Bone morphogenetic proteins in bone stimulate osteoclasts and osteoblasts during bone development
Bone morphogenetic proteins in bone stimulate osteoclasts and osteoblasts during bone development
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DOI：
10.1359/jbmr.060411
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发表时间：
2006-07-01
影响因子：
6.2
通讯作者：
Tsumaki, Noriyuki
中科院分区：
文献类型：
--
作者：
Okamoto, Mina;Murai, Junko;Tsumaki, Noriyuki
骨形态发生蛋白（BMPs）作用于各种类型的细胞。虽然BMP信号在成骨细胞分化中的作用已被广泛研究，但BMP对破骨细胞的影响尚未得到广泛研究。因此，BMP对骨的净效应仍不清楚。本研究的目的是更充分地描绘骨形态发生蛋白在骨骼biology.Materials和方法的作用：我们产生的转基因小鼠，表达骨形态发生蛋白4或头蛋白在骨的控制下的2.3 kb的α 1（I）胶原蛋白链基因（Col 1a 1）启动子，并分析其骨表型。结果：骨中BMP 4过表达的小鼠出现严重的骨质减少，破骨细胞数量增加。在骨中过度表达noggin（一种BMP拮抗剂）的小鼠显示骨体积增加，骨形成率降低，破骨细胞数量减少。头蛋白转基因胫骨表现出骨膜骨形成减少和骨髓腔中未成熟骨吸收减少，与骨干骨折频繁相关。共培养的原代成骨细胞制备的头蛋白转基因颅骨和野生型脾细胞导致破骨细胞形成不良，这是拯救添加重组BMP 2，表明头蛋白抑制破骨细胞形成的头蛋白通过减弱BMP活性在头蛋白转基因小鼠。在来自noggin转基因小鼠的原代成骨细胞中，Rankl的表达水平没有降低。免疫印迹分析显示，在破骨细胞前体细胞中，用BMP处理20分钟后，Smad 1/5/8的磷酸化增加，表明这些细胞受到BMP的刺激。结论：noggin在骨中的过表达揭示了BMP信号通过刺激成骨细胞和破骨细胞来调节骨发育。
Introduction: Bone morphogenetic proteins (BMPs) act on various types of cells. Although involvement of BMP signals in osteoblast differentiation has been studied extensively, the effects of BMPs on osteoclasts have not been widely researched. Consequently, the net effects of BMPs on bone remain unclear. The purpose of this study was to delineate more fully the role of BMPs in skeletal biology.Materials and Methods: We generated transgenic mice that express BMP4 or noggin in bone under the control of the 2.3-kb alpha 1(I) collagen chain gene (Col1a1) promoter, and analyzed their bone phenotype. We also analyzed bone of transgenic mice expressing BMP4 specifically in cartilage.Results: Mice overexpressing BMP4 in bone developed severe osteopenia with increased osteoclast number. Mice overexpressing noggin, a BMP antagonist, in bone showed increased bone volume associated with decreased bone formation rate and decreased osteoclast number. The noggin-transgenic tibias exhibited reduced periosteal bone formation and reduced resorption of immature bone in marrow spaces, associated with frequent fractures at the diaphysis. Co-culture of primary osteoblasts prepared from noggin-transgenic calvariae and wildtype spleen cells resulted in poor osteoclast formation, which was rescued by addition of recombinant BMP2, suggesting that noggin inhibits osteoclast formation by attenuating BMP activities in noggin-transgenic mice. The expression levels of Rankl were not decreased in primary osteoblasts from noggin transgenic mice. Immunoblot analysis showed increased phosphorylation of Smad1/5/8 in osteoclast precursor cells after 20-minute treatment with BMPs, suggesting that these cells are stimulated by BMPs. Mice overexpressing BMP4 in cartilage had enlarged bones containing thick trabeculae, possibly because of expansion of cartilage anlagen.Conclusions: Overexpression of noggin in bone revealed that BMP signals regulate bone development through stimulation of osteoblasts and osteoclasts.