Prostaglandin E2 mediates sensory nerve regulation of bone homeostasis

Abstract

Whether sensory nerve can sense bone density or metabolic activity to control bone homeostasis is unknown. Here we found prostaglandin E2 (PGE2) secreted by osteoblastic cells activates PGE2 receptor 4 (EP4) in sensory nerves to regulate bone formation by inhibiting sympathetic activity through the central nervous system. PGE2 secreted by osteoblasts increases when bone density decreases as demonstrated in osteoporotic animal models. Ablation of sensory nerves erodes the skeletal integrity. Specifically, knockout of the EP4 gene in the sensory nerves or cyclooxygenase-2 (COX2) in the osteoblastic cells significantly reduces bone volume in adult mice. Sympathetic tone is increased in sensory denervation models, and propranolol, a β2-adrenergic antagonist, rescues bone loss. Furthermore, injection of SW033291, a small molecule to increase PGE2 level locally, significantly boostes bone formation, whereas the effect is obstructed in EP4 knockout mice. Thus, we show that PGE2 mediates sensory nerve to control bone homeostasis and promote regeneration.

Ophiopogonin D promotes bone regeneration by stimulating CD31hiEMCNhi vessel formation

“…Flow cytometry analysis confirmed the age‐dependent reduction of CD31 hi Emcn hi endothelial cells (Figure D,E). To investigate the role of CD31 hi EMCN hi vessels in bone regeneration, we constructed a bone regeneration model after surgical ablation of the trabecular bone . We found that abundant CD31 hi EMCN hi vessels, as well as alkaline phosphatase‐positive (ALP + ) osteoprogenitors and OSX + osteoprogenitors, emerged in the bone regeneration area in the 3‐month‐old mice at 1 week after surgery (Figure F and Figure ).…”

“…To investigate the role of CD31 hi EMCN hi vessels in bone regeneration, we constructed a bone regeneration model after surgical ablation of the trabecular bone. 24,25 We found that abundant CD31 hi EMCN hi vessels, as well as alkaline phosphatasepositive (ALP + ) osteoprogenitors and OSX + osteoprogenitors, emerged in the bone regeneration area in the 3-month-old mice at 1 week after surgery ( Figure 1F and Figure S1). The amount of CD31 hi EMCN hi vessels in the femur of the 12-month-old mice was also increased at 1 week after trabecular bone ablation ( Figure 1F).…”

“…017968) were purchased from Jackson Laboratory, and loxP‐flanked Klf3 mice were purchased from Cyagen Biosciences Inc (China). The bone regeneration model was established as described before . A longitudinal incision was made on each knee to expose the femoral condyle by patella dislocation.…”

Nerves in Bone: Evolving Concepts in Pain and Anabolism

“…Recent work has suggested that the osteoanabolic properties of endogenous PGE2 are also mediated by skeletal neurons. Specifically, PGE2 secreted from osteoblasts at active sites of remodeling signals through EP4 receptors in advillin‐expressing nerve fibers to promote bone formation . Loss of this signaling axis results in bone loss, whereas boosting PGE2 activation of advillin + nerves enhances bone regeneration following surgical ablation .…”

Nuciferine prevents bone loss by disrupting multinucleated osteoclast formation and promoting type H vessel formation

“…5,7,27 Angiogenesis plays an important role in sustaining the normal bone structure, and osteogenesis is based on the nutrient supply of blood vessels and requires molecular stimulation from endothelial cells. [1][2][3]28,29 The contribution of type H vessels to bone formation has been verified, [1][2][3]5,7,22,30,31 and its quantity is relevant to bone mass. 8 Although we proved that NCF could inhibit osteoclast formation and increase the quantity of Trap + preosteoclasts, the influence of NCF on the function of endothelial cells and the formation of type H vessels was not clear.…”