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2. Microencapsulated stem cells reduce cartilage damage in a material dependent manner following minimally invasive intra-articular injection in an OA rat model

Author

Johnbosco, Castro, primary, Karbaat, Lisanne, additional, Korthagen, Nicoline M., additional, Warmink, Kelly, additional, Koerselman, Michelle, additional, Coeleveld, Katja, additional, Becker, Malin, additional, van Loo, Bas, additional, Zoetebier, Bram, additional, Both, Sanne, additional, Weinans, Harrie, additional, Karperien, Marcel, additional, and Leijten, Jeroen, additional

Published
2023
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3. Macrophage-Driven Inflammation in Metabolic Osteoarthritis: Implications for Biomarker and Therapy Development

Author

Warmink, Kelly, Vinod, Prateeksha, Korthagen, Nicoline M, Weinans, Harrie, Rios, Jaqueline L, Warmink, Kelly, Vinod, Prateeksha, Korthagen, Nicoline M, Weinans, Harrie, and Rios, Jaqueline L

Abstract

Osteoarthritis (OA) is a common and debilitating joint disorder that leads to progressive joint breakdown and loss of articular cartilage. Accompanied by a state of low-grade inflammation, its etiology extends beyond that of a wear-and-tear disease, and the immune system might have a role in its initiation and progression. Obesity, which is directly associated with an increased incidence of OA, alters adipokine release, increases pro-inflammatory macrophage activity, and affects joint immune regulation. Studying inflammatory macrophage expression and strategies to inhibit inflammatory macrophage phenotype polarization might provide insights into disease pathogenesis and therapeutic applications. In pre-clinical studies, the detection of OA in its initial stages was shown to be possible using imaging techniques such as SPECT-CT, and advances are made to detect OA through blood-based biomarker analysis. In this review, obesity-induced osteoarthritis and its mechanisms in inducing joint degeneration are summarized, along with an analysis of the current developments in patient imaging and biomarker use for diagnostic and therapeutic strategies.

Published
2023

4. Mesenchymal stem/stromal cells-derived extracellular vesicles as a potentially more beneficial therapeutic strategy than MSC-based treatment in a mild metabolic osteoarthritis model

Author

CS_Locomotion, Equine Musculoskeletal Biology, Warmink, Kelly, Rios, Jaqueline L, Varderidou-Minasian, Suzy, Torres-Torrillas, Marta, van Valkengoed, Devin R, Versteeg, Sabine, Eijkelkamp, Niels, Weinans, Harrie, Korthagen, Nicoline M, Lorenowicz, Magdalena J, CS_Locomotion, Equine Musculoskeletal Biology, Warmink, Kelly, Rios, Jaqueline L, Varderidou-Minasian, Suzy, Torres-Torrillas, Marta, van Valkengoed, Devin R, Versteeg, Sabine, Eijkelkamp, Niels, Weinans, Harrie, Korthagen, Nicoline M, and Lorenowicz, Magdalena J

Published
2023

7. Mesenchymal stem/stromal cells-derived extracellular vesicles as a potentially more beneficial therapeutic strategy than MSC-based treatment in a mild metabolic osteoarthritis model

Author

Warmink, Kelly (author), Rios, Jaqueline L. (author), Varderidou-Minasian, Suzy (author), Torres-Torrillas, Marta (author), van Valkengoed, Devin R. (author), Versteeg, Sabine (author), Eijkelkamp, Niels (author), Weinans, Harrie (author), Korthagen, Nicoline M. (author), Lorenowicz, Magdalena J. (author), Warmink, Kelly (author), Rios, Jaqueline L. (author), Varderidou-Minasian, Suzy (author), Torres-Torrillas, Marta (author), van Valkengoed, Devin R. (author), Versteeg, Sabine (author), Eijkelkamp, Niels (author), Weinans, Harrie (author), Korthagen, Nicoline M. (author), and Lorenowicz, Magdalena J. (author)

