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Mechanically-Loaded Breast Cancer Cells Modify Osteocyte Mechanosensitivity by Secreting Factors That Increase Osteocyte Dendrite Formation and Downstream Resorption

Advanced breast cancer predominantly metastasizes to the skeleton, at which point patient prognosis significantly declines concomitant with bone loss, pain, and heightened fracture risk. Given the skeleton's sensitivity to mechanical signals, increased mechanical loading is well-documented to i...

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Autores principales: Wang, Wenbo, Sarazin, Blayne A., Kornilowicz, Gabriel, Lynch, Maureen E.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6043807/
https://www.ncbi.nlm.nih.gov/pubmed/30034365
http://dx.doi.org/10.3389/fendo.2018.00352
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author Wang, Wenbo
Sarazin, Blayne A.
Kornilowicz, Gabriel
Lynch, Maureen E.
author_facet Wang, Wenbo
Sarazin, Blayne A.
Kornilowicz, Gabriel
Lynch, Maureen E.
author_sort Wang, Wenbo
collection PubMed
description Advanced breast cancer predominantly metastasizes to the skeleton, at which point patient prognosis significantly declines concomitant with bone loss, pain, and heightened fracture risk. Given the skeleton's sensitivity to mechanical signals, increased mechanical loading is well-documented to increase bone mass, and it also inhibited bone metastatic tumor formation and progression in vivo, though the underlying mechanisms remain under investigation. Here, we focus on the role of the osteocyte because it is the primary skeletal mechanosensor and in turn directs the remodeling balance between formation and resoprtion. In particular, osteocytic dendrites are important for mechanosensing, but how this function is altered during bone metastatic breast cancer is unknown. To examine how breast cancer cells modulate dendrite formation and function, we exposed osteocytes (MLO-Y4) to medium conditioned by breast cancer cells (MDA-MB231) and to applied fluid flow (2 h per day for 3 days, shear stress 1.1 Pa). When loading was applied to MLOs, dendrite formation increased despite the presence of tumor-derived factors while overall MLO cell number was reduced. We then exposed MLOs to fluid flow as well as media conditioned by MDAs that had been similarly loaded. When nonloaded MLOs were treated with conditioned media from loaded MDAs, their dendrite formation increased in a manner similar to that observed due to loading alone. When MLOs simultaneously underwent loading and treatment with loaded conditioned media, dendrite formation was greatest. To understand potential molecular mechanisms, we then investigated expression of genes related to osteocyte maturation and dendrite formation (E11) and remodeling (RANKL, OPG) as well as osteocyte apoptosis. E11 expression increased with loading, consistent with increased dendrite formation. Though loaded conditioned media decreased MLO cell number, apoptosis was not detected via TUNEL staining, suggesting an inhibition of growth instead. OPG expression was inhibited while RANKL expression was unaffected, leading to an overall increase in the RANKL/OPG ratio with conditioned media from loaded breast cancer cells. Taken together, our results suggest that skeletal mechanical loading stimulates breast cancer cells to alter osteocyte mechanosensing by increasing dendrite formation and downstream resorption.
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spelling pubmed-60438072018-07-20 Mechanically-Loaded Breast Cancer Cells Modify Osteocyte Mechanosensitivity by Secreting Factors That Increase Osteocyte Dendrite Formation and Downstream Resorption Wang, Wenbo Sarazin, Blayne A. Kornilowicz, Gabriel Lynch, Maureen E. Front Endocrinol (Lausanne) Endocrinology Advanced breast cancer predominantly metastasizes to the skeleton, at which point patient prognosis significantly declines concomitant with bone loss, pain, and heightened fracture risk. Given the skeleton's sensitivity to mechanical signals, increased mechanical loading is well-documented to increase bone mass, and it also inhibited bone metastatic tumor formation and progression in vivo, though the underlying mechanisms remain under investigation. Here, we focus on the role of the osteocyte because it is the primary skeletal mechanosensor and in turn directs the remodeling balance between formation and resoprtion. In particular, osteocytic dendrites are important for mechanosensing, but how this function is altered during bone metastatic breast cancer is unknown. To examine how breast cancer cells modulate dendrite formation and function, we exposed osteocytes (MLO-Y4) to medium conditioned by breast cancer cells (MDA-MB231) and to applied fluid flow (2 h per day for 3 days, shear stress 1.1 Pa). When loading was applied to MLOs, dendrite formation increased despite the presence of tumor-derived factors while overall MLO cell number was reduced. We then exposed MLOs to fluid flow as well as media conditioned by MDAs that had been similarly loaded. When nonloaded MLOs were treated with conditioned media from loaded MDAs, their dendrite formation increased in a manner similar to that observed due to loading alone. When MLOs simultaneously underwent loading and treatment with loaded conditioned media, dendrite formation was greatest. To understand potential molecular mechanisms, we then investigated expression of genes related to osteocyte maturation and dendrite formation (E11) and remodeling (RANKL, OPG) as well as osteocyte apoptosis. E11 expression increased with loading, consistent with increased dendrite formation. Though loaded conditioned media decreased MLO cell number, apoptosis was not detected via TUNEL staining, suggesting an inhibition of growth instead. OPG expression was inhibited while RANKL expression was unaffected, leading to an overall increase in the RANKL/OPG ratio with conditioned media from loaded breast cancer cells. Taken together, our results suggest that skeletal mechanical loading stimulates breast cancer cells to alter osteocyte mechanosensing by increasing dendrite formation and downstream resorption. Frontiers Media S.A. 2018-07-03 /pmc/articles/PMC6043807/ /pubmed/30034365 http://dx.doi.org/10.3389/fendo.2018.00352 Text en Copyright © 2018 Wang, Sarazin, Kornilowicz and Lynch. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Endocrinology
Wang, Wenbo
Sarazin, Blayne A.
Kornilowicz, Gabriel
Lynch, Maureen E.
Mechanically-Loaded Breast Cancer Cells Modify Osteocyte Mechanosensitivity by Secreting Factors That Increase Osteocyte Dendrite Formation and Downstream Resorption
title Mechanically-Loaded Breast Cancer Cells Modify Osteocyte Mechanosensitivity by Secreting Factors That Increase Osteocyte Dendrite Formation and Downstream Resorption
title_full Mechanically-Loaded Breast Cancer Cells Modify Osteocyte Mechanosensitivity by Secreting Factors That Increase Osteocyte Dendrite Formation and Downstream Resorption
title_fullStr Mechanically-Loaded Breast Cancer Cells Modify Osteocyte Mechanosensitivity by Secreting Factors That Increase Osteocyte Dendrite Formation and Downstream Resorption
title_full_unstemmed Mechanically-Loaded Breast Cancer Cells Modify Osteocyte Mechanosensitivity by Secreting Factors That Increase Osteocyte Dendrite Formation and Downstream Resorption
title_short Mechanically-Loaded Breast Cancer Cells Modify Osteocyte Mechanosensitivity by Secreting Factors That Increase Osteocyte Dendrite Formation and Downstream Resorption
title_sort mechanically-loaded breast cancer cells modify osteocyte mechanosensitivity by secreting factors that increase osteocyte dendrite formation and downstream resorption
topic Endocrinology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6043807/
https://www.ncbi.nlm.nih.gov/pubmed/30034365
http://dx.doi.org/10.3389/fendo.2018.00352
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