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

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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.