Abstract

Background: Mesenchymal stromal/stem cells (MSCs) and MSC-derived extracellular vesicles (MSC-EVs) hold promise as a disease modifying treatment in osteoarthritis (OA). Obesity, and its associated inflammation, contribute to OA development and metabolic OA represents a specific and significant group of the OA patient population. Given their immunomodulatory properties, MSC and MSC-EVs are especially interesting for this group of patients as a therapeutic option. Here, we were the first to compare the therapeutic efficacy of MSCs and MSC-EVs in a mild OA model taking these metabolic aspects into consideration. Methods: Male Wistar-Han rats (Crl:WI(Han) (n = 36) were fed a high fat diet for 24 weeks, with unilateral induction of OA by groove surgery after 12 weeks. Eight days after surgery rats were randomized in three treatment groups receiving MSCs, MSC-EVs or vehicle injection. Pain-associated behavior, joint degeneration, and local and systemic inflammation were measured. Results: We demonstrated that despite not having a significant therapeutic effect, MSC-EV treatment results in lower cartilage degeneration, less pain behaviour, osteophytosis and joint inflammation, than MSC treatment. Suggesting that MSC-EVs could be a more promising therapeutic strategy than MSCs in this mild metabolic OA model. Conclusion: In summary, we find that MSC treatment has negative effects on the joint in metabolic mild OA. This is an essential finding for the significant group of patients with metabolic OA phenotype, and might help to understand why clinical translation of MSC treatment shows varying therapeutic efficacy thus far. Our results also suggest that MSC-EV-based treatment might be a promising option for these patients, however MSC-EV therapeutic efficacy will need improvement., Biomaterials & Tissue Biomechanics

Published
2023
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8. Macrophage-Driven Inflammation in Metabolic Osteoarthritis: Implications for Biomarker and Therapy Development

Author

Warmink, Kelly (author), Vinod, Prateeksha (author), Korthagen, Nicoline M. (author), Weinans, Harrie (author), Rios, Jaqueline L. (author), Warmink, Kelly (author), Vinod, Prateeksha (author), Korthagen, Nicoline M. (author), Weinans, Harrie (author), and Rios, Jaqueline L. (author)

Abstract

Osteoarthritis (OA) is a common and debilitating joint disorder that leads to progressive joint breakdown and loss of articular cartilage. Accompanied by a state of low-grade inflammation, its etiology extends beyond that of a wear-and-tear disease, and the immune system might have a role in its initiation and progression. Obesity, which is directly associated with an increased incidence of OA, alters adipokine release, increases pro-inflammatory macrophage activity, and affects joint immune regulation. Studying inflammatory macrophage expression and strategies to inhibit inflammatory macrophage phenotype polarization might provide insights into disease pathogenesis and therapeutic applications. In pre-clinical studies, the detection of OA in its initial stages was shown to be possible using imaging techniques such as SPECT-CT, and advances are made to detect OA through blood-based biomarker analysis. In this review, obesity-induced osteoarthritis and its mechanisms in inducing joint degeneration are summarized, along with an analysis of the current developments in patient imaging and biomarker use for diagnostic and therapeutic strategies., Biomaterials & Tissue Biomechanics

Published
2023
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9. Microencapsulated stem cells reduce cartilage damage in a material dependent manner following minimally invasive intra-articular injection in an OA rat model

Author

Orthopaedie Onderzoek, ORT Research, Lab Reumatologie/Klinische Immunologie, Regenerative Medicine and Stem Cells, Johnbosco, Castro, Karbaat, Lisanne, Korthagen, Nicoline M, Warmink, Kelly, Koerselman, Michelle, Coeleveld, Katja, Becker, Malin, van Loo, Bas, Zoetebier, Bram, Both, Sanne, Weinans, Harrie, Karperien, Marcel, Leijten, Jeroen, Orthopaedie Onderzoek, ORT Research, Lab Reumatologie/Klinische Immunologie, Regenerative Medicine and Stem Cells, Johnbosco, Castro, Karbaat, Lisanne, Korthagen, Nicoline M, Warmink, Kelly, Koerselman, Michelle, Coeleveld, Katja, Becker, Malin, van Loo, Bas, Zoetebier, Bram, Both, Sanne, Weinans, Harrie, Karperien, Marcel, and Leijten, Jeroen

