Unknown

Dataset Information

0

Type II cGMP-dependent protein kinase mediates osteoblast mechanotransduction.


ABSTRACT: 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/DeltafosB 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/DeltafosB play a key role in the osteoblast anabolic response to mechanical stimulation.

SUBMITTER: Rangaswami H 

PROVIDER: S-EPMC2685661 | biostudies-literature | 2009 May

REPOSITORIES: biostudies-literature

altmetric image

Publications

Type II cGMP-dependent protein kinase mediates osteoblast mechanotransduction.

Rangaswami Hema H   Marathe Nisha N   Zhuang Shunhui S   Chen Yongchang Y   Yeh Jiunn-Chern JC   Frangos John A JA   Boss Gerry R GR   Pilz Renate B RB  

The Journal of biological chemistry 20090311 22


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/DeltafosB mRNAs; these  ...[more]

Similar Datasets

| S-EPMC2749497 | biostudies-literature
| S-EPMC2780805 | biostudies-literature
| S-EPMC9305209 | biostudies-literature
| S-EPMC4786703 | biostudies-literature
| S-EPMC3928552 | biostudies-literature
| S-EPMC4367287 | biostudies-literature
| S-EPMC4703045 | biostudies-literature
| S-EPMC9234760 | biostudies-literature
| S-EPMC6082575 | biostudies-literature
| S-EPMC2423867 | biostudies-literature