Signaling pathways implicated in androgen regulation of endocortical bone.
Signaling pathways implicated in androgen regulation of endocortical bone.
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DOI：
10.1016/j.bone.2009.10.039
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发表时间：
2010-03
期刊：
影响因子：
4.1
通讯作者：
Zhang, Xiao-Wei
中科院分区：
文献类型：
--
作者：
Wiren, Kristine M.;Semirale, Anthony A.;Hashimoto, Joel G.;Zhang, Xiao-Wei
骨膜扩张是骨骼发育过程中和严重性腺功能减退的成年人对雄激素暴露的公认反应。然而，雄激素也会抑制皮质内骨形成，表明它对骨的影响是二分的和包膜特异性的。事实上，在两种不同的骨骼靶向雄激素受体（AR）过表达的转基因模型中，增强的雄激素信号传导已被证明对整个骨骼的生物力学特性具有显着的不利影响。由于这种反应的机制尚不清楚，我们比较了来自 AR 过表达转基因雄性小鼠及其野生型对应物的无骨膜皮质骨样品中的基因表达模式。然后我们评估了原代培养中野生型和 AR 过表达成骨细胞的直接雄激素效应。在与骨形成相关的主要信号通路中，基于定量 RT-PCR (qPCR) 阵列对野生型与转基因雄性的皮质内骨基因表达进行集中分析，发现转化生长因子-β (TGF-β) 超家族和骨形态发生蛋白 (BMP) 信号在体内受到雄激素的显着改变。生物信息分析表明增殖、成骨细胞分化和矿化是受影响的主要生物过程。与体内阵列数据和生物信息学分析一致，通过对 AR 过表达培养物进行外源 BMP2 处理以刺激 BMP 信号传导，可以减少雄激素暴露对分化的抑制，从而证实了阵列通路分析。此外，不可芳香化的二氢睾酮 (DHT) 抑制成骨细胞增殖、分化和一些矿化指标，包括野生型和 AR 转基因小鼠原代培养物中的矿物质积累和矿化结节形成。这些发现确定了基于 BMP 信号改变的分子机制，该信号有助于雄激素抑制成骨细胞分化和矿化。雄激素对成骨细胞功能的这种有害影响可能是雄激素治疗普遍令人失望的结果的原因。
Periosteal expansion is a recognized response to androgen exposure during bone development and in profoundly hypogonadal adults. However, androgen also suppresses endocortical bone formation, indicating that its effects on bone are dichotomous and envelope-specific. In fact, enhanced androgen signaling has been shown to have dramatic detrimental effects on whole bone biomechanical properties in two different transgenic models with skeletally-targeted androgen receptor (AR) overexpression. As the mechanisms underlying this response are uncharacterized, we compared patterns of gene expression in periosteum-free cortical bone samples derived from AR-overexpressing transgenic male mice and their wild-type counterparts. We then assessed direct androgen effects in both wild-type and AR-overexpressing osteoblasts in primary culture. Among major signaling pathways associated with bone formation, focused quantitative RT-PCR (qPCR) array-based analysis of endocortical bone gene expression from wild-type vs. transgenic males identified the transforming growth factor-beta (TGF-β) superfamily and bone morphogenetic protein (BMP) signaling as significantly altered by androgen in vivo. Bioinformatic analyses indicated proliferation, osteoblast differentiation and mineralization as major biological processes affected. Consistent with the in vivo array data and bioinformatic analyses, inhibition of differentiation observed with androgen exposure was reduced by exogenous BMP2 treatment of AR-overexpressing cultures to stimulate BMP signaling, confirming array pathway analysis. In addition, nonaromatizable dihydrotestosterone (DHT) inhibited osteoblast proliferation, differentiation and several indices of mineralization, including mineral accumulation and mineralized nodule formation in primary cultures from both wild-type and AR-transgenic mice. These findings identify a molecular mechanism based on altered BMP signaling that contributes to androgen inhibition of osteoblast differentiation and mineralization. Such detrimental effects of androgen on osteoblast function may underlie the generally disappointing results of androgen therapy.
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