Cyclic GMP-dependent protein kinase II plays a critical role in C-type natriuretic peptide-mediated endochondral ossification.
Longitudinal bone growth is determined by endochondral ossification at the growth plate, which is located at both ends of long bones and vertebrae, and involves many systemic hormones and local regulators. C-type natriuretic peptide (CNP), a third member of the natriuretic peptide family, occurs at the growth plate and acts locally as a positive regulator of endochondral ossification through the intracellular accumulation of cyclic GMP (cGMP). The increase in cGMP concentrations is known to activate different signaling mediators, such as cyclic nucleotide phosphodiesterases, cGMP-regulated ion channels, and cGMP-dependent protein kinases (cGKs). The type II cGK (cGKII)-deficient mice (Prkg2(-/-) mice) develop dwarfism as a result of impaired endochondral ossification, suggesting that cGKII is important for the CNP-mediated endochondral ossification. However, given that Prkg2(-/-) mice differ from CNP-deficient mice (Nppc(-/-) mice) in the growth plate histology, which downstream mediator(s) of cGMP play key roles in the process is still an enigma. Here we show that targeted expression of CNP in the growth plate chondrocytes fails to rescue the skeletal defect of Prkg2(-/-) mice. Using cultured fetal mouse tibias, an in vitro model system of endochondral ossification, we also demonstrated that CNP cannot increase the longitudinal bone growth, and chondrocytic proliferation and hypertrophy, and cartilage matrix synthesis in Prkg2(-/-) mice. This study provides in vivo and in vitro genetic evidence that cGKII plays a critical role in CNP-mediated endochondral ossification.
Department of Medicine and Clinical Science, Kyoto University Graduate School of Medicine, Sakyo-ku, Kyoto 606-8507, Japan.
Takashi
T
Miyazawa
Yoshihiro
Y
Ogawa
Hideki
H
Chusho
Akihiro
A
Yasoda
Naohisa
N
Tamura
Yasato
Y
Komatsu
Alexander
A
Pfeifer
Franz
F
Hofmann
Kazuwa
K
Nakao
D000818:Animals; D000831:Animals, Newborn; D001846:Bone Development; D001842:Bone and Bones / Q000737:chemistry / Q000473:pathology; D002455:Cell Division; D019902:Chondrocytes / Q000378:metabolism / Q000473:pathology; D024121:Collagen Type X / Q000032:analysis; D006152:Cyclic GMP / Q000032:analysis / Q000378:metabolism; D062967:Cyclic GMP-Dependent Protein Kinase Type II; D017869:Cyclic GMP-Dependent Protein Kinases / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D004392:Dwarfism / Q000235:genetics / Q000473:pathology; D005260:Female; D006132:Growth Plate / Q000473:pathology / Q000502:physiology*; D007150:Immunohistochemistry; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D020098:Natriuretic Peptide, C-Type / Q000235:genetics / Q000502:physiology*; D009924:Organ Culture Techniques; D010012:Osteogenesis / Q000502:physiology*; D013977:Tibia / Q000196:embryology
D024121:Collagen Type X; D020098:Natriuretic Peptide, C-Type; D062967:Cyclic GMP-Dependent Protein Kinase Type II; D017869:Cyclic GMP-Dependent Protein Kinases; C569730:Prkg2 protein, mouse; D006152:Cyclic GMP