Sjögren Klara, Lagerquist Marie, Moverare-Skrtic Sofia, Andersson Niklas, Windahl Sara H, Swanson Charlotte, Mohan Subburaman, Poutanen Matti, Ohlsson Claes
Center for Bone Research, Institute of Medicine, University of Gothenburg, Sahlgrenska Academy, Göteborg, Sweden.
J Bone Miner Res. 2009 Jul;24(7):1263-70. doi: 10.1359/jbmr.090208.
The stimulatory effects of testosterone (T) on bone can either be through a direct activation of the androgen receptor (AR) or mediated through aromatization of T to estradiol (E2), followed by activation of estrogen receptors (ERs) in bone. Aromatase expression in osteoblasts and reproductive tissues is dependent on different promoters, which are differentially regulated. To study the effect of elevated local aromatization of T to E2 in bone, we developed a transgenic mouse model (Coll-1alpha1-Arom) that overexpresses the human aromatase gene under the control of the osteoblast specific rat type I alpha I procollagen promoter. The Coll-1alpha1-Arom mice expressed human aromatase mRNA specifically in bone and had unaffected serum E2 and T levels. Male Coll-1alpha1-Arom mice had clearly increased total body BMD, trabecular BMD, cortical BMD, and cortical thickness associated with elevated osteoprotegerin mRNA levels and reduced number of osteoclasts (p < 0.01). Treatment of ovariectomized mice with T increased cortical and trabecular thickness in the Coll-1alpha1-Arom mice (p < 0.001) but not in the wildtype mice. In conclusion, elevated aromatase expression specifically in osteoblasts results in stimulatory estrogenic effects in bone without increasing serum E2 levels. Because osteoblast-specific aromatase expression results in an increased ER to AR activation ratio in bone, we propose that activation of ERs results in a more pronounced increase in bone mass than what is seen after activation of the AR. Development of osteoblast-specific inducers of aromatase expression might identify substances with stimulatory effects on bone without systemic adverse effects.
睾酮（T）对骨骼的刺激作用既可以通过直接激活雄激素受体（AR）来实现，也可以通过T芳香化转化为雌二醇（E2），随后激活骨骼中的雌激素受体（ERs）来介导。成骨细胞和生殖组织中的芳香化酶表达依赖于不同的启动子，这些启动子受到不同的调控。为了研究骨骼中T向E2局部芳香化增加的影响，我们构建了一种转基因小鼠模型（Coll-1alpha1-Arom），该模型在成骨细胞特异性大鼠I型α1前胶原启动子的控制下过表达人芳香化酶基因。Coll-1alpha1-Arom小鼠在骨骼中特异性表达人芳香化酶mRNA，血清E2和T水平未受影响。雄性Coll-1alpha1-Arom小鼠的全身骨密度、小梁骨密度、皮质骨密度和皮质厚度明显增加，同时骨保护素mRNA水平升高，破骨细胞数量减少（p < 0.01）。用T治疗去卵巢小鼠可增加Coll-1alpha1-Arom小鼠的皮质和小梁厚度（p < 0.001），但对野生型小鼠无此作用。总之，成骨细胞中芳香化酶表达的增加会在不增加血清E2水平的情况下对骨骼产生雌激素刺激作用。由于成骨细胞特异性芳香化酶表达导致骨骼中ER与AR激活比率增加，我们推测ER激活导致的骨量增加比AR激活后更为显著。开发成骨细胞特异性芳香化酶表达诱导剂可能会找到对骨骼有刺激作用且无全身不良反应的物质。
