Agonistic and antagonistic targeting of immune checkpoint molecules differentially regulate osteoclastogenesis

Frontiers in Immunology

Immunology

Andreas C. Strauss¹  Dieter C. Wirtz¹  Christof Burger¹  Victoria C. Brom¹  Frank A. Schildberg¹  Alexander Sieberath²  Jochen Salber³ 

[1] Clinic for Orthopedics and Trauma Surgery, University Hospital Bonn, Bonn, Germany;Department of Experimental Surgery, Centre for Clinical Research, Ruhr-Universität Bochum, Bochum, Germany;Department of Experimental Surgery, Centre for Clinical Research, Ruhr-Universität Bochum, Bochum, Germany;Department of Surgery, Universitätsklinikum Knappschaftskrankenhaus Bochum GmbH, Bochum, Germany;

关键词: immune checkpoint molecules;    osteoclasts;    osteolysis;    osteoporosis;    endoprosthesis loosening;    cancer;    osteoimmunology;    musculoskeletal immunology;   

DOI  :  10.3389/fimmu.2023.988365

 received in 2022-07-07, accepted in 2023-01-19,  发布年份 2023

来源: Frontiers

【 摘 要 】

IntroductionImmune checkpoint inhibitors are used in the treatment of various cancers and have been extensively researched with regard to inflammatory and autoimmune diseases. However, this revolutionary therapeutic strategy often provokes critical auto-inflammatory adverse events, such as inflammatory reactions affecting the cardiovascular, gastrointestinal, nervous, and skeletal systems. Because the function of these immunomodulatory co-receptors is highly cell-type specific and the role of macrophages as osteoclast precursors is widely published, we aimed to analyze the effect of immune checkpoint inhibitors on these bone-resorbing cells.MethodsWe established an in vitro model of osteoclastogenesis using human peripheral blood mononuclear cells, to which various immune checkpoints and corresponding antagonistic antibodies were administered. Formation of osteoclasts was quantified and cell morphology was analyzed via immunofluorescence staining, cell size measurements, and calculation of cell numbers in a multitude of samples.ResultsThese methodical approaches for osteoclast research achieved objective, comparable, and reproducible results despite the great heterogeneity in the form, size, and number of osteoclasts. In addition to the standardization of experimental analyses involving osteoclasts, our study has revealed the substantial effects of agonistic and antagonistic checkpoint modulation on osteoclastogenesis, confirming the importance of immune checkpoints in bone homeostasis.DiscussionOur work will enable more robust and reproducible investigations into the use of immune checkpoint inhibitors in conditions with diminished bone density such as osteoporosis, aseptic loosening of endoprostheses, cancer, as well as the side effects of cancer therapy, and might even pave the way for novel individualized diagnostic and therapeutic strategies.

【 授权许可】

Unknown   
Copyright © 2023 Brom, Strauss, Sieberath, Salber, Burger, Wirtz and Schildberg