Abstract
Knowledge of how the joint functions as an integrated unit in health and disease requires an understanding of the stromal cells populating the joint mesenchyme, including fibroblasts, tissue-resident macrophages and endothelial cells. Knowledge of the physiological and pathological mechanisms that involve joint mesenchymal stromal cells has begun to cast new light on why joint inflammation persists. The shared embryological origins of fibroblasts and endothelial cells might shape the behaviour of these cell types in diseased adult tissues. Cells of mesenchymal origin sustain inflammation in the synovial membrane and tendons by various mechanisms, and the important contribution of newly discovered fibroblast subtypes and their associated crosstalk with endothelial cells, tissue-resident macrophages and leukocytes is beginning to emerge. Knowledge of these mechanisms should help to shape the future therapeutic landscape and emphasizes the requirement for new strategies to address the pathogenic stroma and associated crosstalk between leukocytes and cells of mesenchymal origin.
Key points
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Joint inflammation and tissue damage are mediated by stromal cells of mesodermal origin.
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Stromal activation and memory of previous inflammatory insults are shared mechanisms exhibited by fibroblasts, tissue-resident macrophages and endothelial cells.
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Data characterizing the phenotype and function of cells of mesenchymal origin highlight the distinct fibroblast subtypes that mediate joint inflammation and tissue damage.
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Mesenchymal stromal cell niches and their interactions with leukocytes are implicated in the persistence of joint inflammation.
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For effective treatment of residual joint disease, strategies are needed that target the pathogenic stroma and associated immune cell crosstalk.
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Change history
29 November 2018
In the originally published version of this article, the acknowledgements and affiliations contained errors. In the acknowledgements, “NIHR Oxford and Birmingham Biomedical Research Centres” and “the Department of Health and Social Care” were incorrectly presented as “NIHR Oxford Biomedical Research Centres” and “the Department of Health”. For affiliation 4, “NIHR Birmingham Biomedical Research Centre, University Hospitals Birmingham NHS Foundation Trust and University of Birmingham, Institute of Inflammation and Ageing, Birmingham, UK” was incorrectly presented as “Institute of Inflammation and Ageing, University of Birmingham, Birmingham, UK”. For affiliation 3, "Institute" was incorrectly spelt. These errors have now been corrected in the HTML and PDF versions of the manuscript.
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Acknowledgements
The work of S.G.D. is funded by an Oxford-UCB Prize Fellowship in Biomedical Sciences. The work of the authors is supported by NIHR Oxford and Birmingham Biomedical Research Centres. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health and Social Care.
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Nature Reviews Rheumatology thanks H. -G. Schaible, J. D. Cañete and the other anonymous reviewer(s) for their contribution to the peer review of this work.
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C.D.B., S.G.D., M.C. and J.P.S researched data for the article and wrote the article. C.D.B., S.G.D., M.C., J.P.S and A.J.C made substantial contributions to discussions of the content. All authors reviewed and/or edited the manuscript before submission.
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Glossary
- Mesenchymal
-
Describes the embryonic connective tissue derived from the mesoderm; mesenchymal tissue includes the tissue of the musculoskeletal, circulatory and lymphatic systems.
- Parenchyma
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The important functional elements of each body system.
- Stromal cells
-
Non-haematopoietic, tissue-resident cells.
- Mesoderm
-
The middle embryonic primary germ layer that resides between the ectoderm and the endoderm.
- Stromal cell activation
-
A process whereby stromal cells, including fibroblasts, tissue-resident macrophages and endothelial cells, adopt a pro-inflammatory phenotype and express distinct molecular markers after exposure to an inflammatory stimulus.
- Stromal cell memory
-
A change in the capacity of stromal cells to respond to inflammatory stimuli that persists for future exposures.
- Positional memory
-
Refers to the topographic memory of a cell across different tissues and joints, which for fibroblasts is regulated by homeobox (HOX) genes during development.
- Neoangiogenesis
-
The process by which new blood vessels develop by sprouting from existing vessels.
- Lipid mediator class switching
-
A process whereby eicosanoids at the site of inflammation trigger the release of specialized pro-resolving lipid mediators involved in resolving inflammation.
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Dakin, S.G., Coles, M., Sherlock, J.P. et al. Pathogenic stromal cells as therapeutic targets in joint inflammation. Nat Rev Rheumatol 14, 714–726 (2018). https://doi.org/10.1038/s41584-018-0112-7
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DOI: https://doi.org/10.1038/s41584-018-0112-7
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