Profiling drugs for rheumatoid arthritis that inhibit synovial fibroblast activation

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Abstract

Activation of synovial fibroblasts (SFs) contributes to rheumatoid arthritis (RA) by damaging synovial membranes and generating inflammatory cytokines that recruit immune cells to the joint. In this paper we profile cytokine secretion by primary human SFs from healthy tissues and from donors with RA and show that SF activation by TNF, IL-1α, and polyinosinic-polycytidylic acid (Poly(I:C)) cause secretion of multiple cytokines found at high levels in RA synovial fluids. We used interaction multiple linear regression to quantify therapeutic and countertherapeutic drug effects across activators and donors and found that the ability of drugs to block SF activation was strongly dependent on the identity of the activating cytokine. (5z)-7-oxozeaenol (5ZO), a preclinical drug that targets transforming growth factor-β–activated kinase 1 (TAK1), was more effective at blocking SF activation across all contexts than the approved drug tofacitinib, which supports the development of molecules similar to 5ZO for use as RA therapeutics.

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Figure 1: Experimental strategy exploring SF activation and composition of RA synovial fluids.
Figure 2: Multivariate analysis of the effect of small-molecule kinase inhibitors on induced cytokine secretion.
Figure 3: iMLR to analyze context dependencies in perturbation-response data.
Figure 4: Dependence of SF activation on the identity of the activating ligand.
Figure 5: 5ZO normalizes SF activation across multiple contexts.
Figure 6: Inferring the likely targets of 5ZO on the basis of experiments in SFs and current understanding of the drug.

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Acknowledgements

We thank S. Rudnicki and the HMS ICCB for automation assistance; B. Joughin, D. Clarke, M. Morris, J. Copeland, G. Nabozny, D. Klatte, and S. Pullen for helpful discussions; and N. Gray and T. Zhang at DFCI (Boston, Massachusetts, USA) for providing JNK-IN-8. This work was supported by the NIH (LINCS grant U54HL127365 to P.K.S., grant P50 GM107618 to P.K.S., and NRSA Fellowship 5F32AR062931 to D.S.J.) and by a sponsored research agreement dated 1 August 2009 from Boehringer Ingelheim Inc. to P.K.S. and D.A.L.

Author information

D.S.J. performed experiments and computational analyses, analyzed the results, and wrote and edited the paper; A.P.J. performed experiments; D.A.L. and P.K.S. analyzed the results and wrote and edited the paper; J.M.B. and J.L.S. made key intellectual contributions.

Correspondence to Peter K Sorger.

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Competing interests

J.M.B. and J.L.S. were employees at Boehringer Ingelheim Pharmaceuticals Inc. during the course of the studies; D.A.L. and P.K.S. were consultants to Boehringer Ingelheim Pharmaceuticals Inc.

Supplementary information

Supplementary Text and Figures

Supplementary Results, Supplementary Tables 1–7 and Supplementary Figures 1–18. (PDF 12484 kb)

Supplementary Data 1

SF donor sample N2586. (XLS 602 kb)

Supplementary Data 2

SF donor sample N2645. (XLS 602 kb)

Supplementary Data 3

SF donor sample N2759. (XLS 602 kb)

Supplementary Data 4

SF donor sample RA1869. (XLS 602 kb)

Supplementary Data 5

SF donor sample RA1931. (XLS 602 kb)

Supplementary Data 6

SF donor sample RA2159. (XLS 602 kb)

Supplementary Data 7

SF donor sample RA2708. (XLS 602 kb)

Supplementary Data 8

SF donor sample N2586. (XLS 175 kb)

Supplementary Data 9

SF donor sample N2645. (XLS 175 kb)

Supplementary Data 10

SF donor sample N2759. (XLS 175 kb)

Supplementary Data 11

SF donor sample RA1869. (XLS 175 kb)

Supplementary Data 12

SF donor sample RA1931. (XLS 175 kb)

Supplementary Data 13

SF donor sample RA2159. (XLS 175 kb)

Supplementary Data 14

SF donor sample RA2708. (XLS 175 kb)

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Jones, D., Jenney, A., Swantek, J. et al. Profiling drugs for rheumatoid arthritis that inhibit synovial fibroblast activation. Nat Chem Biol 13, 38–45 (2017) doi:10.1038/nchembio.2211

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