Sympathetic Innervation Regulates Osteocyte-Mediated Cortical Bone Resorption during Lactation

Bone remodeling involves osteoclasts and osteoblasts, but osteocytes also play a role. Their function in cortical bone resorption remains unclear. Prior research has shown that osteocytes sense mechanical stress and influence bone turnover. However, the mechanisms linking sympathetic nerves to osteocyte activity were unknown. This gap motivated an investigation into how sympathetic innervation affects bone resorption. The study aimed to clarify if and how sympathetic nerves regulate osteocyte behavior. No prior work had resolved the role of β-adrenergic signaling in osteocyte-mediated resorption. Understanding this could improve treatment of bone loss in lactation and other conditions.

This research aimed to determine whether sympathetic nerves regulate osteocyte-driven bone resorption in cortical bone. The specific problem is the lack of understanding about how sympathetic innervation influences bone remodeling. The motivation comes from the observation that lactation causes significant bone loss. The authors sought to identify if sympathetic nerves directly affect osteocytes. They also wanted to test if β-adrenergic signaling is involved in this process. The study focused on lactation as a model of physiological bone loss. The goal was to uncover the signaling pathways linking nerves to osteocyte activity. This could lead to new therapeutic approaches for preventing bone loss.

The researchers used mouse models of bone loss, including lactation, ovariectomy, and glucocorticoid treatment. They examined sympathetic nerve activity in cortical bone using histology and immunostaining. Osteocyte-specific gene expression was analyzed via RNA sequencing. Sympathetic nerve depletion was achieved through tyrosine hydroxylase-positive (TH+) nerve ablation. Norepinephrine signaling was tested using β-adrenergic receptor 2 (Adrb2) knockout mice. Extracellular vesicles (EVs) were isolated and analyzed for bone-degrading enzymes. Bone resorption was measured using histomorphometry and micro-CT. The study combined in vivo and in vitro approaches to assess nerve-osteocyte interactions.

Sympathetic activity increased in lactating mice and other models of bone loss. Elevated sympathetic outflow induced netrin-1 expression in osteocytes. This promoted nerve sprouting in the cortical endosteum via a feed-forward loop. Depletion of TH+ sympathetic nerves reduced osteocyte-mediated resorption. Norepinephrine activated Adrb2 signaling in osteocytes. This led to increased extracellular vesicle secretion containing bone-degrading enzymes. Adrb2 deletion or β-blocker treatment lowered bone resorption in lactating mice. These findings suggest that sympathetic nerves drive osteocyte resorption during lactation.

The authors propose that sympathetic innervation regulates osteocyte-driven bone resorption in lactation. They suggest that elevated sympathetic activity promotes netrin-1 expression in osteocytes. This creates a feed-forward loop that enhances nerve sprouting in cortical bone. Norepinephrine activates Adrb2 signaling, which increases extracellular vesicle secretion. These vesicles contain enzymes that degrade bone near lacunae. Adrb2 deletion or β-blockers reduce resorption in lactating mice. The findings imply that sympathetic nerves contribute to lactation-induced bone loss. The authors suggest this may be an adaptive response to meet the mother’s mineral demands.