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Leptin regulation of bone resorption by the sympathetic nervous system and CART

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 β2-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.

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Figure 1: Increased bone formation in Adrb2-deficient mice.
Figure 2: Sympathetic signalling in osteoblasts regulates BR.
Figure 3: Sympathetic regulation of Rankl expression.
Figure 4: SNS and CART antagonistic functions.
Figure 5

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Acknowledgements

We thank T. Townes and A. Hanauer for Atf4 and Rsk2 - / - mice, A. Hanauer and M. Montminy for RSK2 and CREB antibodies, M. Huelskamp and D.A. Horst for Dpd and CTX measurements, P. Ducy for suggestions and critical readings of the manuscript, and L. Li for technical assistance This work was supported by grants from NIH, NSBRI and CNRC (G.K., F.E.), Arthritis Foundation (S.T.) and Children's Brittle Bone Foundation (X.Y.).

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Correspondence to Gerard Karsenty.

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Elefteriou, F., Ahn, J., Takeda, S. et al. Leptin regulation of bone resorption by the sympathetic nervous system and CART. Nature 434, 514–520 (2005). https://doi.org/10.1038/nature03398

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