Published
2023

11. Mesenchymal stem/stromal cells-derived extracellular vesicles as a potentially more beneficial therapeutic strategy than MSC-based treatment in a mild metabolic osteoarthritis model

Author

ORT Research, CTI Eijkelkamp, Brain, Cancer, Child Health, Infection & Immunity, Regenerative Medicine and Stem Cells, Orthopaedie Onderzoek, CMM, CMM Groep Coffer, Warmink, Kelly, Rios, Jaqueline L., Varderidou-Minasian, Suzy, Torres-Torrillas, Marta, van Valkengoed, Devin R., Versteeg, Sabine, Eijkelkamp, Niels, Weinans, Harrie, Korthagen, Nicoline M., Lorenowicz, Magdalena J., ORT Research, CTI Eijkelkamp, Brain, Cancer, Child Health, Infection & Immunity, Regenerative Medicine and Stem Cells, Orthopaedie Onderzoek, CMM, CMM Groep Coffer, Warmink, Kelly, Rios, Jaqueline L., Varderidou-Minasian, Suzy, Torres-Torrillas, Marta, van Valkengoed, Devin R., Versteeg, Sabine, Eijkelkamp, Niels, Weinans, Harrie, Korthagen, Nicoline M., and Lorenowicz, Magdalena J.

Published
2023

12. Inflammation in obesity-driven osteoarthritis: Investigating the role of monocytes and macrophages

Author

Warmink, Kelly, Weinans, H.H., and Korthagen, N.M.

Subjects
Osteoarthritis, inflammation, macrophage, monocyte, metabolic syndrome
Abstract

Osteoarthritis (OA) is a joint disease that causes pain and limitations in mobility. Current treatment of OA is focused on management of symptoms and joint replacement surgery at end stage disease, and no curative or disease-modifying treatment is available. Despite large advances over the past decades, the underlying pathophysiology of OA is still partly unclear as many factors contribute to the development of OA. In addition, the large heterogeneity of the osteoarthritic patient population suggest there might be a different underlying disease etiology in different subset populations, that may need different treatment approaches. We suspect that a large subset of patients is described by the metabolic-OA phenotype, where obesity and its subsequent low-grade systemic inflammation will accelerate the development of OA locally in the joint. Two cell types that contribute tot his low grade inflammation are monocytes and macrophages. This thesis aimed to investigate the effects of obesity-induced systemic inflammation on joint inflammation and OA development. We focused on characterizing macrophage and monocyte inflammation, with the goal to find potential targets for treatment or diagnostics, as there is a great need for better treatment options and early diagnosis tools in OA.

Published
2023

14. Additional file 1 of Mesenchymal stem/stromal cells-derived extracellular vesicles as a potentially more beneficial therapeutic strategy than MSC-based treatment in a mild metabolic osteoarthritis model

Author

Warmink, Kelly, Rios, Jaqueline L., Varderidou-Minasian, Suzy, Torres-Torrillas, Marta, van Valkengoed, Devin R., Versteeg, Sabine, Eijkelkamp, Niels, Weinans, Harrie, Korthagen, Nicoline M., and Lorenowicz, Magdalena J.

