High bone mass in mice expressing a mutant LRP5 gene
High bone mass in mice expressing a mutant LRP5 gene
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DOI：
10.1359/jbmr.2003.18.6.960
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发表时间：
2003-06-01
影响因子：
6.2
通讯作者：
Bex, F
中科院分区：
文献类型：
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作者：
Babij, P;Zhao, WG;Bex, F
LRP5中一种独特的突变与男性的高骨量有关。表达这种LRP5突变的转基因小鼠具有类似的表型，具有高骨量和增强的强度。这些结果强调了LRP5在骨骼调节中的重要性，并为骨骼疾病的治疗提供了靶点。在两个独立的人类家族中，低密度脂蛋白受体相关蛋白5(LRP5)的一个突变(G171V)与高骨量(HBM)有关。为了验证突变的作用，建立了几个转基因小鼠系，在骨中表达人LRP5 G171V替代或野生型LRP5基因。PQCT的体积骨密度(VBMD)分析显示，在5、9、17、26和52周龄时，突变G171V转基因动物股骨远端总vBMD(30-55%)和小梁vBMD(103-250%)均显著增加，股骨骨干端皮质尺寸增大(P<；均为0.01)。此外，对股骨远端和腰椎的高分辨率显微计算机断层扫描(MicroCT)分析显示，突变的G171V小鼠的骨小梁体积分数增加(110-232%)，这是由于骨小梁数量增加(41%-74%)和骨小梁厚度增加(34-46%；p<；全部为0.01)所致。骨量的增加与椎体压缩强度的显著增加(80%-140%)和皮质大小的增加以及股骨弯曲强度的显著增加(50%-130%)相关。17周龄破骨细胞数无明显差异。然而，与对照组相比，突变的G171V转基因小鼠的骨表面矿化活性增加，成骨细胞碱性磷酸酶染色增强，TUNEL阳性的成骨细胞和骨细胞数量显著减少。这些结果表明，突变的G171V小鼠的骨密度增加是由活跃的成骨细胞数量增加引起的，这可能部分是因为它们的功能寿命延长了。虽然野生型LRP5基因的过度表达有轻微的骨合成活性，但很明显，G171V突变，而不是受体本身的过度表达，是导致HBM戏剧性的骨骼效应的主要原因。总之，这些发现证实了脂蛋白受体在调节骨量中这一新的和意想不到的作用的重要性，并提供了一个新的模型来探索LRP5及其最近在骨生物学中与Wnt信号的关联。
A unique mutation in LRP5 is associated with high bone mass in man. Transgenic mice expressing this LRP5 mutation have a similar phenotype with high bone mass and enhanced strength. These results underscore the importance of LRP5 in skeletal regulation and suggest targets for therapies for bone disease.A mutation (G171V) in the low-density lipoprotein receptor related protein 5 (LRP5) has been associated with high bone mass (HBM) in two independent human kindreds. To validate the role of the, mutation, several lines of transgenic mice were created expressing either the human LRP5 G171V substitution or the wildtype LRP5 gene in bone. Volumetric bone mineral density (vBMD) analysis by pQCT showed dramatic increases in both total vBMD (30-55%) and trabecular vBMD (103-250%) of the distal femoral metaphysis and increased cortical size of the femoral diaphysis in mutant G171V transgenics at 5, 9, 17, 26, and 52 weeks of age (p < 0.01 for all). In addition, high-resolution microcomputed tomography (microCT) analysis of the distal femorae and lumbar vertebrae revealed an increase (110-232%) in trabecular bone volume fraction caused by both increased trabecular number (41-74%) and increased trabecular thickness (34-46%; p < 0.01 for all) in the mutant G171V mice. The increased bone mass was associated with significant increases in vertebral compressive strength (80-140%) and the increased cortical size with significant increases in femoral bending strength (50-130%). There were no differences in osteoclast number at 17 weeks of age. However, compared with littermate controls, the mutant G171V transgenic mice showed an increase in actively mineralizing bone surface, enhanced alkaline phosphatase staining in osteoblasts, and a significant reduction in the number of TUNEL-positive osteoblasts and osteocytes. These results suggest that the increased bone mineral density in mutant G171V mice was caused by increased numbers of active osteoblasts, which could in part be because of their increased functional lifespan. While slight bone anabolic activity was observed from overexpression of the wildtype LRP5 gene, it is clear that the G171V mutation, rather than overexpression of the receptor itself, is primarily responsible for the dramatic HBM bone effects. Together, these findings establish the importance of this novel and unexpected role of a lipoprotein receptor in regulating bone mass and afford a new model to explore LRP5 and its recent association with Wnt signaling in bone biology.