The Wnt antagonist secreted frizzled-related protein-1 is a negative regulator of trabecular bone formation in adult mice
The Wnt antagonist secreted frizzled-related protein-1 is a negative regulator of trabecular bone formation in adult mice
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DOI：
10.1210/me.2003-0498
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发表时间：
2004-05-01
影响因子：
--
通讯作者：
Komm, BS
中科院分区：
文献类型：
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作者：
Bodine, PVN;Zhao, WG;Komm, BS
先前的研究已经将成骨细胞中经典Wnt信号的激活与骨形成的增加相关联。在这里，我们报告说，删除小鼠Wnt拮抗剂，分泌卷曲相关蛋白（sFRP）-1，抑制和增强成年动物骨小梁的积累。sFRP-1 mRNA在+/+小鼠的骨和其他组织中表达，但在-/-动物中未观察到。尽管sFRP-1的组织分布广泛，但其消融不会影响血液和尿液化学、大多数非骨骼器官或皮质骨。然而，与+/+对照组相比，sFRP 1-/-小鼠表现出骨小梁密度、体积和矿物质沉积率增加。在13 - 52周龄的成年动物中观察到sFRP-1-/-小鼠的骨小梁质量增加，发生在多个骨骼部位，并且在两种性别中均观察到。从机制上讲，sFRP-1的缺失减少了体内成骨细胞和骨细胞的凋亡。此外，sFRP-1的缺失抑制成骨细胞系细胞凋亡，同时增强这些细胞在体外的增殖和分化。sFRP-1的消融也增加了体外破骨细胞生成，尽管在体内完整动物中未观察到骨吸收的变化。我们的研究结果表明，sFRP-1的缺失优先激活成骨细胞中的Wnt信号传导，导致成人骨小梁形成增强。
Previous studies have associated activation of canonical Wnt signaling in osteoblasts with elevated bone formation. Here we report that deletion of the murine Wnt antagonist, secreted frizzled-related protein (sFRP)-1, prolongs and enhances trabecular bone accrual in adult animals. sFRP-1 mRNA was expressed in bones and other tissues of +/+ mice but was not observed in -/- animals. Despite its broad tissue distribution, ablation of sFRP-1 did not affect blood and urine chemistries, most nonskeletal organs, or cortical bone. However, sFRP1 -/- mice exhibited increased trabecular bone mineral density, volume, and mineral apposition rate when compared with +/+ controls. The heightened trabecular bone mass of sFRP-1-/- mice was observed in adult animals between the ages of 13 - 52 wk, occurred in multiple skeletal sites, and was seen in both sexes. Mechanistically, loss of sFRP-1 reduced osteoblast and osteocyte apoptosis in vivo. In addition, deletion of sFRP-1 inhibited osteoblast lineage cell apoptosis while enhancing the proliferation and differentiation of these cells in vitro. Ablation of sFRP-1 also increased osteoclastogenesis in vitro, although changes in bone resorption were not observed in intact animals in vivo. Our findings demonstrate that deletion of sFRP-1 preferentially activates Wnt signaling in osteoblasts, leading to enhanced trabecular bone formation in adults.