Abstract

Additional file 1: Fig. S1. Characterization of extracellular vesicles derived from human bone marrow MSCs. A MSC-EVs are positive for exosomal markers CD63 and CD9. EVs isolated from conditioned medium derived from primary bone marrow MSCs were subjected to sucrose density gradient followed by Western blot analysis for presence of CD63 and CD9. Representative Western-blots cropped at the molecular weight of CD63 and CD9 respectively are shown. B Nanosight Particle Tracking Analysis derived from 5 measurements showing that the nominal size of these vesicles is 125 nm. Red colour indicates error bar of the mean. Fig. S2. Inflammatory serum markers. Results of the 27 multiplex-assay showing all measured cytokines and chemokines from week 24 serum. One animal was excluded from multiplex analysis due to out of range values. Several EGF data points were excluded from analysis due to out of range values. Graphs represent mean ± 95% confidence interval, p values in graphs are reported with asterisks where p ≤ 0.05 is *, p ≤ 0.01 is **, p ≤ 0.001 is *** and p > 0.05 is not significant. Fig. S3. Body mass and metabolics. A Body mass between week 11 and 24 in the experimental protocol. B Body mass individual values at week 11 and C at week 24. Body mass increase as a percentage from week 11 in individual animals for D PBS, E MSCs and F MSC-EVs groups. G Homeostatic Model Assessment for Insulin Resistance, H triglyceride and I leptin concentrations. J Correlation between body mass and leptin concentration. Three animals were excluded from HOMA-IR analysis and one animal was excluded from leptin concentration analysis, due to out of range values. No animals or data points were excluded from all other analysis shown here, n = 12 per group. Graphs represent mean ± 95% confidence interval, p values in graphs are reported with asterisks where p ≤ 0.05 is *, p ≤ 0.01 is **, p ≤ 0.001 is *** and p > 0.05 is not significant. Fig. S4. Full length gels used in the Fig. S1A.

Published
2023
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15. Sprague Dawley Rats Show More Severe Bone Loss, Osteophytosis and Inflammation Compared toWistar Han Rats in a High-Fat, High-Sucrose Diet Model of Joint Damage

Author

Warmink, Kelly, Rios, Jaqueline L, van Valkengoed, Devin R, Korthagen, Nicoline M, Weinans, Harrie, Warmink, Kelly, Rios, Jaqueline L, van Valkengoed, Devin R, Korthagen, Nicoline M, and Weinans, Harrie

Abstract

In animal models, joint degeneration observed in response to obesogenic diet varies in nature and severity. In this study, we compare joint damage in Sprague Dawley and Wistar-Han rats in response to a high-fat, high-sucrose (HFS) diet groove model of osteoarthritis (OA). Wistar Han ( n = 5) and Sprague Dawley ( n = 5) rats were fed an HFS diet for 24 weeks. OA was induced 12 weeks after the diet onset by groove surgery in the right knee joint. The left knee served as a control. Outcomes were OARSI histopathology scoring, bone changes by µCT imaging, local (synovial and fat pad) and systemic (blood cytokine) inflammation markers. In both rat strains, the HFS diet resulted in a similar change in metabolic parameters, but only Sprague Dawley rats showed a large, osteoporosis-like decrease in trabecular bone volume. Osteophyte count and local joint inflammation were higher in Sprague Dawley rats. In contrast, cartilage degeneration and systemic inflammatory marker levels were similar between the rat strains. The difference in bone volume loss, osteophytosis and local inflammation suggest that both rat strains show a different joint damage phenotype and could, therefore, potentially represent different OA phenotypes observed in humans.

Published
2022

16. Folate Receptor Expression by Human Monocyte-Derived Macrophage Subtypes and Effects of Corticosteroids

Author

Chirurgie, dCSCA RMSC-1, Equine Musculoskeletal Biology, dES RMSC, Dep Clinical Sciences, CS_Locomotion, Warmink, Kelly, Siebelt, Michiel, Low, Philip S, Riemers, Frank M, Wang, Bingbing, Plomp, Saskia G M, Tryfonidou, Marianna A, van Weeren, P René, Weinans, Harrie, Korthagen, Nicoline M, Chirurgie, dCSCA RMSC-1, Equine Musculoskeletal Biology, dES RMSC, Dep Clinical Sciences, CS_Locomotion, Warmink, Kelly, Siebelt, Michiel, Low, Philip S, Riemers, Frank M, Wang, Bingbing, Plomp, Saskia G M, Tryfonidou, Marianna A, van Weeren, P René, Weinans, Harrie, and Korthagen, Nicoline M

