Signaling through the M3 Muscarinic Receptor Favors Bone Mass Accrual by Decreasing Sympathetic Activity

Bone remodeling is regulated by various neuronal inputs, one of the best understood being the sympathetic tone which inhibits bone mass accrual. This function of the sympathetic nervous system raises the prospect that the other arm of the autonomic nervous system, the parasympathetic nervous system, may also affect bone remodeling. Using various mutant mouse strains, each lacking one of the muscarinic receptors that mediate parasympathetic activity, we show here that the parasympathetic nervous system acting through the M 3 muscarinic receptor is a positive regulator of bone mass accrual by increasing bone formation and decreasing bone resorption. Expression studies, cell-specific gene deletion experiments and analysis of compound mutant mice showed that the parasympathetic nervous system favors bone mass accrual by acting centrally and by decreasing the sympathetic tone. By showing that both arms of the autonomic nervous system affect bone remodeling, this study further underscores the importance of its neuronal regulation.