PDF(Pubmed)
Abstract：
Ca2+/calmodulin-dependent protein kinase kinase 2 (CaMKK2) is a multi-functional, serine/threonine protein kinase with predominant roles in inflammation, systemic energy metabolism, and bone remodeling. We previously reported that global ablation of CaMKK2 or its systemic pharmacological inhibition led to bone mass accrual in mice by stimulating osteoblasts and inhibiting osteoclasts. However, a direct, cell-intrinsic role for the kinase in the osteoblast lineage has not been established. Here we report that conditional deletion of CaMKK2 from osteoprogenitors, using the Osterix 1 (Osx1) - GFP::Cre (tetracycline-off) mouse line, resulted in increased trabecular bone mass due to an acute stimulation of osteoblast function in male and female mice. The acute simulation of osteoblasts and bone formation following conditional ablation of osteoprogenitor-derived CaMKK2 was sustained only in female mice. Periosteal bone formation at the cortical bone was enhanced only in male conditional knockout mice without altering cortical bone mass or strength. Prolonged deletion of CaMKK2 in early osteoblasts was accompanied by a stimulation of osteoclasts in both sexes, indicating a coupling effect. Notably, alterations in trabecular and cortical bone mass were absent in the doxycycline-removed \"Cre-only\" Osx1-GFP::Cre mice. Thus, the increase in osteoblast function at the trabecular and cortical bone surfaces following the conditional deletion of CaMKK2 in osteoprogenitors is indicative of a direct but sex-divergent role for the kinase in osteoblasts.
摘要：
Ca2+/钙调蛋白依赖性蛋白激酶激酶2(CaMKK2)是一种多功能,丝氨酸/苏氨酸蛋白激酶在炎症中起主要作用，全身能量代谢，和骨骼重塑。我们先前报道了CaMKK2的整体消融或其全身药理学抑制通过刺激成骨细胞和抑制破骨细胞导致小鼠骨量增加。然而,一个直接的，激酶在成骨细胞谱系中的细胞内在作用尚未确定。在这里，我们报道了骨祖细胞中CaMKK2的条件性缺失，使用Osterix1（Osx1）-GFP::Cre（四环素-off）小鼠系，由于急性刺激了雄性和雌性小鼠的成骨细胞功能，导致小梁骨量增加。仅在雌性小鼠中维持有条件的骨祖细胞衍生的CaMKK2消融后的成骨细胞和骨形成的急性模拟。仅在雄性条件性敲除小鼠中，皮质骨处的骨膜骨形成得到增强，而不会改变皮质骨的质量或强度。早期成骨细胞中CaMKK2的长时间缺失伴随着两性破骨细胞的刺激,表示耦合效应。值得注意的是,去除强力霉素的“仅Cre”Osx1-GFP::Cre小鼠中没有小梁和皮质骨量的改变。因此，在骨祖细胞中条件性缺失CaMKK2后，小梁和皮质骨表面的成骨细胞功能增加表明该激酶在成骨细胞中具有直接但性别不同的作用。