Published
2022

18. Folate Receptor Expression by Human Monocyte-Derived Macrophage Subtypes and Effects of Corticosteroids

Author

ORT Research, Regenerative Medicine and Stem Cells, Orthopaedie Onderzoek, Other research (not in main researchprogram), Warmink, Kelly, Siebelt, Michiel, Low, Philip S, Riemers, Frank M, Wang, Bingbing, Plomp, Saskia G M, Tryfonidou, Marianna A, van Weeren, P René, Weinans, Harrie, Korthagen, Nicoline M, ORT Research, Regenerative Medicine and Stem Cells, Orthopaedie Onderzoek, Other research (not in main researchprogram), Warmink, Kelly, Siebelt, Michiel, Low, Philip S, Riemers, Frank M, Wang, Bingbing, Plomp, Saskia G M, Tryfonidou, Marianna A, van Weeren, P René, Weinans, Harrie, and Korthagen, Nicoline M

Published
2022

19. sj-docx-2-car-10.1177_19476035221081469 ��� Supplemental material for Folate Receptor Expression by Human Monocyte���Derived Macrophage Subtypes and Effects of Corticosteroids

Author

Warmink, Kelly, Siebelt, Michiel, Low, Philip S., Riemers, Frank M., Wang, Bingbing, Plomp, Saskia G. M., Tryfonidou, Marianna A., van Weeren, P. Ren��, Weinans, Harrie, and Korthagen, Nicoline M.

Subjects
FOS: Clinical medicine, FOS: Biological sciences, 110323 Surgery, 110604 Sports Medicine, FOS: Health sciences, 69999 Biological Sciences not elsewhere classified, 110314 Orthopaedics
Abstract

Supplemental material, sj-docx-2-car-10.1177_19476035221081469 for Folate Receptor Expression by Human Monocyte���Derived Macrophage Subtypes and Effects of Corticosteroids by Kelly Warmink, Michiel Siebelt, Philip S. Low, Frank M. Riemers, Bingbing Wang, Saskia G. M. Plomp, Marianna A. Tryfonidou, P. Ren�� van Weeren, Harrie Weinans and Nicoline M. Korthagen in CARTILAGE

Published
2022
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20. Folate Receptor Expression by Human Monocyte-Derived Macrophage Subtypes and Effects of Corticosteroids

Author

Warmink, Kelly, Siebelt, Michiel, Low, Philip S, Riemers, Frank M, Wang, Bingbing, Plomp, Saskia G M, Tryfonidou, Marianna A, van Weeren, P René, Weinans, Harrie, Korthagen, Nicoline M, Chirurgie, dCSCA RMSC-1, Equine Musculoskeletal Biology, dES RMSC, Dep Clinical Sciences, CS_Locomotion, Chirurgie, dCSCA RMSC-1, Equine Musculoskeletal Biology, dES RMSC, Dep Clinical Sciences, CS_Locomotion, and Orthopedics and Sports Medicine

Subjects
Physical Therapy, Macrophage Colony-Stimulating Factor, M1/M2, Biomedical Engineering, Granulocyte-Macrophage Colony-Stimulating Factor, Physical Therapy, Sports Therapy and Rehabilitation, Sports Therapy and Rehabilitation, corticosteroids, macrophages, disease marker, Folic Acid, SDG 3 - Good Health and Well-being, FR-beta, Adrenal Cortex Hormones, Humans, Immunology and Allergy, Folate Receptor 2, Biomarkers
Abstract

