S. Kellenberger et al., FORMOTEROL AND ISOPROTERENOL INDUCE C-FOS GENE-EXPRESSION IN OSTEOBLAST-LIKE CELLS BY ACTIVATING BETA(2)-ADRENERGIC RECEPTORS, Bone, 22(5), 1998, pp. 471-478
Formoterol, a beta(2)-adrenergic agonist has been shown in ovariectomi
zed rat models to have anabolic effects on bone. However, those studie
s did not determine whether the effect of formoterol was by a direct a
ction on bone cells themselves or indirectly via anabolic action on mu
scle. To address the question of whether formoterol could directly aff
ect osteoblast function we investigated the expression patterns of bet
a-adrenergic receptors (beta ARs) in human osteoblast-like cells and f
unctional coupling to gene expression. Northern blot analysis showed t
hat beta AR subtypes are expressed at different levels in the osteobla
st-like cell lines TE-85, SaOS-2, MG-63, and OHS-4, beta(1)AR expressi
on was found in SaOS-2, OHS-4, and TE-85, but not MG-63 cells. beta(2)
ARs are expressed at higher levels in MG-63 cells than in TE-85 and Sa
OS-2 cells, but were not detected in OHS-4 cells. PCR analysis paralle
led the northern blot analysis except that beta(3)AR expression was fo
und in one of three human primary osteoblast cDNAs tested. beta(3)AR e
xpression was not found in any of the osteoblast-like cell lines. The
nonspecific PAR agonist, isoproterenol, and the beta(2)AR-specific ago
nist, formoterol, induced c-fos gene expression in cultured SaOS-2 cel
ls in an immediate early fashion. This effect was inhibited by the bet
a(2)AR-specific antagonist, ICI 118551, but not by the beta(1)AR-speci
fic antagonist, CGP 20712, indicating that induction of c-fos gene exp
ression is specifically mediated by beta(2)ARs, c-fos gene expression
was induced by both isoproterenol and formoterol via increases in cAMP
, which in turn activated the cAMP/PKA pathway; the PKA inhibitor, H89
, inhibited c-fos gene expression, Thus, beta ARs are expressed, in os
teoblast-like cells and are coupled to c-fos gene expression via the b
eta(2)AR, increases in CAMP levels and activation of a PKA-dependent p
athway. (C) 1998 by Elsevier Science Inc. All rights reserved.