Yi TacGhee, Baek Jeong-Hwa, Kim Hye-Jin, Choi Mi-Hye, Seo Sang-Beom, Ryoo Hyun-Mo, Kim Gwan-Shik, Woo Kyung Mi
Department of Cell and Developmental Biology, Dental Research Institute and BK21 Program, School of Dentistry, Seoul National University, Seoul 110-749, Korea.
Exp Mol Med. 2007 Apr 30;39(2):213-21. doi: 10.1038/emm.2007.24.
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.
组蛋白去乙酰化酶抑制剂（HDIs）是一类新型抗癌药物，据报道可抑制破骨细胞前体的形成及其融合为多核细胞。然而，关于HDIs对成熟破骨细胞的影响知之甚少，而这可能对其治疗用途具有重要意义。在此，我们展示了HDIs对破骨细胞凋亡的一种新作用。从小鼠骨髓细胞制备原代多核成熟破骨细胞。用HDIs曲古抑菌素A（TSA）处理破骨细胞会导致凋亡，这通过膜联蛋白V染色和半胱天冬酶激活得以证实。TSA导致破骨细胞中p21WAF1上调。为了解p21（WAF1）上调在TSA处理的破骨细胞中的作用，将针对含p21（WAF1）的慢病毒的短发夹RNA（shRNA）导入破骨细胞。p21（WAF1）的抑制减少了TSA诱导的破骨细胞凋亡。总体而言，我们的结果提供了证据表明TSA导致破骨细胞凋亡，这部分涉及TSA诱导的p21（WAF1）上调，并有力支持HDIs作为过度骨吸收的潜在治疗药物。
