Cyclooxygenase-2 inhibitor reduces simvastatin-induced bone morphogenetic protein-2 and bone formation in vivo.
OBJECTIVE
Simvastatin, a cholesterol-lowering drug, also stimulates oral bone growth when applied topically, without systemic side-effects. However, the mechanisms involved in vivo are not known. We hypothesized that bone morphogenetic protein-2, nitric oxide synthase, and cyclooxygenase-2 are involved, based on prior in vitro evidence.


METHODS
A rat bilateral mandible model, where 0.5 mg of simvastatin in methylcellulose gel was placed on one side and gel alone on the other, was used to quantify nitric oxide, cyclooxygenase-2 and bone morphogenetic protein-2 (via tissue extraction, enzyme activity or immunoassay), and to analyze the bone formation rate (via undecalcified histomorphometry). Cyclooxygenase-2 and nitric oxide synthase inhibitors (NS-398 and L-NAME, respectively) were administered intraperitoneally.


RESULTS
Simvastatin was found to stimulate local bone morphogenetic protein-2, nitric oxide and the regional bone formation rate (p < 0.05), whereas NS-398 inhibited bone morphogenetic protein-2 and reduced the bone formation rate (p < 0.05).


CONCLUSIONS
These data suggest an association between simvastatin-induced bone morphogenetic protein-2 and bone formation in the mandibular microenvironment, and the negative effect of cyclooxygenase-2 inhibitors on bone growth.
Bradley
J D
JD
Department of Surgical Specialties and Oral Biology, University of Nebraska Medical Center College of Dentistry, Lincoln, NE 68583-0740, USA.
Cleverly
D G
DG
Burns
A M
AM
Helm
N B
NB
Schmid
M J
MJ
Marx
D B
DB
Cullen
D M
DM
Reinhardt
R A
RA
D000818:Animals; D000924:Anticholesteremic Agents / Q000494:pharmacology*; D019485:Bone Morphogenetic Proteins / Q000187:drug effects / Q000378:metabolism*; D051546:Cyclooxygenase 2 / Q000187:drug effects / Q000378:metabolism; D052246:Cyclooxygenase 2 Inhibitors / Q000009:adverse effects*; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000009:adverse effects; D019331:NG-Nitroarginine Methyl Ester / Q000008:administration & dosage / Q000009:adverse effects; D019001:Nitric Oxide Synthase / Q000032:analysis / Q000187:drug effects; D009578:Nitrobenzenes / Q000008:administration & dosage / Q000009:adverse effects; D010012:Osteogenesis / Q000187:drug effects*; D051381:Rats; D019821:Simvastatin / Q000494:pharmacology*; D013449:Sulfonamides / Q000008:administration & dosage / Q000009:adverse effects
D000924:Anticholesteremic Agents; D019485:Bone Morphogenetic Proteins; D052246:Cyclooxygenase 2 Inhibitors; D004791:Enzyme Inhibitors; D009578:Nitrobenzenes; D013449:Sulfonamides; C080955:N-(2-cyclohexyloxy-4-nitrophenyl)methanesulfonamide; D019821:Simvastatin; D019001:Nitric Oxide Synthase; D051546:Cyclooxygenase 2; D019331:NG-Nitroarginine Methyl Ester