Department of Medicine, Washington University School of Medicine, St Louis, MO 63131, USA.
J Bone Miner Res. 2013 May;28(5):1160-9. doi: 10.1002/jbmr.1834.
Genetic studies in the mouse have demonstrated multiple roles for β-catenin in the skeleton. In the embryo, β-catenin is critical for the early stages of osteoblast differentiation. Postnatally, β-catenin in mature osteoblasts and osteocytes indirectly suppresses osteoclast differentiation. However, a direct role for β-catenin in regulating osteoblast number and/or function specifically in the postnatal life has not been demonstrated. Addressing this knowledge gap is important because low-density lipoprotein receptor-related protein 5 (LRP5), a coreceptor for WNT signaling proposed to function through β-catenin, controls osteoblast number and function in postnatal mice or humans. To overcome the neonatal lethality caused by embryonic deletion of β-catenin in early-stage osteoblast-lineage cells, we use the Osx-CreER(T2) mouse strain to remove β-catenin in Osterix (Osx)-expressing cells by administering tamoxifen (TM) temporarily to postnatal mice. Lineage-tracing experiments in the long bones demonstrate that Osx-CreER(T2) targets predominantly osteoblast-lineage cells on the bone surface, but also transient progenitors that contribute to bone marrow stromal cells and adipocytes. Deletion of β-catenin by this strategy greatly reduces the bone formation activity of the targeted osteoblasts. However, the targeted osteoblasts rapidly turn over and are replaced by an excessive number of non-targeted osteoblasts, causing an unexpected increase in bone formation, but an even greater increase in osteoclast number and activity produces a net effect of severe osteopenia. With time, the mutant mice also exhibit a marked increase in bone marrow adiposity. Thus, β-catenin in postnatal Osx-lineage cells critically regulates bone homeostasis by promoting osteoblast activity and suppressing osteoblast turnover, while restraining osteoclast and marrow fat formation.
在老鼠中的遗传研究表明β-连环蛋白在骨骼中有多种作用。在胚胎中，β-连环蛋白对于成骨细胞分化的早期阶段至关重要。出生后，成熟的成骨细胞和骨细胞中的β-连环蛋白间接抑制破骨细胞分化。然而，β-连环蛋白在调节成骨细胞数量和/或功能方面的直接作用在出生后阶段尚未得到证明。解决这一知识空白很重要，因为载脂蛋白脂蛋白受体相关蛋白 5（LRP5）是 WNT 信号的核心受体，被认为通过β-连环蛋白发挥作用，控制出生后小鼠或人类的成骨细胞数量和功能。为了克服早期成骨细胞谱系细胞中β-连环蛋白胚胎缺失导致的新生仔鼠致死性，我们使用 Osx-CreER(T2) 小鼠品系，通过给予新生仔鼠他莫昔芬（TM）暂时敲除成骨细胞特异性表达的 Osterix（Osx）中的β-连环蛋白。长骨中的谱系追踪实验表明，Osx-CreER(T2) 主要靶向骨表面的成骨细胞谱系细胞，但也靶向短暂祖细胞，这些祖细胞有助于骨髓基质细胞和脂肪细胞。通过这种策略敲除β-连环蛋白会大大降低靶向成骨细胞的骨形成活性。然而，靶向成骨细胞快速更替，并被大量非靶向成骨细胞取代，导致骨形成的意外增加，但破骨细胞数量和活性的增加更大，导致严重的骨质疏松症。随着时间的推移，突变小鼠还表现出骨髓脂肪含量的显著增加。因此，出生后 Osx 谱系细胞中的β-连环蛋白通过促进成骨细胞活性和抑制成骨细胞更替来严格调节骨稳态，同时抑制破骨细胞和骨髓脂肪形成。
