Iwaniec Urszula T, Wronski Thomas J, Liu Jeff, Rivera Mercedes F, Arzaga Rosemarie R, Hansen Gwenn, Brommage Robert
Department of Physiological Sciences, University of Florida, Gainesville, USA.
J Bone Miner Res. 2007 Mar;22(3):394-402. doi: 10.1359/jbmr.061118.
Lrp5 deficiency decreases bone formation and results in low bone mass. This study evaluated the bone anabolic response to intermittent PTH treatment in Lrp5-deficient mice. Our results indicate that Lrp5 is not essential for the stimulatory effect of PTH on cancellous and cortical bone formation.
Low-density lipoprotein receptor-related protein 5 (Lrp5), a co-receptor in canonical Wnt signaling, increases osteoblast proliferation, differentiation, and function. The purpose of this study was to use Lrp5-deficient mice to evaluate the potential role of this gene in mediating the bone anabolic effects of PTH.
Adult wildtype (WT, 23 male and 25 female) and Lrp5 knockout (KO, 27 male and 26 female) mice were treated subcutaneously with either vehicle or 80 microg/kg human PTH(1-34) on alternate days for 6 weeks. Femoral BMC and BMD were determined using DXA. Lumbar vertebrae were processed for quantitative bone histomorphometry. Bone architecture was evaluated by microCT. Data were analyzed using a multiway ANOVA.
Cancellous and cortical bone mass were decreased with Lrp5 deficiency. Compared with WT mice, cancellous bone volume in the distal femur and the lumbar vertebra in Lrp5 KO mice was 54% and 38% lower, respectively (p<0.0001), whereas femoral cortical thickness was 11% lower in the KO mice (p<0.0001). The decrease in cancellous bone volume in the lumbar vertebrae was associated with a 45% decrease in osteoblast surface (p<0.0001) and a comparable decrease in bone formation rate (p<0.0001). Osteoclast surface, an index of bone resorption, was 24% lower in Lrp5 KO compared with WT mice (p<0.007). Treatment of mice with PTH for 6 weeks resulted in a 59% increase in osteoblast surface (p<0.0001) and a 19% increase in osteoclast surface (p=0.053) in both genotypes, but did not augment cancellous bone volume in either genotype. Femur cortical thickness was 11% higher in PTH-treated mice in comparison with vehicle-treated mice (p<0.0001), regardless of genotype.
Whereas disruption of Lrp5 results in decreased bone mass because of decreased bone formation, Lrp5 does not seem to be essential for the stimulatory effects of PTH on cancellous and cortical bone formation.
低密度脂蛋白受体相关蛋白5（Lrp5）缺乏会减少骨形成并导致低骨量。本研究评估了Lrp5缺乏小鼠对间歇性甲状旁腺激素（PTH）治疗的骨合成代谢反应。我们的结果表明，Lrp5对于PTH对松质骨和皮质骨形成的刺激作用并非必不可少。
低密度脂蛋白受体相关蛋白5（Lrp5）是经典Wnt信号通路中的一种共受体，可增加成骨细胞的增殖、分化和功能。本研究的目的是使用Lrp5缺乏小鼠来评估该基因在介导PTH的骨合成代谢作用中的潜在作用。
成年野生型（WT，雄性23只，雌性25只）和Lrp5基因敲除（KO，雄性27只，雌性26只）小鼠每隔一天皮下注射溶媒或80微克/千克人PTH（1-34），持续6周。使用双能X线吸收法（DXA）测定股骨骨矿含量（BMC）和骨密度（BMD）。对腰椎进行定量骨组织形态计量学分析。通过显微CT评估骨结构。数据使用多因素方差分析进行分析。
Lrp5缺乏导致松质骨和皮质骨量减少。与WT小鼠相比，Lrp5基因敲除小鼠股骨远端和腰椎的松质骨体积分别降低了54%和38%（p<0.0001），而基因敲除小鼠的股骨皮质厚度降低了11%（p<0.0001）。腰椎松质骨体积的减少与成骨细胞表面减少45%（p<0.0001）以及骨形成率的相应降低（p<0.0001）相关。作为骨吸收指标的破骨细胞表面，Lrp5基因敲除小鼠比WT小鼠低24%（p<0.007）。用PTH治疗小鼠6周后，两种基因型的成骨细胞表面均增加了59%（p<0.0001），破骨细胞表面增加了19%（p=0.053），但两种基因型的松质骨体积均未增加。与溶媒处理的小鼠相比，无论基因型如何，PTH处理的小鼠股骨皮质厚度高11%（p<0.0001）。
虽然Lrp5的破坏由于骨形成减少而导致骨量降低，但Lrp5对于PTH对松质骨和皮质骨形成的刺激作用似乎并非必不可少。
