The Tumor-Like Phenotype of Rheumatoid Synovium: Molecular Profiling and Prospects for Precision Medicine

Abstract

Rheumatoid arthritis (RA) is a systemic autoimmune disease characterized by destructive hyperplasia of the synovium. Fibroblast-like synoviocytes (FLS) are a major component of synovial pannus and actively participate in the pathologic progression of RA. How rheumatoid FLS acquire and sustain such a uniquely aggressive phenotype remains poorly understood. We describe the current state of knowledge of the molecular alterations in rheumatoid FLS at the genomic, epigenomic, transcriptomic, proteomic, and metabolomic levels, which offers a means to reconstruct the pathways leading to rheumatoid pannus. Such data provide new pathologic insight and suggest means to more sensitively assess disease activity and response to therapy, as well as support new avenues for therapeutic development.

Figure 1

Schematic model of pathogenic progression of RA with the contribution of FLS-specific genetic factors. Abbreviations: FLS, fibroblast-like synoviocytes; HLA-SE, human leucocyte antigen shared epitope; ACPA, Anti-citrullinated peptide antibody; ROS, reactive oxygen species; RNS, reactive nitrogen species; SNP, single nucleotide polymorphism; mtDNA, mitochondrial DNA.

Figure 2

Epigenetic processes relevant to rheumatoid FLS. Genes in the red box indicate up-regulated processes and genes in the blue box are down-regulated processes. HDAC=histone deacetylase; SIRT1=Sirtuin1; IL=interleukin; TNF-α=tumor necrosis factor-α; EZH2=histone methyltransferase enhancer of zeste homologue 2; SFRP1=secreted frizzled-related protein 1; SENP1=SUMO-specific protease 1; MMP1=metalloproteinase 1; SSAT=spermidine/spermine N1-acetyltransferase; PMFBP1=polyamine-modulated factor 1-binding protein 1; AMD1=S-adenosyl methionine decarboxylase; DNMT1=DNA methyltransferase 1; CXCL12=chemokine (C-X-C motif) ligand 12.

Figure 3

Comparative view of different omics profiles and pathologic signatures of rheumatoid FLS. Differentially expressed genes (DEGs) were first screened using transcriptome data produced for rheumatoid FLS and FLS of osteoarthritic patients (80). Second, the differentially methylated gene (DMGs) signature was obtained from Whitaker et al. (74). Finally, a list of 257 differentially regulated proteins (DRPs) with significant differences in expression or phosphorylation in rheumatoid FLS versus osteoarthritis FLS were found by combining DRPs from five independent studies (–79). GWAS-SNPs, DEGs, DMGs, and DRPs were comapred to identify overlapping and unique lists of genes and proteins. A. The Venn diagram shows the number of common and distinct genes that are detected or differentially expressed in rheumatoid FLS by these comparisons. B. The stacked bar graph depicts the proportion of the overlapping genes harboring RA-associated SNPs in comparison with the proteome, methylome, or transcriptome of rheumatoid FLS. C. The stacked bar graph displays the proportion of the overlapping and non-overlapping genes between at least two different levels of omics data. D. Functional enrichment analysis of the overlapping genes between at least two different levels of omics.

Figure 4

Identification of early synovitis in RA patients or in mice collagen-induced arthritis (CIA) by US, MRI, and SPECT. (A, B). US findings of synovial proliferation in an RA patient. A. Longitudinal grey-scale. US image of the suprapatellar recess in the knee joint shows marked synovial thickening with papillary projection (arrows), accompanied with synovial fluid. B. Power Doppler US image shows increased vascularization (arrowheads). (C and D). MRI and PET findings of early synovitis in a RA patient. C. Axial contrast-enhanced MRI of a patient with RA. Synovial hyperplasia is visualized by signal enhancement on T1-weighted image (arrows). D. Co-localization of metabolic activity and infiammation in vivo using axial hybrid PET/MRI fusion. Increased synovial infiammation is co-localized with altered metabolic activity (arrows). Adapted with permission from ref. 91 (Reproduced from Dysregulated bioenergetics: a key regulator of joint inflammation, Biniecka M, Canavan M, McGarry T, Gao W, McCormick J, Cregan S, et al., 75, 2192-200, 2016 with permission from BMJ Publishing Group Ltd) (E though H). 3D SPECT/CT scans using anti-fibroblast activation protein (FAP) antibody for detection of hyperplastic FLSs. Mice were injected with 15 MBq of ¹¹¹In-labeled FAP antibody (¹¹¹In-28H1). After 24 hrs, radiotracer uptake (arrows) is clearly visible in the infiamed joints of the mouse with CIA (E), but not in the control mouse (F). 3D SPECT/CT scans using ^99mTc-labeled FAP antibody also revealed that increased radiotracer uptake in the joints of an arthritic mouse (G) were reduced by treatment with prednisolone (H). E and F, from adapted with permission from ref. 103 (This research was originally published in JNM. Laverman P, van der Geest T, Terry SY, Gerrits D, Walgreen B, Helsen MM, et al. Immuno-PET and Immuno-SPECT of Rheumatoid Arthritis with Radiolabeled Anti-Fibroblast Activation Protein Antibody Correlates with Severity of Arthritis. J Nucl Med 2015;56:778-83. © by the Society of Nuclear Medicine and Molecular Imaging, Inc.). G and H are adapted with permission from ref. 104 (This research was originally published in JNM. van der Geest T, Laverman P, Gerrits D, Walgreen B, Helsen MM, Klein C, et al. Liposomal Treatment of Experimental Arthritis Can Be Monitored Noninvasively with a Radiolabeled Anti-Fibroblast Activation Protein Antibody. J Nucl Med 2017;58:151-5 © by the Society of Nuclear Medicine and Molecular Imaging, Inc.).