The Journal of biological chemistry, 2009-05, Vol.284 (22), p.14796-14808
2009
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Details
- Autor(en) / Beteiligte
- Titel
- Type II cGMP-dependent Protein Kinase Mediates Osteoblast Mechanotransduction
- Ist Teil von
- The Journal of biological chemistry, 2009-05, Vol.284 (22), p.14796-14808
- Ort / Verlag
- United States: Elsevier Inc
- Erscheinungsjahr
- 2009
- Quelle
- Free E-Journal (出版社公開部分のみ）
- Beschreibungen/Notizen
- Continuous bone remodeling in response to mechanical loading is critical for skeletal integrity, and interstitial fluid flow is an important stimulus for osteoblast/osteocyte growth and differentiation. However, the biochemical signals mediating osteoblast anabolic responses to mechanical stimulation are incompletely understood. In primary human osteoblasts and murine MC3T3-E1 cells, we found that fluid shear stress induced rapid expression of c-fos, fra-1, fra-2, and fosB/ΔfosB mRNAs; these genes encode transcriptional regulators that maintain skeletal integrity. Fluid shear stress increased osteoblast nitric oxide (NO) synthesis, leading to activation of cGMP-dependent protein kinase (PKG). Pharmacological inhibition of the NO/cGMP/PKG signaling pathway blocked shear-induced expression of all four fos family genes. Induction of these genes required signaling through MEK/Erk, and Erk activation was NO/cGMP/PKG-dependent. Treating cells with a membrane-permeable cGMP analog partly mimicked the effects of fluid shear stress on Erk activity and fos family gene expression. In cells transfected with small interfering RNAs (siRNA) specific for membrane-bound PKG II, shear- and cGMP-induced Erk activation and fos family gene expression was nearly abolished and could be restored by transducing cells with a virus encoding an siRNA-resistant form of PKG II; in contrast, siRNA-mediated repression of the more abundant cytosolic PKG I isoform was without effect. Thus, we report a novel function for PKG II in osteoblast mechanotransduction, and we propose a model whereby NO/cGMP/PKG II-mediated Erk activation and induction of c-fos, fra-1, fra-2, and fosB/ΔfosB play a key role in the osteoblast anabolic response to mechanical stimulation.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 0021-9258eISSN: 1083-351XDOI: 10.1074/jbc.M806486200Titel-ID: cdi_proquest_miscellaneous_21089362
- Format
- –
- Schlagworte
- Animals, Calcium - metabolism, Cell Adhesion Molecules - metabolism, Cell Line, Cyclic GMP - biosynthesis, Cyclic GMP - pharmacology, Cyclic GMP-Dependent Protein Kinases - metabolism, Enzyme Activation - drug effects, Extracellular Signal-Regulated MAP Kinases - metabolism, Gene Expression Regulation - drug effects, Humans, Mechanotransduction, Cellular - drug effects, Mice, Microfilament Proteins - metabolism, Mitogen-Activated Protein Kinase 1 - metabolism, Molecular Mimicry - drug effects, Nitric Oxide - biosynthesis, Nitric Oxide Synthase Type III - metabolism, Osteoblasts - cytology, Osteoblasts - drug effects, Osteoblasts - enzymology, Phosphoproteins - metabolism, Phosphorylation - drug effects, Rheology, RNA, Messenger - genetics, RNA, Messenger - metabolism, Signal Transduction - drug effects, Stress, Mechanical