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Toxicology. 2009 Apr 28;258(2-3):148-56. doi: 10.1016/j.tox.2009.01.016. Epub 2009 Jan 22.

Anti-inflammatory drugs suppress proliferation and induce apoptosis through altering expressions of cell cycle regulators and pro-apoptotic factors in cultured human osteoblasts.

Author information

1
Department of Orthopaedics, Kaohsiung Medical University, Kaohsiung, Taiwan.

Abstract

It has been reported that anti-inflammatory drugs (AIDs) inhibited bone repair in animal studies, and suppressed proliferation and induced cell death in rat osteoblast cultures. In this study, we further investigated the molecular mechanisms of AID effects on proliferation and cell death in human osteoblasts (hOBs). We examined the effects of dexamethasone (10(-7) and 10(-6)M), non-selective non-steroidal anti-inflammatory drugs (NSAIDs): indomethacin, ketorolac, piroxicam and diclofenac (10(-5) and 10(-4)M), and COX-2 inhibitor: celecoxib (10(-6) and 10(-5)M) on proliferation, cytotoxicity, cell death, and mRNA and protein levels of cell cycle and apoptosis-related regulators in hOBs. All the tested AIDs significantly inhibited proliferation and arrested cell cycle at G0/G1 phase in hOBs. Celecoxib and dexamethasone, but not non-selective NSAIDs, were found to have cytotoxic effects on hOB, and further demonstrated to induce apoptosis and necrosis (at higher concentration) in hOBs. We further found that indomethacin, celecoxib and dexamethasone increased the mRNA and protein expressions of p27(kip1) and decreased those of cyclin D2 and p-cdk2 in hOBs. Bak expression was increased by celecoxib and dexamethasone, while Bcl-XL level was declined only by dexamethasone. Furthermore, the replenishment of PGE1, PGE2 or PGF2alpha did not reverse the effects of AIDs on proliferation and expressions of p27(kip1) and cyclin D2 in hOBs. We conclude that the changes in expressions of regulators of cell cycle (p27(kip1) and cyclin D2) and/or apoptosis (Bak and Bcl-XL) by AIDs may contribute to AIDs caused proliferation suppression and apoptosis in hOBs. This effect might not relate to the blockage of prostaglandin synthesis by AIDs.

PMID:
19428934
DOI:
10.1016/j.tox.2009.01.016
[Indexed for MEDLINE]

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