Objective Folate receptor beta (FR-β) has been used as a clinical marker and target in multiple inflammatory diseases, including osteoarthritis (OA) and rheumatoid arthritis (RA). However, the conditions under which FR-β+ macrophages arise remain unclear and could be affected by corticosteroids. Therefore, we studied FR-β expression in vitro in macrophage subtypes and determined their response to triamcinolone acetonide (TA), a clinically often-used corticosteroid. Design Human monocyte–derived macrophages were differentiated to the known M0, M1, or M2 macrophage phenotypes. The phenotype and FR-β expression and plasticity of the macrophage subtypes were determined using flow cytometry, reverse transcription-quantitative polymerase chain reaction (RT-qPCR), and enzyme-linked immunosorbent assay (ELISA). Results FR-β expression was low in granulocyte-macrophage colony-stimulating factor (GM-CSF)-generated (M1-like) macrophages and high in macrophage colony-stimulating factor (M-CSF)-generated (M0 and M2-like) macrophages. FR-β expression remained high once the M0 or M2 macrophages were stimulated with pro-inflammatory stimuli (interferon-γ plus lipopolysaccharide) to induce M1-like macrophages. On the contrary, anti-inflammatory TA treatment skewed GM-CSF macrophage differentiation toward an M2 and FR-β+ phenotype. Conclusions As corticosteroids skewed monocytes toward an FR-β-expressing, anti-inflammatory phenotype, even in an M1 priming GM-CSF environment, FR-β has potential as a biomarker to monitor success of treatment with corticosteroids. Without corticosteroid treatment, M-CSF alone induces high FR-β expression which remains high under pro-inflammatory conditions. This explains why pro-inflammatory FR-β+ macrophages (exposed to M-CSF) are observed in arthritis patients and correlate with disease severity.

Published
2022

21. sj-docx-1-car-10.1177_19476035221081469 ��� Supplemental material for Folate Receptor Expression by Human Monocyte���Derived Macrophage Subtypes and Effects of Corticosteroids

Author

Warmink, Kelly, Siebelt, Michiel, Low, Philip S., Riemers, Frank M., Wang, Bingbing, Plomp, Saskia G. M., Tryfonidou, Marianna A., van Weeren, P. Ren��, Weinans, Harrie, and Korthagen, Nicoline M.

Subjects
FOS: Clinical medicine, FOS: Biological sciences, 110323 Surgery, 110604 Sports Medicine, FOS: Health sciences, 69999 Biological Sciences not elsewhere classified, 110314 Orthopaedics
Abstract

Supplemental material, sj-docx-1-car-10.1177_19476035221081469 for Folate Receptor Expression by Human Monocyte���Derived Macrophage Subtypes and Effects of Corticosteroids by Kelly Warmink, Michiel Siebelt, Philip S. Low, Frank M. Riemers, Bingbing Wang, Saskia G. M. Plomp, Marianna A. Tryfonidou, P. Ren�� van Weeren, Harrie Weinans and Nicoline M. Korthagen in CARTILAGE

Published
2022
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24. High-fat feeding primes the mouse knee joint to develop osteoarthritis and pathologic infrapatellar fat pad changes after surgically induced injury

Author

ORT Research, Orthopaedie Onderzoek, Regenerative Medicine and Stem Cells, Other research (not in main researchprogram), Warmink, Kelly, Lippinkhof-Kozijn, Anne, Bobeldijk-Pastorova, Ivana, Stoop, R., Weinans, H, Korthagen, Nicoline, ORT Research, Orthopaedie Onderzoek, Regenerative Medicine and Stem Cells, Other research (not in main researchprogram), Warmink, Kelly, Lippinkhof-Kozijn, Anne, Bobeldijk-Pastorova, Ivana, Stoop, R., Weinans, H, and Korthagen, Nicoline

Published
2020

25. Sprague Dawley Rats Show More Severe Bone Loss, Osteophytosis and Inflammation Compared to Wistar Han Rats in a High-Fat, High-Sucrose Diet Model of Joint Damage.

