Centre for Bone and Arthritis Research, Institute of Medicine, University of Gothenburg, Sahlgrenska Academy, Göteborg, Sweden.
J Bone Miner Res. 2010 Dec;25(12):2690-700. doi: 10.1002/jbmr.156. Epub 2010 Jun 18.
Estrogens enhance skeletal growth during early sexual maturation, whereas high estradiol levels during late puberty result in growth plate fusion in humans. Although the growth plates do not fuse directly after sexual maturation in rodents, a reduction in growth plate height is seen by treatment with a high dose of estradiol. It is unknown whether the effects of estrogens on skeletal growth are mediated directly via estrogen receptors (ERs) in growth plate cartilage and/or indirectly via other mechanisms such as the growth hormone/insulin-like growth factor 1 (GH/IGF-1) axis. To determine the role of ERα in growth plate cartilage for skeletal growth, we developed a mouse model with cartilage-specific inactivation of ERα. Although mice with total ERα inactivation displayed affected longitudinal bone growth associated with alterations in the GH/IGF-1 axis, the skeletal growth was normal during sexual maturation in mice with cartilage-specific ERα inactivation. High-dose estradiol treatment of adult mice reduced the growth plate height as a consequence of attenuated proliferation of growth plate chondrocytes in control mice but not in cartilage-specific ERα(-/-) mice. Adult cartilage-specific ERα(-/-) mice continued to grow after 4 months of age, whereas growth was limited in control mice, resulting in increased femur length in 1-year-old cartilage-specific ERα(-/-) mice compared with control mice. We conclude that during early sexual maturation, ERα in growth plate cartilage is not important for skeletal growth. In contrast, it is essential for high-dose estradiol to reduce the growth plate height in adult mice and for reduction of longitudinal bone growth in elderly mice.
雌激素在性成熟早期促进骨骼生长，而青春期后期高雌二醇水平会导致人类生长板融合。尽管在啮齿动物中，性成熟后生长板不会直接融合，但用高剂量雌二醇处理会导致生长板高度降低。目前尚不清楚雌激素对骨骼生长的影响是通过生长板软骨中的雌激素受体（ER）直接介导的，还是通过其他机制间接介导的，例如生长激素/胰岛素样生长因子 1（GH/IGF-1）轴。为了确定 ERα 在生长板软骨中对骨骼生长的作用，我们开发了一种软骨特异性 ERα 失活的小鼠模型。尽管完全失活 ERα 的小鼠表现出与 GH/IGF-1 轴改变相关的纵向骨生长受影响，但在软骨特异性 ERα 失活的小鼠中，性成熟期间骨骼生长正常。大剂量雌二醇处理成年小鼠会降低生长板高度，这是由于对照小鼠中生长板软骨细胞增殖减弱所致，但在软骨特异性 ERα(-/-)小鼠中则不然。成年软骨特异性 ERα(-/-)小鼠在 4 个月后仍继续生长，而对照小鼠的生长受到限制，导致 1 岁时软骨特异性 ERα(-/-)小鼠的股骨长度比对照小鼠增加。我们得出结论，在性成熟早期，生长板软骨中的 ERα 对骨骼生长不重要。相比之下，ERα 在成年小鼠中降低生长板高度和老年小鼠中减少纵向骨生长至关重要。
