Exp Mol Med.  2007 Apr;39(2):213-221.

Trichostatin A-mediated upregulation of p21

• Yi T
• Baek JH
• Kim HJ
• Choi MH
• Seo SB
• Ryoo HM
• Kim GS
• Woo KM

Abstract

Histone deacetylase inhibitors (HDIs), a new class of anti-cancer agents, have been reported to suppress formation of osteoclast precursors and their fusion into multinucleated cells. However, little is known about the effect of HDIs on mature osteoclasts, which may have significance for their therapeutic use. Here, we demonstrate a novel action of HDIs on osteoclast apoptosis. Primary multinucleated mature osteoclasts were prepared from mouse bone marrow cells. Treatment of osteoclasts with the HDI trichostatin A (TSA) caused apoptosis, as confirmed by annexin V staining and caspase activation. TSA caused the upregulation of p21WAF1 in osteoclasts. To understand the role of p21(WAF1) upregulation in TSA-treated osteoclasts, shRNA against p21(WAF1)-containing lentivirus was introduced into osteoclasts. The suppression of p21(WAF1) decreased TSA-directed osteoclast apoptosis. Collectively, our results provide evidence that TSA causes osteoclast apoptosis, which involves, in part, TSA-induced upregulation of p21(WAF1), and strongly supports HDIs as potential therapeutic agents for excessive bone resorption.

Keyword

apoptosis; CDKN1A protein, mouse; cyclin-dependent kinase inhibitor p21; histone deacetylases; osteoclasts; RNA interference; trichostatin A

MeSH Terms

Animals
Apoptosis/*drug effects
Bone Resorption/metabolism
Cyclin-Dependent Kinase Inhibitor p21/deficiency/*genetics/metabolism
Female
Gene Expression Regulation/drug effects
Humans
Hydroxamic Acids/*pharmacology
Mice
Osteoclasts/*cytology/*drug effects
RANK Ligand/pharmacology
RNA, Messenger/genetics/metabolism
Up-Regulation/*drug effects