Regulation of bone formation by adiponectin through autocrine/paracrine and endocrine pathways
Regulation of bone formation by adiponectin through autocrine/paracrine and endocrine pathways
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DOI：
10.1002/jcb.20890
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发表时间：
2006-09-01
影响因子：
4
通讯作者：
Kawaguchi, Hiroshi
中科院分区：
文献类型：
--
作者：
Shinoda, Yusuke;Yamaguchi, Masayuki;Kawaguchi, Hiroshi
由于骨代谢和脂质代谢之间的相互作用已被提出，本研究通过分析缺陷和过表达的转基因小鼠来研究脂联素，一种代表性的脂肪因子，对骨代谢的调节。我们初步证实脂联素及其受体在成骨细胞和成骨细胞中表达，表明脂联素不仅可以作为脂肪组织分泌的激素通过内分泌途径作用于骨，还可以通过自分泌/旁分泌途径作用于骨。脂联素缺乏（Ad-/-）小鼠的骨量或周转没有异常，可能是由于两种途径的等效平衡。在Ad-/-小鼠骨髓细胞培养中，与野生型（WT）细胞培养物相比，骨生成减少，表明内源性脂联素通过自分泌/旁分泌途径产生积极作用。为了研究脂联素的内分泌作用，我们分析了在肝脏中过表达脂联素的转基因小鼠，发现骨骼中没有异常。在培养的骨祖细胞中添加重组脂联素抑制骨生成，表明循环脂联素的直接作用对骨形成是阴性的。然而，在胰岛素的存在下，这种抑制作用减弱，脂联素增强了胰岛素诱导的主要下游分子胰岛素受体底物-1和Akt的磷酸化。这些结果提示脂联素对骨形成有三种不同的作用：局部产生的脂联素通过自分泌/旁分泌途径的正作用，循环脂联素通过直接途径的负作用，以及循环脂联素通过增强胰岛素信号传导通过间接途径的正作用。
Since interaction between bone and lipid metabolism has been suggested, this study investigated the regulation of bone metabolism by adiponectin, a representative adipokine, by analyzing deficient and overexpressing transgenic mice. We initially confirmed that adiponectin and its receptors were expressed inosteoblastic and osteoclastic cells, indicating that adiponectin can act on bone not only through an endocrine pathway as a hormone secreted from fat tissue, but also through an autocrine/paracrine pathway. There was no abnormality in bone mass or turnover of adiponectin-deficient (Ad-/-) mice, possibly due to an equivalent balance of the two pathways. In the culture of bone marrow cells from the Ad-/- mice, osteogenesis was decreased compared to the wild-type (WT) cell culture, indicating a positive effect of endogenous adiponectin through the autocrine/paracrine pathway. To examine the endocrine action of adiponectin, we analyzed transgenic mice overexpressing adiponectin in the liver, and found no abnormality in the bone. Addition of recombinant adiponectin in cultured osteoprogenitor cells suppressed osteogenesis, suggesting that the direct action of circulating adiponectin was negative for bone formation. In the presence of insulin, however, this suppression was blunted, and adiponectin enhanced the insulin-induced phosphorylations of the main downstream molecule insulin receptor substrate-1 and Akt. These lines of results suggest three distinct adiponectin actions on bone formation: a positive action through the autocrine/paracrine pathway by locally produced adiponectin, a negative action through the direct pathway by circulating adiponectin, and a positive action through the indirect pathway by circulating adiponectin via enhancement of the insulin signaling.