Bone is a mechanosensitive tissue and undergoes constant remodeling to adapt to the mechanical loading environment. However, it is unclear whether the signals of bone cells in response to mechanical stress are processed and interpreted in the brain. In this study, we found that the hypothalamus of the brain regulates bone remodeling and structure by perceiving bone prostaglandin E2 (PGE2) concentration in response to mechanical loading. Bone PGE2 levels are in proportion to their weight bearing. When weight bearing changes in the tail-suspension mice, the PGE2 concentrations in bones change in line with their weight bearing changes. Deletion of cyclooxygenase-2 (COX2) in the osteoblast lineage cells or knockout of receptor 4 (EP4) in sensory nerve blunts bone formation in response to mechanical loading. Moreover, knockout of TrkA in sensory nerve also significantly reduces mechanical load-induced bone formation. Moreover, mechanical loading induces cAMP-response element binding protein (CREB) phosphorylation in the hypothalamic arcuate nucleus (ARC) to inhibit sympathetic tyrosine hydroxylase (TH) expression in the paraventricular nucleus (PVN) for osteogenesis. Finally, we show that elevated PGE2 is associated with ankle osteoarthritis (AOA) and pain. Together, our data demonstrate that in response to mechanical loading, skeletal interoception occurs in the form of hypothalamic processing of PGE2-driven peripheral signaling to maintain physiologic bone homeostasis, while chronically elevated PGE2 can be sensed as pain during AOA and implication of potential treatment.

骨骼是一种机械敏感组织，不断重塑以适应机械负荷环境。然而，目前尚不清楚骨细胞响应机械应力的信号是否在大脑中被处理和解释。在这项研究中，我们发现大脑的下丘脑通过感知响应机械负荷的骨前列腺素 E2 （PGE2） 浓度来调节骨骼重塑和结构。骨 PGE2 水平与其负重成正比。当尾悬小鼠的负重发生变化时，骨骼中的 PGE2 浓度会随着其负重变化而变化。成骨细胞系细胞中环氧合酶 2 （COX2） 的缺失或感觉神经中受体 4 （EP4） 的敲除会响应机械负荷而减弱骨形成。此外，敲除感觉神经中的 TrkA 也显着减少了机械负荷诱导的骨形成。此外，机械负荷诱导下丘脑弓状核 （ARC） 中的 cAMP 反应元件结合蛋白 （CREB） 磷酸化，从而抑制室旁核 （PVN） 中交感神经酪氨酸羟化酶 （TH） 的成骨表达。最后，我们表明 PGE2 升高与踝关节骨关节炎 （AOA） 和疼痛有关。总之，我们的数据表明，在响应机械负荷时，骨骼内感受以 PGE2 驱动的外周信号的下丘脑加工形式发生，以维持生理性骨稳态，而慢性升高的 PGE2 可以在 AOA 期间被感知为疼痛和潜在治疗的含义。