Guiding synovial inflammation by macrophage phenotype modulation: an in vitro study towards a therapy for osteoarthritis

L. Utomo, G. J.V.M. van Osch, Y. Bayon, J. A.N. Verhaar, Y. M. Bastiaansen-Jenniskens*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

Objective The aims of this study were to modulate inflammation in synovial explants with the compounds: dexamethasone, rapamycin, bone morphogenetic protein 7 (BMP-7) and pravastatin, and to investigate the modulatory capacity of the compounds on specific macrophage phenotypes. Design Synovial explants from osteoarthritis (OA) patients were treated with 10−6 M dexamethasone, 100 ng/mL rapamycin, 500 ng/mL BMP-7 or 50 μM pravastatin. Half of the explants were pre-stimulated with IFNγ + TNFα to simulate acute inflammation. Inflammatory state of the synovium was assessed with gene expression analysis. Primary human monocytes were isolated and stimulated towards macrophage phenotypes M(IFNγ + TNFα), M(IL-4) and M(IL-10) with the respective cytokines, followed by treatment with the compounds. Results Dexamethasone had an anti-inflammatory effect on IFNγ + TNFα stimulated and osteoarthritic synovium, likely due to suppression of pro-inflammatory M(IFNγ + TNFα) macrophages while enhancing anti-inflammatory M(IL4) and M(IL10) macrophages. Rapamycin and BMP-7 further enhanced inflammation in stimulated synovium, but rapamycin did not have a clear effect on non-stimulated synovium. Rapamycin suppressed M(IL-4) and M(IL-10) macrophages without affecting M(IFNγ + TNFα). BMP-7 suppressed M(IFNγ + TNFα) and enhanced M(IL-10) in the macrophage cultures. Pravastatin did not affect synovium, but enhanced M(IL-10). Conclusions These data indicate that macrophage phenotype modulation can be used to guide joint inflammation and thereby contribute to the development of new therapies to delay the progression of OA. The varying effects of the compounds on synovium of different degrees of inflammation, indicate that the modulatory capacity of the compounds depends on OA stage and underlines the importance of identifying this stadium for adequate treatment.

Original languageEnglish
Pages (from-to)1629-1638
Number of pages10
JournalOsteoarthritis and Cartilage
Volume24
Issue number9
DOIs
Publication statusPublished - 1 Sept 2016
Externally publishedYes

Keywords

  • Inflammation
  • Macrophage phenotypes
  • Modulation
  • Osteoarthritis
  • Synovium

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