Trichostatin A-mediated upregulation of p21(WAF1) contributes to osteoclast apoptosis.
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.
Yi
TacGhee
T
Department of Cell and Developmental Biology, Dental Research Institute and BK21 Program, School of Dentistry, Seoul National University, Seoul 110-749, Korea.
Baek
Jeong-Hwa
JH
Kim
Hye-Jin
HJ
Choi
Mi-Hye
MH
Seo
Sang-Beom
SB
Ryoo
Hyun-Mo
HM
Kim
Gwan-Shik
GS
Woo
Kyung Mi
KM
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D001862:Bone Resorption / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D051379:Mice; D010010:Osteoclasts / Q000166:cytology* / Q000187:drug effects*; D053245:RANK Ligand / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation / Q000187:drug effects*
D050759:Cyclin-Dependent Kinase Inhibitor p21; D006877:Hydroxamic Acids; D053245:RANK Ligand; D012333:RNA, Messenger; C012589:trichostatin A