Mechanical loading releases osteoclastogenesis-modulating factors through stimulation of the P2X7 receptor in hematopoietic progenitor cells

C. Bratengeier, A.D. Bakker, A. Fahlgren

Research output: Contribution to JournalArticleAcademicpeer-review

Abstract

Mechanical instability of bone implants stimulate osteoclast differentiation and peri‐implant bone loss, leading to prosthetic loosening. It is unclear which cells at the periprosthetic interface transduce mechanical signals into a biochemical response, and subsequently facilitate bone loss. We hypothesized that mechanical overloading of hematopoietic bone marrow progenitor cells, which are located near to the inserted bone implants, stimulates the release of osteoclast‐inducing soluble factors. Using a novel in vitro model to apply mechanical overloading, we found that hematopoietic progenitor cells released adenosine triphosphate (ATP) after only 2 min of mechanical loading. The released ATP interacts with its specific receptor P2X7 to stimulate the release of unknown soluble factors that inhibit (physiological loading) or promote (supraphysiological loading) the differentiation of multinucleated osteoclasts derived from bone marrow cultures. Inhibition of ATP‐receptor P2X7 by Brilliant Blue G completely abolished the overloading‐induced stimulation of osteoclast formation. Likewise, stimulation of P2X7 receptor on hematopoietic cells by BzATP enhanced the release of osteoclastogenesis‐stimulating signaling molecules to a similar extent as supraphysiological loading. Supraphysiological loading affected neither gene expression of inflammatory markers involved in aseptic implant loosening (e.g., interleukin‐1β (IL‐1β), IL‐6, tumor necrosis factor‐α, and PTGES2) nor expression of the osteoclast modulators receptor activator of nuclear factor κ‐Β ligand and osteoprotegerin. Our findings suggest that murine hematopoietic progenitor cells are a potential key player in local mechanical loading‐induced bone implant loosening via the ATP/P2X7‐axis. Our approach identifies potential therapeutic targets to prevent prosthetic loosening.
Original languageEnglish
Pages (from-to)13057-13067
JournalJournal of Cellular Physiology
Volume234
Issue number8
DOIs
Publication statusPublished - Aug 2019

Bibliographical note

Export Date: 17 October 2019

Funding

The authors wish to thank Prof. Dr. Emeritus Per Aspenberg for his involvement in discussions and resulting advice contributing to this project. The authors wish to thank Teresa H. Jungwirth for her involvement in discussions and practical contribution to this project during her internship at Linköping University, Sweden as well as Janneke van Oosterhout, for her support in literature research and debate regarding possible targets on P2X7‐receptor induced ectodo-main shedding process during her internship at ACTA, The Netherlands. This study also supported by Swedish Research Council (Grant Nos. 521‐2013‐2593, 2016‐01822, 2016‐06097) and Swedish Governmental Agency for Innovation Systems (Grant No. 2012‐04409). The authors wish to thank Prof. Dr. Emeritus Per Aspenberg for his involvement in discussions and resulting advice contributing to this project. The authors wish to thank Teresa H. Jungwirth for her involvement in discussions and practical contribution to this project during her internship at Link?ping University, Sweden as well as Janneke van Oosterhout, for her support in literature research and debate regarding possible targets on P2X7-receptor induced ectodomain shedding process during her internship at ACTA, The Netherlands. This study also supported by Swedish Research Council (Grant Nos. 521-2013-2593, 2016-01822, 2016-06097) and Swedish Governmental Agency for Innovation Systems (Grant No. 2012-04409).

FundersFunder number
Alliance for California Traditional Arts
VINNOVA2012‐04409
Vetenskapsrådet2016‐01822, 521‐2013‐2593, 2016‐06097

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