title: Mechanical loading up-regulates early remodeling signals from osteocytes subjected to physical damage.
abstract: In the mineralized bone matrix, mechanical loading causes micrometer-sized cracks. These cracks trigger targeted remodeling along the micro-crack. Physical damage to osteocytes was shown to be involved in the initiation of this remodeling process. However, the role of subsequent mechanical loading osteocyte response to physical damage is unclear. In this study, we have designed and developed an in vitro cell model to study the impact of mechanical loading on osteocytes with physical damage. Specifically, a system was developed to create sub-cellular physical damage on MLO-Y4 osteocytes in vitro. This model re-created the spatial distribution of non-viable cells and VEGF expression around microdamage as reported in vivo. Using this system, the short term (24h) effects of fluid shear stress in regulation of osteocyte response to physical damage were investigated. We have observed that the mechanical stimuli had an additive effect in terms of COX-2, VEGF mRNA expressions, as well as PGE2, VEGF concentrations in the media. Interestingly, other inflammatory signals such as IL-6 and TNF-α did not change with these stimuli, at this time point. Moreover, fluid shear also had a modulating effect in regulation of osteoclast differentiation by osteocyte with physical damage. These results show that (1) subcellular physical damage upregulates remodeling signals in osteocytes at early time point, (2) mechanical loading substantially upregulates these signals for remodeling in osteocytes with physical damage.
authors.affiliation: Institute of Biomaterials and Biomedical Engineering, University of Toronto, Toronto, ON, Canada. Electronic address: ccc.liu@mail.utoronto.ca.
authors.forename: Chao
authors.initials: C
authors.lastname: Liu
authors.affiliation: Division of Engineering Science, University of Toronto, Toronto, ON, Canada. Electronic address: xiaoqing.zhang@mail.utoronto.ca.
authors.forename: Xiaoqing
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada. Electronic address: jvlichael.wu@mail.utoronto.ca.
authors.forename: Michael
authors.initials: M
authors.lastname: Wu
authors.affiliation: Institute of Biomaterials and Biomedical Engineering, University of Toronto, Toronto, ON, Canada; Department of Mechanical and Industrial Engineering, University of Toronto, Toronto, ON, Canada. Electronic address: youlidan@mie.utoronto.ca.
authors.forename: Lidan
authors.initials: L
authors.lastname: You
mesh_terms: D000818:Animals; D001696:Biomechanical Phenomena; D016723:Bone Remodeling; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism; D015232:Dinoprostone / Q000378:metabolism; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D010011:Osteocytes / Q000502:physiology*; D053245:RANK Ligand / Q000235:genetics / Q000378:metabolism; D000067996:RAW 264.7 Cells; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D059467:Transcriptome; D015854:Up-Regulation; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism
chemical_list: D015850:Interleukin-6; D053245:RANK Ligand; D012333:RNA, Messenger; C505689:Tnfsf11 protein, mouse; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2; D015232:Dinoprostone
keywords: Osteoclastogenesis; Osteocyte; PGE(2); Physical damage; VEGF