Bone vs. fat: embryonic origin of progenitors determines response to androgen in adipocytes and osteoblasts.
Bone vs. fat: embryonic origin of progenitors determines response to androgen in adipocytes and osteoblasts.
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DOI：
10.1016/j.bone.2011.06.010
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发表时间：
2011-10
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.;Hashimoto, Joel G.;Semirale, Anthony A.;Zhang, Xiao-Wei
虽然雄激素被认为是一种合成代谢激素，但雄激素受体（AR）过表达的后果在经尿道靶向AR转基因品系中突出了增强的雄激素敏感性对皮质骨质量的不利影响。仅在雄性而非雌性AR 3.6转基因（tg）小鼠中观察到隔室特异性合成代谢反应，骨膜骨形成和颅骨增厚增加。为了鉴定具有增加骨形成潜力的合成代谢信号级联，采用qPCR阵列分析来确定AR 3.6-tg和野生型（WT）骨膜组织之间的表达差异。值得注意的是，两种基因型之间显著不同的类别包括轴突引导、CNS发育和Wnt信号传导的负调控，其中节点以干细胞途径为中心。此外，AR3.6-tg颅骨的精细映射显示，在体内合成代谢增厚在整个颅骨中是不均匀的，仅发生在额骨而不是顶骨。将来自两种基因型的多能部分1祖细胞群体分别培养为额骨神经嵴干细胞样细胞（fNCSC）和顶骨间充质干细胞样细胞（pMSC）。这些祖细胞群体的成骨细胞和成脂细胞分化受到胚胎谱系和基因型的影响。与pMSC相比，WT fNCSC中的脂肪生成增强，但转基因培养物仅在fNCSC细胞中显示出对脂质积累的强烈抑制。与WT相比，转基因fNCSC培养物中的成骨细胞生成显著增加，通过茜素红和von Kossa染色评估碱性磷酸酶（ALP）活性升高以及矿化和结节形成的诱导。与WT相比，来自AR 3.6-tg的fNCSC培养物中骨钙素（OC）和ALP mRNA水平也增加，但在AR 3.6-tg细胞中，pMSC培养物中ALP mRNA水平、矿化和结节形成减少。在fNCSC样品中重现了通过阵列在来自AR 3.6-tg与WT的长骨骨膜组织中鉴定的表达差异，而pMSC谱反映了皮质表达。这些观察结果揭示了雄激素信号传导对谱系定型和成骨细胞分化的相反作用，其在源自神经嵴起源的细胞中增强，但在源自中胚层起源的细胞中抑制，这与体内对雄激素的隔室特异性反应一致。结合起来，这些结果突出了雄激素在体内的复杂作用，这取决于胚胎谱系和细胞的发育起源。此外，这些数据表明，长骨周围的骨膜来源于神经嵴。
Although androgen is considered an anabolic hormone, the consequences of androgen receptor (AR) overexpression in skeletally-targeted AR-transgenic lines highlight the detrimental effect of enhanced androgen sensitivity on cortical bone quality. A compartment-specific anabolic response is observed only in male but not female AR3.6-transgenic (tg) mice, with increased periosteal bone formation and calvarial thickening. To identify anabolic signaling cascades that have the potential to increase bone formation, qPCR array analysis was employed to define expression differences between AR3.6-tg and wild-type (WT) periosteal tissue. Notably, categories that were significantly different between the two genotypes included axonal guidance, CNS development and negative regulation of Wnt signaling with a node centered on stem cell pathways. Further, fine mapping of AR3.6-tg calvaria revealed that anabolic thickening in vivo is not uniform across the calvaria, occurring only in frontal but not parietal bones. Multipotent fraction 1 progenitor populations from both genotypes were cultured separately as frontal bone neural crest stem-like cells (fNCSC) and parietal bone mesenchymal stem-like cells (pMSC). Both osteoblastic and adipogenic differentiation in these progenitor populations was influenced by embryonic lineage and by genotype. Adipogenesis was enhanced in WT fNCSC compared to pMSC, but transgenic cultures showed strong suppression of lipid accumulation only in fNCSC cells. Osteoblastogenesis was significantly increased in transgenic fNCSC cultures compared to WT, with elevated alkaline phosphatase (ALP) activity and induction of mineralization and nodule formation assessed by alizarin red and von Kossa staining. Osteocalcin (OC) and ALP mRNA levels were also increased in fNCSC cultures from AR3.6-tg vs. WT, but in pMSC cultures ALP mRNA levels, mineralization and nodule formation were decreased in AR3.6-tg cells. Expression differences identified by array in long bone periosteal tissue from AR3.6-tg vs. WT were recapitulated in the fNCSC samples while pMSCs profiles reflected cortical expression. These observations reveal the opposing effects of androgen signaling on lineage commitment and osteoblast differentiation that is enhanced in cells derived from a neural crest origin but inhibited in cells derived from a mesodermal origin, consistent with in vivo compartment-specific responses to androgen. Combined, these results highlight the complex action of androgen in the body that is dependent on the embryonic lineage and developmental origin of the cell. Further, these data these data suggest that the periosteum surrounding long bone is derived from neural crest.
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