrosis induced by unilateral obstruction."Journal of Clinical Investigation. 112. 1486-1494 (2003)
  • Description: 「研究成果報告書概要(和文)」より
• [Publications] Saika, S., Kono-Saika, S., Sato, M., Muragaki Y., et al.: "Smad3 signaling is required for epithelial-mesenchymal transition of lens epithelium after injury."American Journal of Pathology. 164. 651-663 (2004)
  • Description: 「研究成果報告書概要(和文)」より
• [Publications] Sato, M., Muragaki, Y., Saika, S., Roberts, A.B., Ooshima, A.: "Targeted disruption of TGF-b1/Smad3 signaling protects against renal tubulointerstitial fibrosis induced by unilateral uret-eral obstruction"J Clin Invest. 112. 1486-1494 (2003)
  • Description: 「研究成果報告書概要(欧文)」より
• [Publications] Kanauchi, Y., Muragaki Y., Ogino T., Takahara, M., Tsuchida, H., Ishigaki, D.: "FGFR2 mutation in a patient with Apert syndrome associated with humeroradial synostosis"Cong Anom. 43. 302-305 (2003)
  • Description: 「研究成果報告書概要(欧文)」より
• [Publications] Saika, S., Kono-Saika, S., Ohnishi, Y., Sato, M., Muragaki, Y., Ooshima, A., Flanders, K.C., Yoo, J., Anzano, M., Liu, C., Kao, W.W.-Y., Roberts, A.B.: "Smad3 signaling is required for epithelial-mesenchymal transition of lens epithelium after injury"Am J Pathol. 164. 651-663 (2004)
  • Description: 「研究成果報告書概要(欧文)」より