生物谷报道：骨结构和功能是由骨重塑来维持的，后者是“破骨细胞”的骨再吸收作用与“造骨细胞”的骨形成作用之间的一种平衡。用小鼠进行的新的研究工作显示，Leptin（一种调节体重和性腺功能的激素，对其这种作用人们最为了解）在维持这种平衡中可能扮演一个重要角色。在一个通道中，Leptin对交感神经元的刺激会促进“破骨细胞”的分异（促进骨再吸收），而在另一通道中，一个被称为CART的神经肽抑制“破骨细胞”的分异。阻断这一由Leptin调节的神经通道，也许能防止骨质疏松病患中的骨质损失。
本刊发表在： Nature 434, 514 - 520 (24 March 2005); doi:10.1038/nature03398
Nature AOP, published online 20 February 2005
Leptin regulation of bone resorption by the sympathetic nervous system and CART
FLORENT ELEFTERIOU1,2,3, JONG DEOK AHN1,2, SHU TAKEDA1,2,4,5, MICHAEL STARBUCK1,2, XIANGLI YANG1,2, XIUYUN LIU1,2, HISATAKA KONDO5,6, WILLIAM G. RICHARDS7, TONY W. BANNON7, MASAKI NODA5,6, KARINE CLEMENT8, CHRISTIAN VAISSE9 & GERARD KARSENTY1,2,3
1 Department of Molecular and Human Genetics,
2 Bone Disease Program of Texas,
3 Children's Nutrition Research Center, Baylor College of Medicine, Houston, Texas 77030, USA
4 Department of Orthopedics,
5 Center of Excellence Program for Frontier Research on Molecular Destruction and Reconstruction of Tooth and Bone,
6 Department of Molecular Pharmacology, Medical Research Institute, Tokyo Medical and Dental University, Tokyo 101-0062, Japan
7 Amgen Inc., Neuroscience, Thousand Oaks, California 91320, USA
8 INSERM Avenir team–University Paris 6, EA3502, and CHRU Pitié Salpétrière, Hôtel-Dieu Nutrition Department, F-75004 Paris, France
9 Diabetes Center and Department of Medicine, University of California San Francisco, San Francisco, California 94143, USA
Correspondence and requests for materials should be addressed to G.K. (karsenty@bcm.tmc.edu).
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 2-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.
