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Vol. 54, Issue 1, 70-77, July 1998
Department of Bone Biology and Osteoporosis Research, Merck
Research Laboratories, WP26A-1000, West Point, Pennsylvania 19486
Prostaglandin E stimulates bone formation in humans and animals, and
increases intracellular cAMP in osteoblastic cells. We found that cAMP
inhibits apoptosis in osteoblastic cells, and examined the mechanism of
this effect. We report that the cAMP elevating agent, forskolin,
increases cell number in the rat periosteal cell line (RP-11), by
suppressing apoptosis in a cell type-specific manner. In RP-11,
forskolin transiently up-regulates extracellular signal-regulated
kinase activity, a known suppressor of apoptosis. PD98059, a selective
inhibitor of the extracellular signal-regulated kinase pathway, only
partially reverses the antiapoptotic effect of forskolin, which
suggests an additional mechanism for cAMP action. We found that
forskolin stimulates cytosolic sphingosine kinase (SPK) activity in
these cells; in two other osteoblastic cell lines, however, forskolin
does not suppress apoptosis. In contrast to the partial opposing effect
of PD98059 to forskolin action,
N,N-dimethylsphingosine, a specific
inhibitor of SPK, completely reverses the antiapoptotic effect of
forskolin, and has no effect on apoptosis in the absence of forskolin.
These findings show for the first time that cAMP activates SPK in a cell-type-specific manner, and suggest that cAMP suppression of apoptosis in RP-11 periosteal cells is mediated by its stimulation of
SPK.
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