Department of Medicine III, Technische Universität Dresden, Dresden, Germany.
Center for Healthy Aging, Technische Universität Dresden, Dresden, Germany.
J Bone Miner Res. 2018 Sep;33(9):1698-1707. doi: 10.1002/jbmr.3463. Epub 2018 Jun 12.
The Wnt antagonist Dickkopf-1 (Dkk1) is a negative regulator of osteoblast function and bone mass. However, because of the lack of appropriate models, many aspects of its role in the regulation of postnatal bone turnover and its cellular source have remained unknown. In this study, we deleted Dkk1 postnatally and in different cell types using various Cre-drivers (Rosa26-ERT2-Cre, Osx-cre, Dmp1-Cre) and assessed to which extent cells of the osteoblastic lineage contribute to the effects of Dkk1 on bone turnover and homeostasis. Female and male mice were examined at 12 weeks of age. Mice with a global or cell type-specific deletion of Dkk1 showed a two- to threefold higher bone volume compared with their Cre-negative littermates. The mineral apposition rate and the bone formation rate were increased two- to fourfold in all three mouse lines, despite a significant increase in systemic and skeletal levels of sclerostin. Dkk1 deletion further reduced the number of osteoclasts about twofold, which was accompanied by a strong decrease in the receptor activator of nuclear factor-κB ligand/osteoprotegerin mRNA ratio in femoral bone. Despite similar increases in bone mass, the deletion of Dkk1 in osterix-expressing cells reduced circulating Dkk1 significantly (males, -79%; females, -77%), whereas they were not changed in Dkk1 ;Dmp1-Cre mice. However, both lines showed significantly reduced Dkk1 mRNA levels in bone. In summary, we show that lack of Dkk1 in cells of the osteoblastic lineage leads to high bone mass with increased bone formation, despite increased levels of sclerostin. Moreover, the majority of systemic Dkk1 appears to originate from osteoprogenitors but not from mature osteoblasts or osteocytes. Nevertheless, the amount of Dkk1 produced locally by more mature osteogenic cells is sufficient to modulate bone mass. Thus, this study highlights the importance of local Wnt signaling on postnatal bone homeostasis. © 2018 American Society for Bone and Mineral Research.
Wnt 拮抗剂 Dickkopf-1（DKK1）是成骨细胞功能和骨量的负调节剂。然而，由于缺乏合适的模型，其在调节产后骨转换及其细胞来源方面的许多方面仍然未知。在这项研究中，我们使用各种 Cre 驱动子（Rosa26-ERT2-Cre、Osx-cre、Dmp1-Cre）在产后和不同细胞类型中删除 Dkk1，并评估成骨细胞谱系的细胞在多大程度上有助于 Dkk1 对骨转换和平衡的影响。在 12 周龄时检查雌性和雄性小鼠。与 Cre 阴性同窝仔相比，具有全局或细胞类型特异性 Dkk1 缺失的小鼠的骨体积高 2 至 3 倍。所有三种小鼠品系的矿化率和骨形成率均增加了 2 至 4 倍，尽管全身性和骨骼性骨硬化蛋白水平显著增加。Dkk1 缺失进一步将破骨细胞数量减少了约 2 倍，这伴随着股骨中核因子-κB 受体激活剂配体/骨保护素 mRNA 比率的强烈下降。尽管骨量增加相似，但在表达osterix 的细胞中删除 Dkk1 可使循环 Dkk1 显著降低（雄性，-79%；雌性，-77%），而在 Dkk1;Dmp1-Cre 小鼠中则没有变化。然而，这两种品系的骨中均显示 Dkk1 mRNA 水平显著降低。总之，我们表明，成骨细胞谱系中缺乏 Dkk1 会导致骨形成增加，骨量增加，尽管骨硬化蛋白水平增加。此外，大多数系统性 Dkk1 似乎来自成骨前体细胞，而不是成熟的成骨细胞或骨细胞。尽管如此，由更成熟的成骨细胞产生的局部 Dkk1 量足以调节骨量。因此，这项研究强调了局部 Wnt 信号在产后骨平衡中的重要性。
