Synovial macrophages promote TGF-β signaling and protect against influx of S100A8/S100A9-producing cells after intra-articular injections of oxidized.

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Synovial macrophages promote TGF-β signaling and protect against influx of S100A8/S100A9-producing cells after intra-articular injections of oxidized low-density lipoproteins W. de Munter, E.J.W. Geven, A.B. Blom, B. Walgreen, M.M.A. Helsen, L.A.B. Joosten, J. Roth, T. Vogl, F.A.J. van de Loo, M.I. Koenders, W.B. van den Berg, P.M. van der Kraan, P.L.E.M. van Lent Osteoarthritis and Cartilage Volume 25, Issue 1, Pages 118-127 (January 2017) DOI: 10.1016/j.joca.2016.07.020 Copyright © 2016 Osteoarthritis Research Society International Terms and Conditions

Fig. 1 Apolipoprotein B is present in human osteoarthritic synovium. Synovial tissue obtained from 12 OA patients was stained against human apoB (A). ApoB was clearly expressed in synovial lining (black arrows) and endothelial cells (yellow arrows) of most patients. B shows detailed photomicrographs of apoB-accumulation in fibroblasts, macrophages, and directly alongside blood vessels. Osteoarthritis and Cartilage 2017 25, 118-127DOI: (10.1016/j.joca.2016.07.020) Copyright © 2016 Osteoarthritis Research Society International Terms and Conditions

Fig. 2 Repeated injections of oxLDL in murine joints do not cause activation of the synovial lining. Mice were injected five times with PBS, LDL or oxLDL, after which histological sections were stained with H&E and scored (A). Figure B shows no regulation S100a8 and S100a9 (RNA expression corrected for Gapdh), nor were any effects found on immunohistochemistry for S100A8 (C). S100A8/9 protein levels in synovial wash-outs were decreased after injection of oxLDL (D). Statistics were performed using a one-way ANOVA followed by Dunnett's posttest. n = 9 mice per group for histology and n = 8 mice per group for RNA expression and synovial wash-outs. Osteoarthritis and Cartilage 2017 25, 118-127DOI: (10.1016/j.joca.2016.07.020) Copyright © 2016 Osteoarthritis Research Society International Terms and Conditions

Fig. 3 OxLDL injection enhance anabolic and decrease catabolic processes. While RNA expression of synovium did not show increased regulation of TGF-β (A), synovial wash-outs, tested in a functional TGF-β reporter gene assay (CAGA-Luciferase reporter plasmid), showed increased presence of active TGF-β signaling in oxLDL injected joints (B). Immunohistochemistry for NITEGE (C) and VDIPEN (E) shows decreased expression in cartilage adjacent to synovial tissue after injection of oxLDL. Figures D and F show representative photomicrographs including isotype control. Statistics were performed using a one-way ANOVA followed by Dunnett's posttest. n = 8 mice per group for synovial wash-outs and RNA expression and n = 4 mice per group for histology. Osteoarthritis and Cartilage 2017 25, 118-127DOI: (10.1016/j.joca.2016.07.020) Copyright © 2016 Osteoarthritis Research Society International Terms and Conditions

Fig. 4 OxLDL injection in macrophage depleted joints leads to synovial thickening and S100A8/9 production. Synovial lining macrophages were depleted by intra-articular injection of clodronate liposomes. Subsequent injection of oxLDL led to increased synovial thickening (A). B shows representative H&E stained photomicrographs. Quantitative real-time PCR analysis showed increased expression of S100a8 (C) and S100a9 (D) after oxLDL injection. In addition, protein levels of S100A8/A9 were significantly increased in synovial wash-outs (E). F shows representative pictures of immunohistochemical staining for S100A8 and S100A9, including isotype control. Statistics were performed using a one-way ANOVA followed by Dunnett's posttest. n = 9 mice per group for histology and n = 8 mice per group for RNA expression. Osteoarthritis and Cartilage 2017 25, 118-127DOI: (10.1016/j.joca.2016.07.020) Copyright © 2016 Osteoarthritis Research Society International Terms and Conditions

Fig. 5 OxLDL injections in macrophage-depleted joints lead to cell attraction. Injection of oxLDL in macrophage-depleted knee joints results in increased production of CCL2 (A), CCL3 (B) and CXCL1 (C). FCM-analysis revealed increased amounts of monocytes and neutrophils in the synovium (D), which was confirmed by immunohistochemical staining, showing infiltrating cells both positively and negatively stained for NIMP.R14 (photomicrographs in E, including isotype control), while. Statistics were performed using a one-way ANOVA followed by Dunnett's posttest (for PCR and protein measurements) or a Student's t-test (for FACS data). n = 8 mice per group. Osteoarthritis and Cartilage 2017 25, 118-127DOI: (10.1016/j.joca.2016.07.020) Copyright © 2016 Osteoarthritis Research Society International Terms and Conditions

Fig. 6 In the absence of lining macrophages, oxLDL injections increase expression of neo-epitopes of aggregenases. After depletion of macrophages, repeated oxLDL injections did not increase the amount of active TGF-β signaling in synovial wash-outs (A). Although oxLDL injection showed a trend towards decreased VDIPEN expression (B), it significantly increased expression of NITEGE (C, with representative photomicrographs in D). Statistics were performed using a one-way ANOVA followed by Dunnett's posttest. n = 8 mice per group for synovial wash-outs and n = 4 mice per group for histology. Osteoarthritis and Cartilage 2017 25, 118-127DOI: (10.1016/j.joca.2016.07.020) Copyright © 2016 Osteoarthritis Research Society International Terms and Conditions