Cyclic GMP-dependent protein kinase II plays a critical role in C-type natriuretic peptide-mediated endochondral ossification

Takashi Miyazawa, Yoshihiro Ogawa, Hideki Chusho, Akihiro Yasoda, Naohisa Tamura, Yasato Komatsu, Alexander Pfeifer, Franz Hofmann, Kazuwa Nakao

Research output: Contribution to journalArticle

86 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)3604-3610
Number of pages7
JournalEndocrinology
Volume143
Issue number9
DOIs
Publication statusPublished - Sep 1 2002
Externally publishedYes

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C-Type Natriuretic Peptide
Cyclic GMP-Dependent Protein Kinases
Osteogenesis
Growth Plate
Cyclic GMP
Bone Development
Cyclic GMP-Dependent Protein Kinase Type II
Dwarfism
Natriuretic Peptides
Cyclic Nucleotides
Phosphoric Diester Hydrolases
Chondrocytes
Tibia
Ion Channels
Hypertrophy
Cartilage
Histology
Spine
Hormones
Bone and Bones

All Science Journal Classification (ASJC) codes

  • Endocrinology

Cite this

Cyclic GMP-dependent protein kinase II plays a critical role in C-type natriuretic peptide-mediated endochondral ossification. / Miyazawa, Takashi; Ogawa, Yoshihiro; Chusho, Hideki; Yasoda, Akihiro; Tamura, Naohisa; Komatsu, Yasato; Pfeifer, Alexander; Hofmann, Franz; Nakao, Kazuwa.

In: Endocrinology, Vol. 143, No. 9, 01.09.2002, p. 3604-3610.

Research output: Contribution to journalArticle

Miyazawa, T, Ogawa, Y, Chusho, H, Yasoda, A, Tamura, N, Komatsu, Y, Pfeifer, A, Hofmann, F & Nakao, K 2002, 'Cyclic GMP-dependent protein kinase II plays a critical role in C-type natriuretic peptide-mediated endochondral ossification', Endocrinology, vol. 143, no. 9, pp. 3604-3610. https://doi.org/10.1210/en.2002-220307
Miyazawa, Takashi ; Ogawa, Yoshihiro ; Chusho, Hideki ; Yasoda, Akihiro ; Tamura, Naohisa ; Komatsu, Yasato ; Pfeifer, Alexander ; Hofmann, Franz ; Nakao, Kazuwa. / Cyclic GMP-dependent protein kinase II plays a critical role in C-type natriuretic peptide-mediated endochondral ossification. In: Endocrinology. 2002 ; Vol. 143, No. 9. pp. 3604-3610.
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