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J. Biol. Chem., Vol. 278, Issue 36, 34018-34025, September 5, 2003
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Mechanical Strain Differentially Regulates Endothelial Nitric-oxide Synthase and Receptor Activator of Nuclear 
B Ligand Expression via ERK1/2 MAPK*
From the Department of Medicine, Veterans Affairs Medical Center and Emory University School of Medicine, Atlanta, Georgia 30033
Exercise promotes positive bone remodeling through controlling cellular
processes in bone. Nitric oxide (NO), generated from endothelial nitric-oxide
synthase (eNOS), prevents resorption, whereas receptor activator of nuclear
B ligand (RANKL) promotes resorption through regulating osteoclast
activity. Here we show that mechanical strain differentially regulates eNOS
and RANKL expression from osteoprogenitor stromal cells in a
magnitude-dependent fashion. Strain (0.25–2%) induction of eNOS
expression was magnitude-dependent, reaching a plateau at 218 ± 36% of
control eNOS. This was accompanied by increases in eNOS protein and a doubling
of NO production. Concurrently, 0.25% strain inhibited RANKL expression with
increasing response up to 1% strain (44 ± 3% of control RANKL). These
differential responses to mechanical input were blocked when an ERK1/2
inhibitor was present during strain application. Inhibition of NO generation
did not prevent strain-activated ERK1/2. To confirm the role of ERK1/2, cells
were treated with an adenovirus encoding a constitutively activated MEK;
Ad.caMEK significantly increased eNOS expression and NO production by more
than 4-fold and decreased RANKL expression by half. In contrast, inhibition of
strain-activated c-Jun kinase failed to prevent strain effects on either eNOS
or RANKL. Our data suggest that physiologic levels of mechanical strain
utilize ERK1/2 kinase to coordinately regulate eNOS and RANKL in a manner
leading to positive bone remodeling.
Received for publication, March 19, 2003 , and in revised form, May 30, 2003.
* This work was supported by NIAMS, National Institutes of Health, Grant AR42360 and Merit and Research Enhancement Award Program grants from the Veterans Administration. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
To whom correspondence should be addressed: VAMC-151, 1670 Clairmont Rd.,
Decatur, GA 30033. Tel.: 404-321-6111 (ext. 2080); Fax: 404-235-3011; E-mail:
jrubi02{at}emory.edu.
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