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J Biol Chem, Vol. 275, Issue 2, 999-1006, January 14, 2000
From the Endocrine Division, Lilly Research Laboratories,
Indianapolis, Indiana 46285
Osteocalcin is a major noncollagenous protein
component of bone extracellular matrix, synthesized and secreted
exclusively by osteoblastic cells in the late stage of maturation, and
is considered indicator of osteoblast differentiation. Osteocalcin expression is modulated by parathyroid hormone (PTH) and a variety of
other factors. The cAMP-dependent protein kinase pathway
has been shown previously to have an essential role in PTH signaling and regulation of osteocalcin expression. To determine the extent to
which other pathways may also participate in osteocalcin expression, we
used rat and human osteoblast-like cell lines to generate stably transfected clones in which the osteocalcin promoter was fused to a
luciferase reporter gene. These clones were examined for their
responsiveness to agents known to activate or interfere with protein
kinase A (PKA)- and protein kinase C (PKC)-dependent pathways. We have found that forskolin, cAMP, and PTH, as well as
insulin-like growth factor I (IGF-I) and basic fibroblast growth factor, all were effective in activating the osteocalcin promoter. Phorbol 12-myristate 13-acetate (PMA) was also a strong inducer of the
promoter, indicating that PKC plays a role in expression of
osteocalcin. In combination with PTH or forskolin, the effect of PMA
was additive to synergistic. Calphostin C, a selective inhibitor of
PKC, decreased the PMA-, PTH-, and IGF-I-induced luciferase activity in
a dose-dependent manner; a PKA inhibitor, H-89, also
blocked the induction by PTH and IGF-I but not by PMA. We conclude that
regulation of osteocalcin transcription is mediated by both
PKA-dependent and PKC-dependent mechanisms and
that the respective kinases reside on a linear or convergent pathway.
Activation of Osteocalcin Transcription Involves Interaction of
Protein Kinase A- and Protein Kinase C-dependent
Pathways*
*
The costs of publication of this
article were defrayed in part by the
payment of page charges. The 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: Endocrine Research,
Lilly Research Laboratories, Corporate Center, Eli Lilly and Company,
Indianapolis, IN 46285. Tel.: 317-276-6929; E-mail:
Chandra@lilly.com.
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