Tam Joseph, Trembovler Victoria, Di Marzo Vincenzo, Petrosino Stefania, Leo Gabriella, Alexandrovich Alex, Regev Eran, Casap Nardy, Shteyer Arie, Ledent Catherine, Karsak Meliha, Zimmer Andreas, Mechoulam Raphael, Yirmiya Raz, Shohami Esther, Bab Itai
Bone Laboratory, Hadassah School of Dental Medicine, Hebrew University of Jerusalem, Jerusalem 91120, Israel.
FASEB J. 2008 Jan;22(1):285-94. doi: 10.1096/fj.06-7957com. Epub 2007 Aug 17.
We have recently reported that in bone the cannabinoid CB1 receptor is present in sympathetic terminals. Here we show that traumatic brain injury (TBI), which in humans enhances peripheral osteogenesis and fracture healing, acutely stimulates bone formation in a distant skeletal site. At this site we demonstrate i) a high level of the main endocannabinoid, 2-arachidonoylglycerol (2-AG), and expression of diacylglycerol lipases, enzymes essential for 2-AG synthesis; ii) that the TBI-induced increase in bone formation is preceded by elevation of the 2-AG and a decrease in norepinephrine (NE) levels. The TBI stimulation of bone formation was absent in CB1-null mice. In wild-type animals it could be mimicked, including the suppression of NE levels, by 2-AG administration. The TBI- and 2-AG-induced stimulation of osteogenesis was restrained by the beta-adrenergic receptor agonist isoproterenol. NE from sympathetic terminals is known to tonically inhibit bone formation by activating osteoblastic beta2-adrenergic receptors. The present findings further demonstrate that the sympathetic control of bone formation is regulated through 2-AG activation of prejunctional CB1. Elevation of bone 2-AG apparently suppresses NE release from bone sympathetic terminals, thus alleviating the inhibition of bone formation. The involvement of osteoblastic CB2 signaling in this process is minimal, if any.
我们最近报道，在骨骼中，大麻素CB1受体存在于交感神经末梢。在此我们表明，创伤性脑损伤（TBI）在人类中可增强外周骨生成和骨折愈合，它能急性刺激远处骨骼部位的骨形成。在这个部位，我们证实：i）主要内源性大麻素2-花生四烯酸甘油酯（2-AG）水平很高，且二酰基甘油脂肪酶（2-AG合成所必需的酶）有表达；ii）TBI诱导的骨形成增加之前，2-AG水平升高且去甲肾上腺素（NE）水平降低。在CB1基因敲除小鼠中，TBI对骨形成的刺激作用不存在。在野生型动物中，通过给予2-AG可以模拟这种刺激作用，包括抑制NE水平。β-肾上腺素能受体激动剂异丙肾上腺素可抑制TBI和2-AG诱导的成骨作用。已知来自交感神经末梢的NE通过激活成骨细胞β2-肾上腺素能受体来持续抑制骨形成。目前的研究结果进一步表明，骨形成的交感神经控制是通过2-AG对突触前CB1的激活来调节的。骨骼中2-AG水平升高显然抑制了NE从骨骼交感神经末梢的释放，从而减轻了对骨形成的抑制。成骨细胞CB2信号在此过程中的参与程度极小（如果有参与的话）。
