HES1 (Hairy and Enhancer of Split 1) Is a Determinant of Bone Mass
HES1 (Hairy and Enhancer of Split 1) Is a Determinant of Bone Mass
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DOI：
10.1074/jbc.m110.183038
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发表时间：
2011-01-28
影响因子：
4.8
通讯作者：
Canalis, Ernesto
中科院分区：
文献类型：
--
作者：
Zanotti, Stefano;Smerdel-Ramoya, Anna;Canalis, Ernesto
HES1(Split的毛发和增强子)是一种在体外调节成骨细胞生成的转录因子。研究了HES1错误表达对骨骼的影响。在转基因小鼠中，1型胶原α1启动子的3.6kb碱基片段指导HES1的过度表达。由于雌性小鼠的成骨细胞功能降低和雄性小鼠的骨吸收增加，转基因小鼠是骨量减少的。在体外，HES1抑制成骨细胞的形成，转基因成骨细胞增强共培养破骨细胞前体细胞的吸收活性。纯合Hes1 loxP靶向等位基因的小鼠被培育成转基因小鼠，其中配对相关的同源盒基因增强子或骨钙素启动子直接Cre重组酶表达来灭活肢体芽或成骨细胞中的Hes1。为了避免遗传补偿，在Hes3和Hes5的全局缺失的情况下，Hes1被灭活。Hes3和Hes5基因缺失小鼠没有骨骼表型。肢芽中HES1的失活增加了股骨长度和骨小梁数量。成骨细胞中HES1的失活增加了骨小梁的体积、数量和连通性，这是由于增加了矿物质沉积速率和抑制了骨吸收。体外灭活HES1可增加共培养破骨细胞前体细胞碱性磷酸酶的表达，并抑制其吸收活性。总之，通过抑制成骨细胞功能和诱导骨吸收，HES1是骨量和结构的细胞内决定因素。
HES1 (hairy and enhancer of split) is a transcription factor that regulates osteoblastogenesis in vitro. The skeletal effects of HES1 misexpression were studied. Transgenic mice where a 3.6-kilobase fragment of the collagen type 1 alpha 1 promoter directs HES1 overexpression were created. Transgenics were osteopenic due to decreased osteoblast function in female and increased bone resorption in male mice. HES1 impaired osteoblastogenesis in vitro, and transgenic osteoblasts enhanced the resorptive activity of co-cultured osteoclast precursors. Mice homozygous for a Hes1 loxP-targeted allele were bred to transgenics, where the paired-related homeobox gene enhancer or the osteocalcin promoter direct Cre recombinase expression to inactivate Hes1 in the limb bud or in osteoblasts. To avoid genetic compensation, Hes1 was inactivated in the context of the global deletion of Hes3 and Hes5. Hes3 and Hes5 null mice had no skeletal phenotype. Hes1 inactivation in the limb bud increased femoral length and trabecular number. Hes1 inactivation in osteoblasts increased trabecular bone volume, number, and connectivity due to increased mineral apposition rate and suppressed bone resorption. Hes1 inactivation in vitro increased alkaline phosphatase expression and suppressed the resorptive activity of co-cultured osteoclast precursors. In conclusion, by inhibiting osteoblast function and inducing bone resorption, HES1 is an intracellular determinant of bone mass and structure.