Author

Warmink, Kelly, Rios, Jaqueline L., van Valkengoed, Devin R., Korthagen, Nicoline M., and Weinans, Harrie

Subjects
*SPRAGUE Dawley rats, *LABORATORY rats, *KNEE joint, *ANIMAL nutrition, *SUCROSE, *CANCELLOUS bone
Abstract

In animal models, joint degeneration observed in response to obesogenic diet varies in nature and severity. In this study, we compare joint damage in Sprague Dawley and Wistar-Han rats in response to a high-fat, high-sucrose (HFS) diet groove model of osteoarthritis (OA). Wistar Han (n = 5) and Sprague Dawley (n = 5) rats were fed an HFS diet for 24 weeks. OA was induced 12 weeks after the diet onset by groove surgery in the right knee joint. The left knee served as a control. Outcomes were OARSI histopathology scoring, bone changes by µCT imaging, local (synovial and fat pad) and systemic (blood cytokine) inflammation markers. In both rat strains, the HFS diet resulted in a similar change in metabolic parameters, but only Sprague Dawley rats showed a large, osteoporosis-like decrease in trabecular bone volume. Osteophyte count and local joint inflammation were higher in Sprague Dawley rats. In contrast, cartilage degeneration and systemic inflammatory marker levels were similar between the rat strains. The difference in bone volume loss, osteophytosis and local inflammation suggest that both rat strains show a different joint damage phenotype and could, therefore, potentially represent different OA phenotypes observed in humans. [ABSTRACT FROM AUTHOR]

Published
2022
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26. Folate Receptor Expression by Human Monocyte-Derived Macrophage Subtypes and Effects of Corticosteroids.

Author

Warmink K, Siebelt M, Low PS, Riemers FM, Wang B, Plomp SGM, Tryfonidou MA, van Weeren PR, Weinans H, and Korthagen NM

Subjects
Biomarkers metabolism, Folic Acid metabolism, Humans, Macrophage Colony-Stimulating Factor metabolism, Macrophage Colony-Stimulating Factor pharmacology, Adrenal Cortex Hormones, Folate Receptor 2 metabolism, Granulocyte-Macrophage Colony-Stimulating Factor metabolism, Granulocyte-Macrophage Colony-Stimulating Factor pharmacology, Macrophages
Abstract

Objective: Folate receptor beta (FR-β) has been used as a clinical marker and target in multiple inflammatory diseases, including osteoarthritis (OA) and rheumatoid arthritis (RA). However, the conditions under which FR-β + macrophages arise remain unclear and could be affected by corticosteroids. Therefore, we studied FR-β expression in vitro in macrophage subtypes and determined their response to triamcinolone acetonide (TA), a clinically often-used corticosteroid., Design: Human monocyte-derived macrophages were differentiated to the known M0, M1, or M2 macrophage phenotypes. The phenotype and FR-β expression and plasticity of the macrophage subtypes were determined using flow cytometry, reverse transcription-quantitative polymerase chain reaction (RT-qPCR), and enzyme-linked immunosorbent assay (ELISA)., Results: FR-β expression was low in granulocyte-macrophage colony-stimulating factor (GM-CSF)-generated (M1-like) macrophages and high in macrophage colony-stimulating factor (M-CSF)-generated (M0 and M2-like) macrophages. FR-β expression remained high once the M0 or M2 macrophages were stimulated with pro-inflammatory stimuli (interferon-γ plus lipopolysaccharide) to induce M1-like macrophages. On the contrary, anti-inflammatory TA treatment skewed GM-CSF macrophage differentiation toward an M2 and FR-β + phenotype., Conclusions: As corticosteroids skewed monocytes toward an FR-β-expressing, anti-inflammatory phenotype, even in an M1 priming GM-CSF environment, FR-β has potential as a biomarker to monitor success of treatment with corticosteroids. Without corticosteroid treatment, M-CSF alone induces high FR-β expression which remains high under pro-inflammatory conditions. This explains why pro-inflammatory FR-β + macrophages (exposed to M-CSF) are observed in arthritis patients and correlate with disease severity.

Published
2022
Full Text
View/download PDF

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