Elucidation of molecular mechanism of endochondral ossification targeting novel therapeutic strategy for skeletal dysplasia

• Project/Area Number: 17590959
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Endocrinology
• Research Institution: Kyoto University
• Principal Investigator: YASODA Akihiro Kyoto University, Graduate School of Medicine, assistant professor, 医学研究科, 助手 (50378642)
• Co-Investigator(Kenkyū-buntansha): KOMATSU Yasato Kyoto University, Graduate School of Medicine, part time lecturer, 医学研究科, 非常勤講師 (40322648)
• Project Period (FY): 2005 – 2006
• Project Status: Completed (Fiscal Year 2006)
• Budget Amount: ¥3,500,000 (Direct Cost: ¥3,500,000); Fiscal Year 2006: ¥1,300,000 (Direct Cost: ¥1,300,000); Fiscal Year 2005: ¥2,200,000 (Direct Cost: ¥2,200,000)
• Keywords: CNP-GC-B system / endochondral ossification / achondroplasia / FGF system / intracellular signaling

Research Abstract

Natriuretic peptide family consists of three endogenous ligands, ANP, BNP and CNP, and their membranous guanylyl cyclase receptors, GC-A and GC-B. We have shown that CNP-GC-B system is a strong stimulator of endochondral bone growth and that disturbed endochondral bone growth in mice model of achondroplastic with an activated FGFR3 in cartilage is greatly improved by activation of CNP-GC-B system. As for the mechanism, CNP/GC-B/cGMP restores the decreased cartilaginous matrix synthesis by inhibiting activation of MAPK pathway of FGF signaling.
In this project, further we investigated the intracellular signaling interaction between CNP-GC-B system and FGF system in cartilage. First we showed that FGF system stimulates both MAPK and STAT1 pathway and that CNP-GC-B system does not interfere to STAT1 pathway. We also showed that FGF signaling stimulates PI3/PKB pathway to which CNP-GC-B system interferes, and that PI3/PKB system is suppressed under the condition with heparin. On the other hand, activation of FGF pathway decreased the production of cGMP, the second messenger of CNP-GC-B system, dose-dependently. These results exhibit the reciprocal regulation of CNP-GC-B system and FGF system in cartilage.
Next we investigated local natriuretic peptide clearance system in cartilage by using fetal mice tibial organ culture system. Selective agonist for natriuretic peptide clearance receptor, C-ANF (4-23), elongated cultured fetal tibiae dose-dependently, and accordingly, we concluded that local natriuretic peptide clearance system works as one of the regulator of CNP-GC-B system in cartilage.

Research Products

• [Journal Article] High-dose glucocorticoid treatment induces rapid loss of trabecular bone mineral density and lean body mass. (2006)
  • Author(s): Natsui K, Tanaka K, Suda M, Yasoda A, Sakuma Y, Ozasa A, Ozaki S, Nakao K
  • Journal Title: Osteoporos Int. 17 Pages: 105-108
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Antithyroid drugs inhibit thyroid hormone receptor-mediated transcription. (2006)
  • Author(s): Moriyama K, Tagami T, Usui T, Naruse M, Nambu T, Hataya Y, Kanamoto N, Li YS, Yasoda A, Arai H, Nakao K
  • Journal Title: J Clin Endocrinol Metab. 92・3 Pages: 1066-1072
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] High-dose glucocorticoid treatment induces rapid loss of trabecular bone mineral density and lean body mass. (2006)
  • Author(s): Natsui K, Tanaka K, Suda M, Yasoda A, Sakuma Y, Ozasa A, Ozaki S, Nakao K.
  • Journal Title: Osteoporos Int. 17 Pages: 105-108
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Antithyroid drugs inhibit thyroid hormone receptor-mediated transcription. (2006)
  • Author(s): Moriyama K, Tagami T, Usui T, Naruse M, Nambu T, Hataya Y, Kanamoto N, Li YS, Yasoda A, Arai H, Nakao K.
  • Journal Title: J Clin Endocrinol Metab. 92 Pages: 1066-72
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Antithyroid drugs inhibit thyroid hormone receptor-mediated transcription. (2006)
  • Author(s): Moriyama K, Tagami T, Usui T, Naruse M, Nambu T, Hataya Y, Kanamoto N, Li YS, Yasoda A, Arai H, Nakao K.
  • Journal Title: J Clin Endocrinol Metab. 92・3 Pages: 1066-1072
• [Journal Article] Expression of the aderenomedullin gene in adipose tissue. (2005)
  • Author(s): Nambu T, Arai H, Komatsu Y, Yasoda A, Moriyama K, Kanamoto N, Itoh H, Nakao K
  • Journal Title: Regul Pept 132 Pages: 17-22
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Complementary antagonistic actions between C-Type natriuretic peptide and MAPK pathway through FGFR-3 in ATDC5 Cells. (2005)
  • Author(s): Ozasa A, Komatsu Y, Yasoda A, Miura M, Nakatsuru Y, Sakuma Y, Arai H, Itoh N, Nakao N
  • Journal Title: Bone 36 Pages: 1056-1064
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Complementary antagonistic actions between C-type natriuretic peptide and the MAPK pathway through FGFR-3 in ATDC5 cells. (2005)
  • Author(s): Ozasa, et al.
  • Journal Title: Bone 36・6 Pages: 1056-1064