The effect of risedronate on osteogenic lineage is mediated by cyclooxygenase-2 gene upregulation.
BACKGROUND
The purpose of this study was to evaluate the effects of risedronate (Ris) in the modulation of bone formation in rats with glucocorticoid (GC)-induced osteoporosis by histomorphometric, immunohistochemical and gene expression analyses.


METHODS
We analyzed structure, turnover and microarchitecture, cyclooxygenase 2 (COX-2) levels and osteocyte apoptosis in 40 female rats divided as follows: 1) vehicle of methylprednisolone (vGC) + vehicle of risedronate (vRis); 2) Ris 5 μg/Kg + vGC; 3) methylprednisolone (GC) 7 mg/Kg + vRis; 4) GC 7 mg/Kg +Ris 5 μg/Kg. In addition, we evaluated cell proliferation and expression of COX-2 and bone alkaline phosphatase (b-ALP) genes in bone marrow cells and MLO-y4 osteocytes treated with Ris alone or in co-treatment with the selective COX-2 inhibitor NS-398 or with dexametasone.


RESULTS
Ris reduced apoptosis induced by GC of osteocytes (41% vs 86%, P < 0.0001) and increased COX-2 expression with respect to controls (Immuno-Hystochemical Score (IHS): 8.75 vs 1.00, P < 0.0001). These positive effects of Ris in bone formation were confirmed by in vitro data as the viability and expression of b-ALP gene in bone marrow cells resulted increased in a dose dependent manner.


CONCLUSIONS
These findings suggest a positive effect of Ris in bone formation and support the hypothesis that the up-regulation of COX-2 could be an additional mechanism of anabolic effect of Ris.
Valenti
Maria Teresa
MT
Department of Medicine, University of Verona Piazzale L, Scuro, Verona, Italy. mariateresa.valenti@univr.it
Giannini
Sandro
S
Donatelli
Luca
L
Zanatta
Mirko
M
Bertoldo
Francesco
F
Sella
Stefania
S
Vilei
Maria Teresa
MT
Ossi
Elena
E
Realdi
Giuseppe
G
Lo Cascio
Vincenzo
V
Dalle Carbonare
Luca
L
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D050071:Bone Density Conservation Agents / Q000494:pharmacology*; D001854:Bone Marrow Cells / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D002460:Cell Line / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D051546:Cyclooxygenase 2 / Q000235:genetics*; D012968:Etidronic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D005938:Glucocorticoids / Q000494:pharmacology; D010011:Osteocytes / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology; D010012:Osteogenesis / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D000068296:Risedronic Acid; D015854:Up-Regulation / Q000187:drug effects
D050071:Bone Density Conservation Agents; D005938:Glucocorticoids; D051546:Cyclooxygenase 2; D000068296:Risedronic Acid; D012968:Etidronic Acid