Institute of Biomaterials & Biomedical Engineering, 164 College Street, Room 407, University of Toronto, Toronto, Ontario M5S 3G9.
Bone. 2012 Jan;50(1):104-10. doi: 10.1016/j.bone.2011.09.052. Epub 2011 Oct 1.
Osteocyte apoptosis precedes osteoclast resorption, and may act as a critical signal to trigger bone remodeling. While osteoclast precursors are known to travel via the circulation, the specific mechanisms by which they accumulate at remodeling sites are unclear. We hypothesized that osteocyte apoptosis mediates osteoclast precursor adhesion to vascular endothelium by regulating osteocytic secretion of IL-6 and soluble IL-6 receptor (sIL-6R) to promote endothelial ICAM-1 expression. We found that conditioned media from TNF-α-induced apoptotic MLO-Y4 osteocytes promoted RAW264.7 osteoclast precursor adhesion onto D4T endothelial cells (P<0.05). Blocking osteocyte apoptosis with a pan-caspase inhibitor (ZVAD-FMK) reduced osteoclast precursor adhesion to baseline levels (P<0.001). Endothelial cells treated with apoptotic osteocyte conditioned media had elevated surface expression of ICAM-1 (P<0.05), and blocking ICAM-1 abolished apoptosis-induced osteoclast precursor adhesion. Apoptotic osteocyte conditioned media contained more IL-6 (P<0.05) and sIL-6R (P<0.05) than non-apoptotic osteocyte conditioned media. When added exogenously, both IL-6 and sIL-6R were required for endothelial activation, and blocking IL-6 reduced apoptosis-induced osteoclast precursor adhesion to baseline levels (P<0.05). Therefore, we conclude that osteocyte apoptosis can promote osteoclast precursor adhesion to endothelial cells via ICAM-1; this is likely through increased osteocytic IL-6 and sIL-6R secretion, both of which are indispensible to endothelial activation.
破骨细胞前体通过血液循环迁移，但其在重塑部位聚集的具体机制尚不清楚。我们假设破骨细胞前体通过调节破骨细胞前体黏附血管内皮细胞的黏附，从而介导破骨细胞凋亡。我们发现，肿瘤坏死因子-α诱导的凋亡 MLO-Y4 成骨细胞条件培养基可促进 RAW264.7 破骨细胞前体黏附到 D4T 内皮细胞上（P<0.05）。用泛半胱天冬酶抑制剂（ZVAD-FMK）阻断破骨细胞凋亡可使破骨细胞前体黏附降低至基线水平（P<0.001）。用凋亡成骨细胞条件培养基处理的内皮细胞表面 ICAM-1 表达升高（P<0.05），阻断 ICAM-1 可消除凋亡诱导的破骨细胞前体黏附。凋亡成骨细胞条件培养基中含有更多的 IL-6（P<0.05）和 sIL-6R（P<0.05），而非凋亡成骨细胞条件培养基。外源性添加时，IL-6 和 sIL-6R 均对外皮细胞的激活是必需的，阻断 IL-6 可使凋亡诱导的破骨细胞前体黏附降低至基线水平（P<0.05）。因此，我们得出结论，破骨细胞前体可以通过 ICAM-1 促进破骨细胞前体黏附到内皮细胞上；这可能是通过增加破骨细胞的 IL-6 和 sIL-6R 分泌来实现的，这两者对内皮细胞的激活都是不可或缺的。
