Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA.
Bone. 2011 May 1;48(5):1117-26. doi: 10.1016/j.bone.2011.01.007. Epub 2011 Jan 19.
Histone deacetylase (Hdac) inhibitors are used clinically to treat cancer and epilepsy. Although Hdac inhibition accelerates osteoblast maturation and suppresses osteoclast maturation in vitro, the effects of Hdac inhibitors on the skeleton are not understood. The purpose of this study was to determine how the pan-Hdac inhibitor, suberoylanilide hydroxamic acid (SAHA; a.k.a. vorinostat or Zolinza(TM)) affects bone mass and remodeling in vivo. Male C57BL/6J mice received daily SAHA (100mg/kg) or vehicle injections for 3 to 4weeks. SAHA decreased trabecular bone volume fraction and trabecular number in the distal femur. Cortical bone at the femoral midshaft was not affected. SAHA reduced serum levels of P1NP, a bone formation marker, and also suppressed tibial mRNA levels of type I collagen, osteocalcin and osteopontin, but did not alter Runx2 or osterix transcripts. SAHA decreased histological measures of osteoblast number but interestingly increased indices of osteoblast activity including mineral apposition rate and bone formation rate. Neither serum (TRAcP 5b) nor histological markers of bone resorption were affected by SAHA. P1NP levels returned to baseline in animals which were allowed to recover for 4weeks after 4weeks of daily SAHA injections, but bone density remained low. In vitro, SAHA suppressed osteogenic colony formation, decreased osteoblastic gene expression, induced cell cycle arrest, and caused DNA damage in bone marrow-derived adherent cells. Collectively, these data demonstrate that bone loss following treatment with SAHA is primarily due to a reduction in osteoblast number. Moreover, these decreases in osteoblast number can be attributed to the deleterious effects of SAHA on immature osteoblasts, even while mature osteoblasts are resistant to the harmful effects and demonstrate increased activity in vivo, indicating that the response of osteoblasts to SAHA is dependent upon their differentiation state. These studies suggest that clinical use of SAHA and other Hdac inhibitors to treat cancer, epilepsy or other conditions may potentially compromise skeletal structure and function.
组蛋白去乙酰化酶（Hdac）抑制剂临床上用于治疗癌症和癫痫。尽管 Hdac 抑制在体外加速成骨细胞成熟并抑制破骨细胞成熟，但 Hdac 抑制剂对骨骼的影响尚不清楚。本研究旨在确定泛 Hdac 抑制剂，琥珀酰亚胺基羟肟酸（SAHA；又名 vorinostat 或 Zolinza(TM)）如何影响体内骨量和重塑。雄性 C57BL/6J 小鼠每天接受 SAHA（100mg/kg）或载体注射 3 至 4 周。SAHA 降低了远端股骨的小梁骨体积分数和小梁数量。股骨中段皮质骨不受影响。SAHA 降低了血清骨形成标志物 P1NP 的水平，同时还抑制了胫骨Ⅰ型胶原、骨钙素和骨桥蛋白的 mRNA 水平，但不改变 Runx2 或osterix 转录物。SAHA 减少了成骨细胞数量的组织学测量，但有趣的是增加了成骨细胞活性的指标，包括矿化沉积率和骨形成率。SAHA 既不影响血清（TRAcP 5b）也不影响骨吸收的组织学标志物。在接受 4 周每日 SAHA 注射后允许恢复 4 周的动物中，P1NP 水平恢复到基线，但骨密度仍然较低。在体外，SAHA 抑制成骨细胞集落形成，降低成骨细胞基因表达，诱导细胞周期停滞，并在骨髓源性贴壁细胞中引起 DNA 损伤。总的来说，这些数据表明，SAHA 治疗后的骨丢失主要是由于成骨细胞数量减少。此外，成骨细胞数量的减少可以归因于 SAHA 对不成熟成骨细胞的有害影响，即使成熟成骨细胞对有害影响具有抗性并表现出体内活性增加，这表明成骨细胞对 SAHA 的反应取决于其分化状态。这些研究表明，临床使用 SAHA 和其他 Hdac 抑制剂治疗癌症、癫痫或其他疾病可能潜在地损害骨骼结构和功能。
