Cyclic GMP-dependent protein kinase II is a molecular switch from proliferation to hypertrophic differentiation of chondrocytes

Chikuda, Hirotaka; Kugimiya, Fumitaka; Hoshi, Kazuto; Ikeda, Toshiyuki; Ogasawara, Toru; Shimoaka, Takashi; Kawano, Hirotaka; Kamekura, Satoru; Tsuchida, Atsuko; Yokoi, Norihide; Nakamura, Kozo; Komeda, Kajuro; Chung, Ung‐il; Kawaguchi, Hiroshi

doi:10.1101/gad.1224204

Cited by 123 publications

(112 citation statements)

References 37 publications

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“…One modification is phosphorylation by cGMP-dependent protein kinase II (cGKII), which prevents Sox9 from entering the nucleus (Chikuda et al, 2004). The Komeda miniature rat Ishikawa has a naturally occurring mutation in CGKII, revealing the importance of its function.…”

Section: Sox9 Is a Master Regulator Of Cartilage Developmentmentioning

confidence: 99%

Back to basics: Sox genes

Kiefer

2007

Developmental Dynamics

196

157

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Sox genes are indispensable for multiple aspects of development. This primer briefly describes shared properties of the Sox gene family, and five well-characterized examples of vertebrate developmental mechanisms governed by Sox gene subgroups: testis development, central nervous system neurogenesis, oligodendrocyte development, chondrogenesis, and neural crest cell development. Also featured is an interview about current issues in the field with experts

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Section: Sox9 Is a Master Regulator Of Cartilage Developmentmentioning

confidence: 99%

Back to basics: Sox genes

Kiefer

2007

Developmental Dynamics

196

157

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“…Evidence from gene-knockout studies shows that bone formation and resorption are regulated by nitric oxide (NO): mice deficient in endothelial NO synthase (eNOS) or cyclic guanosine 3Ј,5Ј-monophosphate (cGMP)-dependent protein kinase (PKG) show bone abnormalities (Aguirre et al, 2001;Chae et al, 1997;Chikuda et al, 2004;Miyazawa et al, 2002;Otsuka et al, 1998;Talts et al, 1998) and inducible NO synthase (iNOS)-null mice show imbalances in bone osteogenenis (van't Hof et al, 2000). However, the mechanisms through which NO influences osteogenesis remain unclear.…”

Section: Introductionmentioning

confidence: 99%

Cbfa-1 mediates nitric oxide regulation of MMP-13 in osteoblasts

Zaragoza

López-Rivera

García-Rama

et al. 2006

Journal of Cell Science

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During bone development, osteoblast differentiation requires remodeling of the extracellular matrix. Although underlying mechanisms have not been elucidated, evidence points to the participation of the nitric oxide (NO) and cyclic guanosine 3′,5′-monophosphate (cGMP) system. Here, we detected increased matrix metalloproteinase (MMP)-13 mRNA, protein and activity, as well as increased inducible NO synthase (iNOS) and NO production during the differentiation of MC3T3-E1 osteoblasts. Transcriptional activity of the MMP-13 promoter was augmented by NO, 8-bromo-cGMP (8-Br-cGMP), and by a dominant-positive form of protein kinase G (PKG1-α). The stimulatory effect on the MMP-13 promoter was partially inhibited by mutation of the osteoblast-specific element 2 (OSE-2) binding site. Core binding factor-1 (Cbfa-1) expression peaked at 7 days of differentiation, and was phosphorylated by PKG in vitro. Cbfa-1 was localized to cell nuclei, and its translocation was inhibited by the iNOS inhibitor 1400W. Immunohistological examination revealed that MMP-13 and Cbfa-1 expression levels are both reduced in 17-day-old embryos of iNOS-deficient mice. Silencing of Cbfa-1 mRNA blocked MMP-13 expression without interfering with endogenous NO production, confirming its role in NO-induced MMP-13 expression by MC3T3-E1 cells. The results described here suggest a mechanism by which NO regulates osteogenesis.

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“…In addition to growth retardation resulting from cGKII deficiency in mice, our previous positional cloning analysis identified a deletion in Prkg2, the rat gene encoding cGKII, in the Komeda miniature rat Ishikawa (KMI), a naturally occurring mutant rat, which also exhibited dwarfism with 20%-30% shorter long bones and vertebrae (9). The deletion resulted in a frame shift and a premature stop codon, predicting a truncated cGKII protein that lacks the kinase domain (cGKII-Δkinase).…”

Section: Introductionmentioning

confidence: 99%

Phosphorylation of GSK-3β by cGMP-dependent protein kinase II promotes hypertrophic differentiation of murine chondrocytes

Kawasaki

Kugimiya²,

Chikuda³

et al. 2008

J. Clin. Invest.

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cGMP-dependent protein kinase II (cGKII; encoded by PRKG2) is a serine/threonine kinase that is critical for skeletal growth in mammals; in mice, cGKII deficiency results in dwarfism. Using radiographic analysis, we determined that this growth defect was a consequence of an elongated growth plate and impaired chondrocyte hypertrophy. To investigate the mechanism of cGKII-mediated chondrocyte hypertrophy, we performed a kinase substrate array and identified glycogen synthase kinase-3β (GSK-3β; encoded by Gsk3b) as a principal phosphorylation target of cGKII. In cultured mouse chondrocytes, phosphorylation-mediated inhibition of GSK-3β was associated with enhanced hypertrophic differentiation. Furthermore, cGKII induction of chondrocyte hypertrophy was suppressed by cotransfection with a phosphorylation-deficient mutant of GSK-3β. Analyses of mice with compound deficiencies in both protein kinases (Prkg2 -/-Gsk3b +/-) demonstrated that the growth retardation and elongated growth plate associated with cGKII deficiency were partially rescued by haploinsufficiency of Gsk3b. We found that β-catenin levels decreased in Prkg2 -/-mice, while overexpression of cGKII increased the accumulation and transactivation function of β-catenin in mouse chondroprogenitor ATDC5 cells. This effect was blocked by coexpression of phosphorylation-deficient GSK-3β. These data indicate that hypertrophic differentiation of growth plate chondrocytes during skeletal growth is promoted by phosphorylation and inactivation of GSK-3β by cGKII.

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Cyclic GMP-dependent protein kinase II is a molecular switch from proliferation to hypertrophic differentiation of chondrocytes

Cited by 123 publications

References 37 publications

Back to basics: Sox genes

Back to basics: Sox genes

Cbfa-1 mediates nitric oxide regulation of MMP-13 in osteoblasts

Phosphorylation of GSK-3β by cGMP-dependent protein kinase II promotes hypertrophic differentiation of murine chondrocytes

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