Leptin regulation of bone resorption by the sympathetic nervous system and CART
Leptin regulation of bone resorption by the sympathetic nervous system and CART
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DOI：
10.1038/nature03398
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发表时间：
2005-03-24
期刊：
影响因子：
64.8
通讯作者：
Karsenty, G
中科院分区：
文献类型：
--
作者：
Elefteriou, F;Ahn, JD;Karsenty, G
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。成骨细胞是也控制破骨细胞分化的多功能细胞。通过成骨细胞上存在的 β 2-肾上腺素能受体 (Adrb2) 发出的交感信号传导控制瘦素下游的骨形成(1)。在这里，我们通过分析Adrb2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。这种交感功能需要 ATF4 的磷酸化（通过蛋白激酶 A），ATF4 是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 (2)。性腺切除的 Adrb2 缺陷小鼠的骨吸收不能增加，这凸显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 小鼠的骨吸收增加形成鲜明对比 (3)。这种差异的部分原因是 CART（“可卡因安非他明调节转录物”）是一种神经肽，其表达受瘦素控制，在 ob/ob 小鼠中几乎被消除(4)，它通过调节 Rankl 表达来抑制骨吸收。我们的研究证实，瘦素调节的神经通路控制骨重塑的两个方面，并证明交感信号的完整性对于性腺衰竭引起的骨吸收的增加是必要的。
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 beta 2-adrenergic receptors (Adrb2) present on osteoblasts controls bone formation downstream of leptin(1). 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(2). 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(3). 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(4), 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.