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首页> 美国卫生研究院文献>Molecular and Cellular Biology >High Bone Resorption in Adult Aging Transgenic Mice Overexpressing Cbfa1/Runx2 in Cells of the Osteoblastic Lineage
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High Bone Resorption in Adult Aging Transgenic Mice Overexpressing Cbfa1/Runx2 in Cells of the Osteoblastic Lineage

机译：成骨转基因细胞中过表达Cbfa1 / Runx2的成年衰老转基因小鼠的高骨吸收

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The runt family transcription factor core-binding factor α1 (Cbfa1) is essential for bone formation during development. Surprisingly, transgenic mice overexpressing Cbfa1 under the control of the 2.3-kb collagen type I promoter developed severe osteopenia that increased progressively with age and presented multiple fractures. Analysis of skeletally mature transgenic mice showed that osteoblast maturation was affected and that specifically in cortical bone, bone resorption as well as bone formation was increased, inducing high bone turnover rates and a decreased degree of mineralization. To understand the origin of the increased bone resorption, we developed bone marrow stromal cell cultures and reciprocal coculture of primary osteoblasts and spleen cells from wild-type or transgenic mice. We showed that transgenic cells of the osteoblastic lineage induced an increased number of tartrate-resistant acid phosphatase-positive multinucleated cells, suggesting that primary osteoblasts as well as bone marrow stromal cells from transgenic mice have stronger osteoclastogenic properties than cells derived from wild-type animals. We investigated the candidate genes whose altered expression could trigger this increase in bone resorption, and we found that the expression of receptor activator of NF-κB ligand (RANKL) and collagenase 3, two factors involved in bone formation-resorption coupling, was markedly increased in transgenic cells. Our data thus suggest that overexpression of Cbfa1 in cells of the osteoblastic lineage does not necessarily induce a substantial increase in bone formation in the adult skeleton but has a positive effect on osteoclast differentiation in vitro and can also dramatically enhance bone resorption in vivo, possibly through increased RANKL expression.
机译：矮小家族转录因子核心结合因子α1（Cbfa1）对于发育过程中的骨形成至关重要。出人意料的是，在2.3-kb I型胶原启动子控制下过表达Cbfa1的转基因小鼠出现严重的骨质减少，并随着年龄的增长而逐渐增加，并出现多处骨折。对骨骼成熟的转基因小鼠的分析表明，成骨细胞的成熟受到影响，特别是在皮质骨中，骨吸收和骨形成增加，导致高骨转换率和矿化度降低。为了了解骨吸收增加的起源，我们开发了骨髓基质细胞培养物以及来自野生型或转基因小鼠的原代成骨细胞和脾细胞的相互共培养。我们表明，成骨细胞谱系的转基因细胞诱导了抗酒石酸酸性磷酸酶阳性的多核细胞数量增加，这表明来自转基因小鼠的原代成骨细胞和骨髓基质细胞比来自野生型动物的细胞具有更强的破骨细胞生成特性。我们调查了表达改变的触发基因可能导致骨吸收增加的候选基因，并且发现与骨形成-吸收耦合有关的两个因子NF-κB配体（RANKL）和胶原酶3的受体激活因子的表达明显增加。在转基因细胞中。因此，我们的数据表明成骨细胞谱系细胞中Cbfa1的过度表达不一定会导致成年骨骼中骨形成的实质性增加，但对破骨细胞的体外分化具有积极作用，并且还可能通过体内途径显着增强体内的骨吸收。 RANKL表达增加。

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