Oleoyl serine, an endogenous N-acyl amide, modulates bone remodeling and mass
Oleoyl serine, an endogenous N-acyl amide, modulates bone remodeling and mass
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DOI：
10.1073/pnas.0912479107
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发表时间：
2010-10-12
影响因子：
11.1
通讯作者：
Mechoulam, Raphael
中科院分区：
文献类型：
--
作者：
Smoum, Reem;Bar, Arik;Mechoulam, Raphael
骨量是由一个连续的重塑过程决定的，在这个过程中，矿化的基质被破骨细胞移除，随后被成骨细胞产生的新形成的骨组织所取代。在这里，我们报告了长链脂肪酸与氨基酸或乙醇胺(N-酰基酰胺)在小鼠骨中的内源性酰胺的存在。在这些化合物中，N-油酰-L-丝氨酸(OS)的成骨细胞增殖活性最高。在这些细胞中，OS激活GI蛋白偶联受体和ERK1/2。它还通过抑制ERK1/2的磷酸化和核转录激活因子B配体(RANKL)在骨髓基质细胞和成骨细胞中的表达来促进破骨细胞的凋亡，从而减少破骨细胞的数量。在完整的小鼠中，OS主要通过抑制骨吸收适度增加骨体积密度。然而，在骨质疏松的小鼠卵巢切除(OVX)模型中，OS通过增加骨形成和显著抑制骨吸收而有效地挽救骨丢失。外源性OS在OVX和完整动物中的差异效应显然是OVX诱导的骨骼OS水平下降的结果。这些数据表明，OS是一种以前未被发现的骨重塑的脂质调节因子。它代表了抗骨质疏松症药物的发现，有利于目前可用的治疗方法，这些治疗方法基本上要么是形成性的，要么是抗吸收的。
Bone mass is determined by a continuous remodeling process, whereby the mineralized matrix is being removed by osteoclasts and subsequently replaced with newly formed bone tissue produced by osteoblasts. Here we report the presence of endogenous amides of long-chain fatty acids with amino acids or with ethanolamine (N-acyl amides) in mouse bone. Of these compounds, N-oleoyl-L-serine (OS) had the highest activity in an osteoblast proliferation assay. In these cells, OS triggers a Gi-protein-coupled receptor and Erk1/2. It also mitigates osteoclast number by promoting osteoclast apoptosis through the inhibition of Erk1/2 phosphorylation and receptor activator of nuclear-kappa B ligand (RANKL) expression in bone marrow stromal cells and osteoblasts. In intact mice, OS moderately increases bone volume density mainly by inhibiting bone resorption. However, in a mouse ovariectomy (OVX) model for osteoporosis, OS effectively rescues bone loss by increasing bone formation and markedly restraining bone resorption. The differential effect of exogenous OS in the OVX vs. intact animals is apparently a result of an OVX-induced decrease in skeletal OS levels. These data show that OS is a previously unexplored lipid regulator of bone remodeling. It represents a lead to antiosteoporotic drug discovery, advantageous to currently available therapies, which are essentially either proformative or antiresorptive.