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Mechanical loading releases osteoclastogenesis-modulating factors through stimulation of the P2X7 receptor in hematopoietic progenitor cells
Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
Univ Amsterdam, Netherlands; Vrije Univ Amsterdam, Netherlands.
Linköping University, Department of Clinical and Experimental Medicine, Division of Cell Biology. Linköping University, Faculty of Medicine and Health Sciences.
2019 (English)In: Journal of Cellular Physiology, ISSN 0021-9541, E-ISSN 1097-4652, Vol. 234, no 8, p. 13057-13067Article in journal (Refereed) Published
Abstract [en]

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 2min 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-1 (IL-1), IL-6, tumor necrosis factor-, and PTGES2) nor expression of the osteoclast modulators receptor activator of nuclear factor -B ligandand 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.

Place, publisher, year, edition, pages
WILEY , 2019. Vol. 234, no 8, p. 13057-13067
Keywords [en]
fluid flow; implant loosening; mechanoresponsive hematopoietic progenitor cells; osteolysis; purinergic signaling
National Category
Cell and Molecular Biology
Identifiers
URN: urn:nbn:se:liu:diva-158040DOI: 10.1002/jcp.27976ISI: 000467240800083PubMedID: 30536959OAI: oai:DiVA.org:liu-158040DiVA, id: diva2:1330180
Note

Funding Agencies|Swedish Research Council [2016-01822, 2016-06097, 521-2013-2593]; Swedish Governmental Agency for Innovation Systems [2012-04409]

Available from: 2019-06-25 Created: 2019-06-25 Last updated: 2019-08-21
In thesis
1. Mechanisms of mechanically induced Osteoclastogenesis: in a novel in vitro model for bone implant loosening
Open this publication in new window or tab >>Mechanisms of mechanically induced Osteoclastogenesis: in a novel in vitro model for bone implant loosening
2019 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Total joint arthroplasty is the primary intervention in the treatment of end-stage osteoarthritis. Despite the high success rate, in some patients, the replacement will fail during their lifetime requiring a revision of the implant. These revisions are strenuous for the patient and costly for health care. Joint replacement at a younger age, in combination with a more active lifestyle, increases the need for an early revision of the joint prosthesis. The main reason for revision surgeries is aseptic loosening, a condition where the prosthesis is loosening due to bone degradation at the peri-prosthetic interface in the absence of infections. The most well-established pathological mechanism for aseptic loosening is related to wear particles, generated from different parts of the prosthesis that will trigger bone degradation and bone loss. In addition, early micromotions of the prosthesis and resulting local pressurized fluid flow in the peri-prosthetic interface (supraphysiological loading) have also been identified as a cause for aseptic loosening. However, it remains unknown what cells are the primary responders to supraphysiological loading, and what underlying physical, cellular and molecular mechanism that triggers osteoclast differentiation and osteolysis.

In this thesis, we intended to shed light on three currently unknown aspects of mechanical loading-induced peri-prosthetic osteolysis, leading to aseptic loosening of orthopedic prostheses: (1)Which cells are the primary responder to supraphysiological loading? (2)What characteristics of the mechanical stimulus induce an osteo-protective or osteo-destructive response? (3)Which cellular mechano-sensing mechanisms are involved in an osteo-destructive response?

We successfully implemented supraphysiological mechanical loading, mimicking the periprosthetic pressurized fluid flow around a loosening implant, in an in vitro model for bone implant loosening. Using this model, we uncovered the involvement of mesenchymal stem cells and myeloid progenitor cells (monocytes) in mechanical loading-induced peri-prosthetic osteolysis. Applying supraphysiological loading on cells from patients undergoing primary hip arthroplasty, successfully validated the in vitro model for the use of cells of human origin. We further identified in murine myeloid progenitor cells that a combination of high loading amplitude (3.0±0.2Pa), prolonged active loading duration per cycle (duty cycle 22%-50%), and rapid alterations in minimum/maximum values of the loading profile (square wave) is necessary to induce an osteo-destructive response. Further, the loading-induced ATP release and subsequent activation of the P2X7 receptor was essential for the release of soluble factors modulating osteoclastogenesis.

In conclusion, we expect that the proposed new in vitro model is a helpful tool to further advance the knowledge in aseptic loosening, by uncovering the mechanoresponsive cellular mechanism to supraphysiological mechanical loading. The identification of the respondent cells in mechanical loading-induced prosthetic loosening gives the opportunity to deliver targeted treatment strategies. Furthermore, identifying the physical parameters that define the shift towards an osteo-destructive response emphasizes the importance of the prosthetic design and surgical technique to reduce mechanical loading-induced bone degradation around a prosthesis.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2019. p. 47
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1696
National Category
Cell and Molecular Biology
Identifiers
urn:nbn:se:liu:diva-159776 (URN)10.3384/diss.diva-159776 (DOI)9789176850145 (ISBN)
Public defence
2019-09-24, Belladonna, Building 511, Campus US, Linköping, 13:00 (English)
Opponent
Supervisors
Available from: 2019-08-21 Created: 2019-08-21 Last updated: 2019-08-21Bibliographically approved

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