title: Thermally induced osteocyte damage initiates a remodelling signaling cascade.
abstract: Thermal elevations experienced by bone during orthopaedic procedures, such as cutting and drilling, exothermal reactions from bone cement, and thermal therapies such as tumor ablation, can result in thermal damage leading to death of native bone cells (osteocytes, osteoblasts, osteoclasts and mesenchymal stem cells). Osteocytes are believed to be the orchestrators of bone remodeling, which recruit nearby osteoclast and osteoblasts to control resorption and bone growth in response to mechanical stimuli and physical damage. However, whether heat-induced osteocyte damage can directly elicit bone remodelling has yet to be determined. This study establishes the link between osteocyte thermal damage and the remodeling cascade. We show that osteocytes directly exposed to thermal elevations (47°C for 1 minute) become significantly apoptotic and alter the expression of osteogenic genes (Opg and Cox2). The Rankl/Opg ratio is consistently down-regulated, at days 1, 3 and 7 in MLO-Y4s heat-treated to 47°C for 1 minute. Additionally, the pro-osteoblastogenic signaling marker Cox2 is significantly up-regulated in heat-treated MLO-Y4s by day 7. Furthermore, secreted factors from heat-treated MLO-Y4s administered to MSCs using a novel co-culture system are shown to activate pre-osteoblastic MSCs to increase production of the pro-osteoblastic differentiation marker, alkaline phosphatase (day 7, 14), and calcium deposition (day 21). Most interestingly, an initial pro-osteoclastogenic signaling response (increase Rankl and Rankl/Opg ratio at day 1) followed by later stage pro-osteoblastogenic signaling (down-regulation in Rankl and the Rankl/Opg ratio and an up-regulation in Opg and Cox2 by day 7) was observed in non-heat-treated MLO-Y4s in co-culture when these were exposed to the biochemicals produced by heat-treated MLO-Y4s. Taken together, these results elucidate the vital role of osteocytes in detecting and responding to thermal damage by means of thermally induced apoptosis followed by a cascade of remodelling responses.
authors.affiliation: Biomechanics Research Centre (BMEC), Biomedical Engineering, College of Engineering and Informatics, National University of Ireland, Galway, Ireland; National Centre for Biomedical Engineering Science (NCBES), National University of Ireland, Galway, Ireland.
authors.forename: Eimear B
authors.initials: EB
authors.lastname: Dolan
authors.affiliation: Biomechanics Research Centre (BMEC), Biomedical Engineering, College of Engineering and Informatics, National University of Ireland, Galway, Ireland; National Centre for Biomedical Engineering Science (NCBES), National University of Ireland, Galway, Ireland.
authors.forename: Matthew G
authors.initials: MG
authors.lastname: Haugh
authors.affiliation: Biomechanics Research Centre (BMEC), Biomedical Engineering, College of Engineering and Informatics, National University of Ireland, Galway, Ireland; National Centre for Biomedical Engineering Science (NCBES), National University of Ireland, Galway, Ireland.
authors.forename: Muriel C
authors.initials: MC
authors.lastname: Voisin
authors.affiliation: Stryker Ireland, Carrigtwohill, Cork, Ireland.
authors.forename: David
authors.initials: D
authors.lastname: Tallon
authors.affiliation: Biomechanics Research Centre (BMEC), Biomedical Engineering, College of Engineering and Informatics, National University of Ireland, Galway, Ireland; National Centre for Biomedical Engineering Science (NCBES), National University of Ireland, Galway, Ireland.
authors.forename: Laoise M
authors.initials: LM
authors.lastname: McNamara
mesh_terms: D000469:Alkaline Phosphatase / Q000378:metabolism; D000704:Analysis of Variance; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D016723:Bone Remodeling / Q000502:physiology*; D001842:Bone and Bones / Q000293:injuries*; D002118:Calcium / Q000378:metabolism; D005434:Flow Cytometry; D005786:Gene Expression Regulation / Q000502:physiology; D006358:Hot Temperature; D051379:Mice; D008807:Mice, Inbred BALB C; D008856:Microscopy, Fluorescence; D019637:Orthopedic Procedures / Q000009:adverse effects*; D010011:Osteocytes / Q000473:pathology*; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D000469:Alkaline Phosphatase; D002118:Calcium