Leptin regulation of bone resorption by the sympathetic nervous system and CART
| Autor: | Shu Takeda, Xiuyun Liu, Gerard Karsenty, Tony W. Bannon, Karine Clément, Jong Deok Ahn, Christian Vaisse, Hisataka Kondo, William G. Richards, Michael Starbuck, Florent Elefteriou, Xiangli Yang, Masaki Noda |
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| Rok vydání: | 2005 |
| Předmět: |
Leptin
Male musculoskeletal diseases medicine.medical_specialty Sympathetic nervous system Sympathetic Nervous System Models Neurological Nerve Tissue Proteins Response Elements Bone resorption Cell Line Bone remodeling Mice Osteogenesis Osteoclast Internal medicine medicine Animals Humans Amino Acid Sequence Bone Resorption Child Membrane Glycoproteins Osteoblasts Multidisciplinary Receptor Activator of Nuclear Factor-kappa B biology RANK Ligand Osteoblast Activating Transcription Factor 4 Cyclic AMP-Dependent Protein Kinases Neoplasm Proteins Resorption Endocrinology medicine.anatomical_structure RANKL Child Preschool biology.protein Receptor Melanocortin Type 4 Receptors Leptin Receptors Adrenergic beta-2 Carrier Proteins Gene Deletion Signal Transduction Transcription Factors |
| Zdroj: | Nature. 434:514-520 |
| ISSN: | 1476-4687 0028-0836 |
| DOI: | 10.1038/nature03398 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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