Elefteriou Florent, Ahn Jong Deok, Takeda Shu, Starbuck Michael, Yang Xiangli, Liu Xiuyun, Kondo Hisataka, Richards William G, Bannon Tony W, Noda Masaki, Clement Karine, Vaisse Christian, Karsenty Gerard
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030, USA.
Nature. 2005 Mar 24;434(7032):514-20. doi: 10.1038/nature03398. Epub 2005 Feb 20.
Bone remodelling, the mechanism by which vertebrates regulate bone mass, comprises two phases, namely resorption by osteoclasts and formation by osteoblasts; osteoblasts are multifunctional cells also controlling osteoclast differentiation. Sympathetic signalling via beta2-adrenergic receptors (Adrb2) present on osteoblasts controls bone formation downstream of leptin. Here we show, by analysing Adrb2-deficient mice, that the sympathetic nervous system favours bone resorption by increasing expression in osteoblast progenitor cells of the osteoclast differentiation factor Rankl. This sympathetic function requires phosphorylation (by protein kinase A) of ATF4, a cell-specific CREB-related transcription factor essential for osteoblast differentiation and function. That bone resorption cannot increase in gonadectomized Adrb2-deficient mice highlights the biological importance of this regulation, but also contrasts sharply with the increase in bone resorption characterizing another hypogonadic mouse with low sympathetic tone, the ob/ob mouse. This discrepancy is explained, in part, by the fact that CART ('cocaine amphetamine regulated transcript'), a neuropeptide whose expression is controlled by leptin and nearly abolished in ob/ob mice, inhibits bone resorption by modulating Rankl expression. Our study establishes that leptin-regulated neural pathways control both aspects of bone remodelling, and demonstrates that integrity of sympathetic signalling is necessary for the increase in bone resorption caused by gonadal failure.
骨重塑是脊椎动物调节骨量的机制，包括两个阶段，即破骨细胞的吸收和成骨细胞的形成；成骨细胞是多功能细胞，也控制破骨细胞的分化。通过成骨细胞上存在的β2-肾上腺素能受体（Adrb2）进行的交感神经信号传导控制瘦素下游的骨形成。在这里，我们通过分析Adrb2基因缺陷小鼠表明，交感神经系统通过增加破骨细胞分化因子Rankl在成骨细胞祖细胞中的表达来促进骨吸收。这种交感神经功能需要ATF4（一种对成骨细胞分化和功能至关重要的细胞特异性CREB相关转录因子）被蛋白激酶A磷酸化。去势的Adrb2基因缺陷小鼠的骨吸收不能增加，这突出了这种调节的生物学重要性，但也与另一种交感神经张力低的性腺功能减退小鼠ob/ob小鼠骨吸收增加形成鲜明对比。这种差异部分是由于CART（“可卡因苯丙胺调节转录物”），一种其表达受瘦素控制且在ob/ob小鼠中几乎消失的神经肽，通过调节Rankl表达来抑制骨吸收。我们的研究表明，瘦素调节的神经通路控制骨重塑的两个方面，并证明交感神经信号的完整性对于性腺功能衰竭引起的骨吸收增加是必要的。
