Low nitric oxide concentrations inhibit osteoclast formation in
mouse marrow cultures by a cgmp-dependent mechanism.
Holliday, L. Shannon, Alan D. Dean, Royana H. Lin, James E. Greenwald,
and Stephen L. Gluck.
Departments of Internal Medicine and Cell Biology and Physiology,
and the George M. O'Brien Center for Kidney and Urological Diseases,
Washington University School of Medicine, St. Louis, MO 63110
APStracts 3:0208F, 1996.
High concentrations of nitric oxide (NO) inhibit bone resorption by
mature osteoclasts. We examined the effects of low NO concentrations
on osteoclast formation in mouse bone marrow cultures. The NO
-releasers sodium nitroprusside (SNP) and S-nitroso-N-acetyl-D,L
-penicillamine (SNAP) inhibited the formation of multinucleated cells
expressing tartrate-resistant acid phosphatase (TRAP, a marker for
osteoclasts) when administered during the last three days of six day
cultures (differentiation stage), but not during the first three days
(proliferation stage). 1 [mu]M SNP completely inhibited pit formation
on dentine wafers when added to cultures during osteoclast formation,
but 100 [mu]M was required to inhibit pitting by mature osteoclasts.
Conversely, the nitric oxide synthase inhibitors aminoguanidine and
N-nitro-L-arginine (NAME) both increased osteoclast formation.
Inhibition of osteoclast formation by NO likely was cGMP-dependent,
as SNP increased cGMP in marrow cultures, and 1 mM 8-bromo or
dibutyryl cGMP reduced osteoclast formation when administered during
the differentiation stage. The cGMP-specific type V phosphodiesterase
inhibitor zaprinast (M&B 22948) also inhibited osteoclast
formation (IC50 =100 [mu]M) only when added during the
differentiation stage. We conclude that the differentiation stage of
osteoclast formation is inhibited by increases in cGMP-levels
elicited by NO.
Received 15 March 1996; accepted in final form 8 November 1996.
APS Manuscript Number F87-6.
Article publication pending Am. J. Physiol. (Renal Fluid Electrolyte
Physiology).
ISSN 1080-4757 Copyright 1996 The American Physiological Society.
Published in APStracts on 31 December 1996