A new study published in Nature Communications provides a feedback mechanism to explain how sensory innervation of the bones is required for maintenance of optimal bone mass. “Sensory nerves can detect bone density changes by responding to the concentration of prostaglandin E2 (PGE2) in the bones,” says Xu Cao, corresponding author.

Credit: Panther Media GmbH/Alamy Stock Photo

PGE2, which is produced from arachidonic acid by the enzymatic activity of cyclooxygenase 2 (COX2) and is widely known for its function in inflammatory pain, was previously thought to regulate bone turnover by directly affecting osteoblasts via the PGE2 receptor EP4 subtype (EP4). However, the researchers found no effect on bone turnover when they deleted this receptor specifically from osteoblasts in mice. By contrast, mice lost bone mass when EP4 was deleted from the sensory nerves.

This same bone loss phenotype was achieved in osteoblast-specific COX2-knockout mice, indicating that osteoblast production of COX2 controls expression of PGE2, which might in turn sensitize sensory neurons.

Sympathetic tone is known to favour bone loss and CREB signalling can reduce this sympathetic activity, so any signal that drives CREB activity in the sensory nerves can loop back to maintain bone mass. Indeed, unlike in wild-type mice, the researchers show that CREB signalling in the hypothalamus of sensory nerve-specific EP4-knockout mice was unresponsive to PGE2 injection.

To provide further evidence of this centrally processed homeostatic mechanism, the researchers injected the β-adrenergic antagonist (to inhibit sympathetic activity) propranolol into the mice with bone loss phenotypes (that is, sensory-nerve-specific EP4-knockout mice and osteoblast-specific COX2-knockout mice). In both groups, injection with propranolol reduced the degree of bone loss.

Another therapeutic strategy tested was to increase levels of PGE2 in the bones of mice; injection of a small-molecule inhibitor of the PGE2-degrading enzyme PGDH (SW033291) boosted the regeneration of trabecular bone in surgically induced defects.

mice lost bone mass when EP4 was deleted from the sensory nerves

Together these findings provide a neuro–bone crosstalk mechanism for bone homeostasis and provide new strategies to regenerate bone.