Baldock P A, Lin S, Zhang L, Karl T, Shi Y, Driessler F, Zengin A, Hörmer B, Lee N J, Wong I P L, Lin E J D, Enriquez R F, Stehrer B, During M J, Yulyaningsih E, Zolotukhin S, Ruohonen S T, Savontaus E, Sainsbury A, Herzog H
Neurological Disease Division, Garvan Institute of Medical Research, St Vincent's Hospital, Sydney, Australia; Osteoporosis and Bone Biology Division, Garvan Institute of Medical Research, St Vincent's Hospital, Sydney, Australia; Faculty of Medicine, University of New South Wales, Sydney, Australia.
J Bone Miner Res. 2014 Oct;29(10):2238-49. doi: 10.1002/jbmr.2205.
Chronic stress and depression have adverse consequences on many organ systems, including the skeleton, but the mechanisms underlying stress-induced bone loss remain unclear. Here we demonstrate that neuropeptide Y (NPY), centrally and peripherally, plays a critical role in protecting against stress-induced bone loss. Mice lacking the anxiolytic factor NPY exhibit more anxious behavior and elevated corticosterone levels. Additionally, following a 6-week restraint, or cold-stress protocol, Npy-null mice exhibit three-fold greater bone loss compared to wild-type mice, owing to suppression of osteoblast activity. This stress-protective NPY pathway acts specifically through Y2 receptors. Centrally, Y2 receptors suppress corticotropin-releasing factor expression and inhibit activation of noradrenergic neurons in the paraventricular nucleus. In the periphery, they act to control noradrenaline release from sympathetic neurons. Specific deletion of arcuate Y2 receptors recapitulates the Npy-null stress response, coincident with elevated serum noradrenaline. Importantly, specific reintroduction of NPY solely in noradrenergic neurons of otherwise Npy-null mice blocks the increase in circulating noradrenaline and the stress-induced bone loss. Thus, NPY protects against excessive stress-induced bone loss, through Y2 receptor-mediated modulation of central and peripheral noradrenergic neurons.
慢性应激和抑郁会对包括骨骼在内的许多器官系统产生不良影响，但应激诱导的骨质流失背后的机制仍不清楚。在这里，我们证明神经肽Y（NPY）在中枢和外周对防止应激诱导的骨质流失起着关键作用。缺乏抗焦虑因子NPY的小鼠表现出更多的焦虑行为和更高的皮质酮水平。此外，在经过6周的束缚或冷应激实验后，与野生型小鼠相比，Npy基因敲除小鼠由于成骨细胞活性受到抑制，骨质流失增加了两倍。这种应激保护NPY途径特异性地通过Y2受体起作用。在中枢，Y2受体抑制促肾上腺皮质激素释放因子的表达，并抑制室旁核中去甲肾上腺素能神经元的激活。在外周，它们控制交感神经元释放去甲肾上腺素。弓状核Y2受体的特异性缺失重现了Npy基因敲除小鼠的应激反应，同时血清去甲肾上腺素升高。重要的是，仅在其他方面为Npy基因敲除小鼠的去甲肾上腺素能神经元中特异性重新引入NPY，可阻止循环去甲肾上腺素的增加和应激诱导的骨质流失。因此，NPY通过Y2受体介导的对中枢和外周去甲肾上腺素能神经元的调节，防止过度应激诱导的骨质流失。
