Positive Regulation of Osteoclastic Differentiation by Growth Differentiation Factor 15 Upregulated in Osteocytic Cells Under Hypoxia
Positive Regulation of Osteoclastic Differentiation by Growth Differentiation Factor 15 Upregulated in Osteocytic Cells Under Hypoxia
复制标题
DOI：
10.1002/jbmr.1538
复制
发表时间：
2012-04-01
影响因子：
6.2
通讯作者：
Yoneda, Yukio
中科院分区：
文献类型：
--
作者：
Hinoi, Eiichi;Ochi, Hiroki;Yoneda, Yukio
骨细胞被认为通过骨内的通讯网络起着机械传感器的作用。骨细胞是骨中最丰富的细胞，但其在骨形成中的生理病理功能却很少被关注。在这里，我们试图描述骨细胞在病理条件下骨重塑调节中的关键功能作用。我们首先发现，在条件培养基（CM）下，先前暴露于体外缺氧的成骨细胞MLO-Y4细胞的破骨细胞分化明显增加。通过微阵列和实时PCR分析，我们发现生长分化因子15 （GDF15）是缺氧条件下骨细胞分泌的关键候选因子。重组GDF15以浓度依赖性的方式显著促进破骨细胞分化，同时在核因子- κ B配体受体激活剂存在下促进p65和抑制- κ B的磷酸化。为了研究GDF15在体内可能的功能意义，我们对小鼠进行了右股动脉结扎作为缺氧模型。在结扎肢体的胫骨中观察到GDF15表达显著增加，而在正常灌注肢体的胫骨中则没有。在这些实验条件下，结扎肢体胫骨近端松质骨的骨体积明显减少，而破骨细胞表面/骨表面的范围明显增加。最后，抗gdf15抗体通过抑制股动脉结扎小鼠体内胫骨破骨细胞的活化来防止骨丢失，此外，在体外暴露于缺氧的骨细胞中，抑制CM增强的破骨细胞活性。这些研究结果表明，GDF15可能在缺氧相关的骨丢失发病机制中发挥关键作用，通过促进邻近骨细胞在骨废用和/或缺血时分泌破骨细胞。(c) 2012年美国骨与矿物研究学会。
Osteocytes are thought to play a role as a mechanical sensor through their communication network in bone. Although osteocytes are the most abundant cells in bone, little attention has been paid to their physiological and pathological functions in skeletogenesis. Here, we have attempted to delineate the pivotal functional role of osteocytes in regulation of bone remodeling under pathological conditions. We first found markedly increased osteoclastic differentiation by conditioned media (CM) from osteocytic MLO-Y4 cells previously exposed to hypoxia in vitro. Using microarray and real-time PCR analyses, we identified growth differentiation factor 15 (GDF15) as a key candidate factor secreted from osteocytes under hypoxia. Recombinant GDF15 significantly promoted osteoclastic differentiation in a concentration-dependent manner, with concomitant facilitation of phosphorylation of both p65 and inhibitory-kappa B in the presence of receptor activator of nuclear factor-kappa B ligand. To examine the possible functional significance of GDF15 in vivo, mice were subjected to ligation of the right femoral artery as a hypoxic model. A significant increase in GDF15 expression was specifically observed in tibias of the ligated limb but not in tibias of the normally perfused limb. Under these experimental conditions, in cancellous bone of proximal tibias in the ligated limb, a significant reduction was observed in bone volume, whereas a significant increase was seen in the extent of osteoclast surface/bone surface when determined by bone histomorphometric analysis. Finally, the anti-GDF15 antibody prevented bone loss through inhibiting osteoclastic activation in tibias from mice with femoral artery ligation in vivo, in addition to suppressing osteoclastic activity enhanced by CM from osteocytes exposed to hypoxia in vitro. These findings suggest that GDF15 could play a pivotal role in the pathogenesis of bone loss relevant to hypoxia through promotion of osteoclastogenesis after secretion from adjacent osteocytes during disuse and/or ischemia in bone. (c) 2012 American Society for Bone and Mineral Research.