High bone resorption in adult aging Transgenic mice overexpressing Cbfa1/Runx2 in cells of the osteoblastic lineage
High bone resorption in adult aging Transgenic mice overexpressing Cbfa1/Runx2 in cells of the osteoblastic lineage
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DOI：
10.1128/mcb.22.17.6222-6233.2002
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发表时间：
2002-09-01
影响因子：
5.3
通讯作者：
Matthias, P
中科院分区：
文献类型：
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作者：
Geoffroy, V;Kneissel, M;Matthias, P
侏儒家族转录因子核心结合因子α 1（Cbfa 1）是发育过程中骨形成所必需的。令人惊讶的是，在2.3 kb I型胶原启动子的控制下过表达Cbfa 1的转基因小鼠出现了严重的骨质减少，随着年龄的增长而逐渐增加，并出现多处骨折。对骨骼成熟转基因小鼠的分析表明，成骨细胞成熟受到影响，特别是在皮质骨中，骨吸收和骨形成增加，诱导高骨转换率和矿化程度降低。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野生型或转基因小鼠原代成骨细胞和脾细胞的相互共培养。我们发现，成骨细胞系的转基因细胞诱导的抗酒石酸酸性磷酸酶阳性多核细胞的数量增加，这表明，原代成骨细胞以及骨髓基质细胞从转基因小鼠有更强的破骨细胞比细胞来自野生型动物。我们研究了其表达改变可触发骨吸收增加的候选基因，我们发现，在转基因细胞中，参与骨形成-吸收偶联的两个因子NF-κ B配体受体激活因子（RANKL）和胶原酶3的表达显著增加。因此，我们的数据表明，成骨细胞系细胞中Cbfa 1的过度表达不一定会诱导成人骨骼中骨形成的实质性增加，但对体外破骨细胞分化具有积极作用，也可能通过增加RANKL表达显著增强体内骨吸收。
The runt family transcription factor core-binding factor alpha1 (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-kappaB 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.