| Autor: |
Chikazu, Daichi, Li, Xiaodong, Kawaguchi, Hiroshi, Sakuma, Yoko, Voznesensky, Olga S., Adams, Douglas J., Xu, Manshan, Hoshi, Kazuto, Katavić, Vedran, Herschman, Harvey R., Raisz, Lawrence G., Pilbeam, Carol C. |
| Jazyk: |
angličtina |
| Rok vydání: |
2002 |
| Předmět: |
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| Popis: |
We tested the hypothesis that induction of cyclooxygenase (COX)-2 mediates some effects of bone morphogenetic protein-2 (BMP-2) on bone. BMP-2 induced COX-2 mRNA and prostaglandin production in cultured osteoblasts. BMP-2 increased luciferase activity in calvarial osteoblasts from mice transgenic for a COX-2 promoter-luciferase reporter construct (Pluc) and in MC3T3-E1 cells transfected with Pluc. Deletion analysis identified the -300 to -213 bp region of the COX-2 promoter as necessary for BMP-2 stimulation of luciferase activity. Mutation of a Cbfa1 consensus sequence (5’ ; -AACCACA-3’ ; ) at -267/-261 bp decreased BMP-2 stimulation of luciferase activity by 82%. Binding of nuclear proteins to an oligonucleotide spanning the Cbfa1 site was inhibited or supershifted by specific antibodies to Cbfa1. In cultured osteoblasts from calvariae of COX-2 knockout (-/-) and wild type (+/+) mice, the absence of COX-2 expression reduced the BMP-2 stimulation of both alkaline phosphatase activity and osteocalcin mRNA expression. In cultured marrow cells flushed from long bones, BMP-2 induced osteoclast formation in cells from COX-2+/+ mice but not in cells from COX-2-/- mice. In vivo, BMP-2 (10 microg/pellet) induced mineralization in pellets of lyophilized collagen implanted in the flanks of mice. Mineralization of pellets, measured by microCT, was decreased by 78% in COX-2-/- mice compared to COX-2+/+ mice. We conclude that BMP-2 transcriptionally induces COX-2 in osteoblasts via a Cbfa1 binding site and that the BMP-2 induction of COX-2 can contribute to effects of BMP-2 on osteoblastic differentiation and osteoclast formation in vitro and to the BMP-2 stimulation of ectopic bone formation in vivo. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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