Sensory innervation induced by osteoblast-derived netrin-4 attenuates bone loss in aged mice

The sensory denervation has a causal role in bone loss. The mechanism of bone cells regulation of sensory nerve wiring and sprouting for maintaining bone homeostasis remains unclear. Here we found that netrin-4, secreted by osteoblasts, facilitates the sprouting of sensory nerves through the DCC receptor and plays a regulatory role in bone formation. Decreased bone formation is coupled with reduced sensory innervation in aged mice and ablation of sensory nerves recapitulates this phenotype. Both mice and human data reveal that netrin-4 is positively correlated with bone volume, which expression was not affected by ablation of sensory nerves in mice. The sensory sprouting and bone formation are inhibited by siDCC, a netrin-4 receptor antagonist, in vivo and in vitro. Specifically, knockout of the netrin4 gene in the osteoblastic cells significantly reduces both sensory innervation and bone volume in adult mice. Thus, we show that sensory innervation induced by osteoblast-derived netrin-4 preserve bone homeostasis and attenuates bone loss in aged mice. Overall design: RNA-seq profiling of bone marrow from young (3-month-old) and aged (20-month-old) female C57BL/6 mice to identify differentially expressed genes associated with sensory innervation during aging.