Division of Endocrinology and Metabolism, Central Arkansas Veterans Healthcare System and University of Arkansas for Medical Sciences, Little Rock, Arkansas 72205, USA.
Endocrinology. 2011 Sep;152(9):3323-31. doi: 10.1210/en.2011-0170. Epub 2011 Jul 19.
The adverse skeletal effects of glucocorticoid excess are due to increased osteoclast survival, decreased production of osteoblasts, and increased apoptosis of osteoblasts and osteocytes, but it remains unknown which of these is the principle cause of the decrease in bone strength. Previous studies suggested that osteocytes contribute to bone strength independently of changes in bone mass. Administration of the receptor activator for nuclear factor κB ligand (RANKL) antagonist osteoprotegerin (OPG) rapidly decreases osteoclasts followed by a decrease in osteoblasts but should not affect the long-lived osteocytes. Therefore, to distinguish between glucocorticoid effects on osteoclasts, osteoblasts, or osteocytes, we administered glucocorticoids, alone or in combination with OPG with the fragment crystallizable region of Ig heavy chains (OPG-Fc), to mice. The suppressive effect of glucocorticoids on spinal bone mineral density, cortical thickness, and strength was prevented by OPG-Fc. OPG-Fc, with or without glucocorticoids, profoundly reduced osteoclasts, osteoblasts, and bone formation. Unexpectedly, OPG-Fc prevented the glucocorticoid-induced increase in osteocyte apoptosis and reduction in solute transport from the systemic circulation to the osteocyte-lacunar-canalicular network. The fluid in the osteocyte-lacunar-canalicular network was inversely related to osteocyte apoptosis and directly related to bone mineral density. Consistent with the in vivo findings, Both OPG-Fc and OPG decreased glucocorticoid-induced apoptosis of MLO-Y4 osteocytic cells. OPG can also bind and antagonizes the activity of the TNF-related apoptosis-inducing ligand (TRAIL), but glucocorticoids did not change TRAIL expression, and knockdown of TRAIL did not prevent OPG-Fc from reducing glucocorticoid-induced osteocyte apoptosis. Based on these results, we conclude that at least part of the OPG-induced preservation of bone strength is due to the maintenance of osteocyte viability and the lacunar-canalicular network.
糖皮质激素过量对骨骼的不良影响是由于破骨细胞存活增加、成骨细胞生成减少以及成骨细胞和骨细胞凋亡增加所致，但尚不清楚这些因素中哪一个是骨强度降低的主要原因。先前的研究表明，骨细胞通过改变骨量以外的方式对骨强度产生贡献。核因子 κB 配体（RANKL）受体激活剂骨保护素（OPG）的给药可迅速减少破骨细胞，随后减少成骨细胞，但不应影响寿命长的骨细胞。因此，为了区分糖皮质激素对破骨细胞、成骨细胞或骨细胞的作用，我们单独或联合使用糖皮质激素和 OPG 与免疫球蛋白重链片段结晶区（OPG-Fc）给药于小鼠。OPG-Fc 可预防糖皮质激素对脊柱骨矿物质密度、皮质厚度和强度的抑制作用。OPG-Fc 与或不与糖皮质激素一起，可显著减少破骨细胞、成骨细胞和骨形成。出乎意料的是，OPG-Fc 可预防糖皮质激素诱导的骨细胞凋亡增加和从全身循环向骨细胞-骨陷窝-小管网络的溶质转运减少。骨细胞-骨陷窝-小管网络中的液体与骨细胞凋亡呈负相关，与骨矿物质密度呈正相关。与体内发现一致，OPG-Fc 和 OPG 均可降低糖皮质激素诱导的 MLO-Y4 骨细胞凋亡。OPG 还可以结合并拮抗 TNF 相关凋亡诱导配体（TRAIL）的活性，但糖皮质激素不会改变 TRAIL 的表达，而且 TRAIL 的敲低也不能阻止 OPG-Fc 减少糖皮质激素诱导的骨细胞凋亡。基于这些结果，我们得出结论，至少部分 OPG 诱导的骨强度保留是由于骨细胞活力和骨陷窝-小管网络的维持。
