It is uncertain whether
adenosine 3',5'-cyclic monophosphate (cAMP) or the
inositol-
calcium pathway mediates the stimulation of
bone resorption by
parathyroid hormone (PTH). Incubation of bone organ cultures with cAMP analogues and
forskolin has not resolved this question because of the cellular inhomogeneity of bone and the consequent presence of
adenylate cyclase-linked receptors for both PTH and
calcitonin,
hormones with opposite effects on
bone resorption. We have used two new inhibitors of
adenylate cyclase, 9-(tetrahydro-2-furyl)adenine (
SQ 22536) and
2',5'-dideoxyadenosine (
DDA), to directly reassess the role of cAMP in PTH-stimulated
osteolysis.
SQ 22536 (0.01-1.0 mM) and
DDA (0.01-1.0 mM) completely blocked PTH stimulation of cAMP production measured in the absence of a
phosphodiesterase blocker. In the presence of 1 mM
3-isobutyl-1-methylxanthine, half-maximal inhibition of PTH-induced cAMP production occurred with 0.2 mM SQ and 0.1 mM
DDA, respectively. These concentrations of SQ and
DDA had no effect on PTH-stimulated 45Ca release from calvaria, although both agents inhibited
bone resorption when present at concentrations of 1-2 mM. At these levels, SQ and
DDA caused equivalent inhibition of 45Ca release stimulated by
1,25-dihydroxyvitamin D3 but did not affect basal 45Ca release or [3H]-
phenylalanine incorporation. It is concluded that substantial blockade of PTH-induced cAMP production does not affect this
hormone's stimulation of
bone resorption, which is therefore likely to be mediated by another intracellular messenger system, possibly
calcium. In millimolar concentrations, SQ and
DDA appear to be nonspecific blockers of osteoclastic
bone resorption.