Departments of Orthopedic Surgery, Integrated Bone Metabolism and Immunology, and Musculoskeletal Reconstruction and Regeneration Surgery, Keio Kanrinmaru Project, and Department of Dentistry and Oral Surgery, School of Medicine, Keio University, Tokyo 160-8582, Japan.
Proc Natl Acad Sci U S A. 2013 Oct 8;110(41):16568-73. doi: 10.1073/pnas.1308755110. Epub 2013 Sep 10.
In women, estrogen deficiency after menopause frequently accelerates osteoclastic bone resorption, leading to osteoporosis, the most common skeletal disorder. However, mechanisms underlying osteoporosis resulting from estrogen deficiency remain largely unknown. Here we show that in bone-resorbing osteoclasts, estrogen-dependent destabilization of hypoxia-inducible factor 1 alpha (HIF1α), which is unstable in the presence of oxygen, plays a pivotal role in promoting bone loss in estrogen-deficient conditions. In vitro, HIF1α was destabilized by estrogen treatment even in hypoxic conditions, and estrogen loss in ovariectomized (Ovx) mice stabilized HIF1α in osteoclasts and promoted their activation and subsequent bone loss in vivo. Osteoclast-specific HIF1α inactivation antagonized bone loss in Ovx mice and osteoclast-specific estrogen receptor alpha deficient mice, both models of estrogen-deficient osteoporosis. Oral administration of a HIF1α inhibitor protected Ovx mice from osteoclast activation and bone loss. Thus, HIF1α represents a promising therapeutic target in osteoporosis.
在女性中，绝经后雌激素缺乏常常加速破骨细胞的骨吸收，导致骨质疏松症，这是最常见的骨骼疾病。然而，雌激素缺乏导致骨质疏松症的机制在很大程度上仍不清楚。在这里，我们表明在破骨细胞中，雌激素依赖性缺氧诱导因子 1α（HIF1α）的不稳定性在缺氧条件下起着关键作用，促进了雌激素缺乏条件下的骨丢失。在体外，即使在缺氧条件下，雌激素处理也会使 HIF1α失稳，而卵巢切除（Ovx）小鼠中的雌激素丧失会稳定破骨细胞中的 HIF1α，并促进其激活以及随后的体内骨丢失。破骨细胞特异性 HIF1α失活拮抗了 Ovx 小鼠和破骨细胞特异性雌激素受体α缺乏小鼠的骨丢失，这两种模型都是雌激素缺乏性骨质疏松症。HIF1α 抑制剂的口服给药可防止 Ovx 小鼠的破骨细胞激活和骨丢失。因此，HIF1α 是骨质疏松症的一个有前途的治疗靶点。
