title: Osteocyte apoptosis regulates osteoclast precursor adhesion via osteocytic IL-6 secretion and endothelial ICAM-1 expression.
abstract: 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.
authors: Institute of Biomaterials & Biomedical Engineering, 164 College Street, Room 407, University of Toronto, Toronto, Ontario M5S 3G9. wingyee.cheung@utoronto.ca
authors: Wing-Yee
authors: WY
authors: Cheung
authors: Craig A
authors: CA
authors: Simmons
authors: Lidan
authors: L
authors: You
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D002448:Cell Adhesion / Q000502:physiology*; D017077:Culture Media, Conditioned / Q000378:metabolism; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism*; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism*; D015850:Interleukin-6 / Q000378:metabolism*; D051379:Mice; D010010:Osteoclasts / Q000166:cytology / Q000502:physiology*; D010011:Osteocytes / Q000166:cytology / Q000502:physiology*; D019947:Receptors, Interleukin-6 / Q000378:metabolism; D013234:Stem Cells / Q000166:cytology / Q000502:physiology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D017077:Culture Media, Conditioned; D015850:Interleukin-6; D019947:Receptors, Interleukin-6; D014409:Tumor Necrosis Factor-alpha; D018799:Intercellular Adhesion Molecule-1