2011 Fiscal Year Final Research Report
The elucidation of the between PTH and COX-2 in bone reconstruction
| Project/Area Number |
21592513
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Surgical dentistry
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| Research Institution | Tokyo Medical University (2011)
The University of Tokyo (2009-2010) |
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Principal Investigator |
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| Project Period (FY) |
2009 – 2011
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| Keywords | PTH / COX-2 |
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| Research Abstract |
Murine MC3T3-E1 and MC-4 cells were stably transfected with-371/+70 bp of the murine cyclooxygenase-2(COX-2) promoter fused to a luciferase reporter(Pluc371) or with Pluc371 carrying site-directed mutations. Mutations were made in(1) the cAMP response element(CRE) at-57/-52 bp,(2) the activating protein-1(AP-1)-binding site at-69/-63 bp,(3) the nuclear factor of activated T-cells(NFAT)-binding site at-77/-73 bp, and(4) both the AP-1 and NFAT sites, which comprise a composite consensus sequence for NFAT/AP-1.Single mutation of CRE, AP-1, or NFAT sites decreased parathyroid hormone(PTH)-stimulated COX-2 promoter activity 40% to 60%, whereas joint mutation of NFAT and AP-1 abrogated the induction. On electrophoretic mobility shift analysis, PTH stimulated binding of phosphorylated CREB to an oligonucleotide spanning the CRE and binding of NFATc1, c-Fos, and c-Jun to an oligonucleotide spanning the NFAT/AP-1 composite site. Mutation of the NFAT site was less effective than mutation of the AP-1 site in competing binding to the composite element, suggesting that cooperative interactions of NFATc1 and AP-1 are more dependent on NFAT than on AP-1.Both PTH and forskolin, an activator of adenylyl cyclase, stimulated NFATc1 nuclear translocation. PTH-and forskolin-stimulated COX-2 promoter activity was inhibited 56% to 80% by calcium chelation or calcineurin inhibitors and 60% to 98% by protein kinase A(PKA) inhibitors. These results indicate an important role for the calcium-calcineurin-NFAT signaling pathway in the PTH induction of COX-2 and suggest that cross-talk between the cAMP/PKA pathway and the calcium-calcineurin-NFAT pathway may play a role in other functions of PTH in osteoblasts.
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