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 to: Gerard Karsenty^1,2,3 Correspondence and requests for materials should be addressed to G.K. (Email: karsenty@bcm.tmc.edu).

Abstract

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 leptin¹. 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 function². 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 mouse³. 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 mice⁴, 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.

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 to: Gerard Karsenty^1,2,3 Correspondence and requests for materials should be addressed to G.K. (Email: karsenty@bcm.tmc.edu).

MORE ARTICLES LIKE THIS

These links to content published by NPG are automatically generated.