c-Fms-mediated differentiation and priming of monocyte lineage cells play a central role in autoimmune arthritis.
BACKGROUND
Tyrosine kinases are key mediators of multiple signaling pathways implicated in rheumatoid arthritis (RA). We previously demonstrated that imatinib mesylate--a Food and Drug Administration (FDA)-approved, antineoplastic drug that potently inhibits the tyrosine kinases Abl, c-Kit, platelet-derived growth factor receptor (PDGFR), and c-Fms--ameliorates murine autoimmune arthritis. However, which of the imatinib-targeted kinases is the principal culprit in disease pathogenesis remains unknown. Here we examine the role of c-Fms in autoimmune arthritis.


METHODS
We tested the therapeutic efficacy of orally administered imatinib or GW2580, a small molecule that specifically inhibits c-Fms, in three mouse models of RA: collagen-induced arthritis (CIA), anti-collagen antibody-induced arthritis (CAIA), and K/BxN serum transfer-induced arthritis (K/BxN). Efficacy was evaluated by visual scoring of arthritis severity, paw thickness measurements, and histological analysis. We assessed the in vivo effects of imatinib and GW2580 on macrophage infiltration of synovial joints in CIA, and their in vitro effects on macrophage and osteoclast differentiation, and on osteoclast-mediated bone resorption. Further, we determined the effects of imatinib and GW2580 on the ability of macrophage colony-stimulating factor (M-CSF; the ligand for c-Fms) to prime bone marrow-derived macrophages to produce tumor necrosis factor (TNF) upon subsequent Fc receptor ligation. Finally, we measured M-CSF levels in synovial fluid from patients with RA, osteoarthritis (OA), or psoriatic arthritis (PsA), and levels of total and phosphorylated c-Fms in synovial tissue from patients with RA.


RESULTS
GW2580 was as efficacious as imatinib in reducing arthritis severity in CIA, CAIA, and K/BxN models of RA. Specific inhibition of c-Fms abrogated (i) infiltration of macrophages into synovial joints of arthritic mice; (ii) differentiation of monocytes into macrophages and osteoclasts; (iii) osteoclast-mediated bone resorption; and (iv) priming of macrophages to produce TNF upon Fc receptor stimulation, an important trigger of synovitis in RA. Expression and activation of c-Fms in RA synovium were high, and levels of M-CSF were higher in RA synovial fluid than in OA or PsA synovial fluid.


CONCLUSIONS
These results suggest that c-Fms plays a central role in the pathogenesis of RA by mediating the differentiation and priming of monocyte lineage cells. Therapeutic targeting of c-Fms could provide benefit in RA.
Paniagua
Ricardo T
RT
Department of Medicine, Division of Immunology and Rheumatology, Stanford University School of Medicine, CCSR 4135, 269 Campus Drive, Stanford, CA 94305, USA. rpaniagu@stanford.edu
Chang
Anna
A
Mariano
Melissa M
MM
Stein
Emily A
EA
Wang
Qian
Q
Lindstrom
Tamsin M
TM
Sharpe
Orr
O
Roscow
Claire
C
Ho
Peggy P
PP
Lee
David M
DM
Robinson
William H
WH
D000818:Animals; D000840:Anisoles / Q000494:pharmacology; D018501:Antirheumatic Agents / Q000494:pharmacology*; D001169:Arthritis, Experimental / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D001172:Arthritis, Rheumatoid / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D001549:Benzamides; D001862:Bone Resorption / Q000276:immunology / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects / Q000276:immunology*; D019070:Cell Lineage / Q000187:drug effects / Q000276:immunology; D016236:Genes, fms / Q000276:immunology*; D006801:Humans; D000068877:Imatinib Mesylate; D007150:Immunohistochemistry; D007249:Inflammation / Q000276:immunology; D008262:Macrophage Activation / Q000187:drug effects / Q000276:immunology; D016173:Macrophage Colony-Stimulating Factor; D008264:Macrophages / Q000166:cytology / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008811:Mice, Inbred DBA; D009000:Monocytes / Q000166:cytology* / Q000276:immunology; D010010:Osteoclasts / Q000187:drug effects; D010879:Piperazines / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D016186:Receptor, Macrophage Colony-Stimulating Factor / Q000187:drug effects / Q000276:immunology / Q000378:metabolism
C506269:5-(3-methoxy-4-((4-methoxybenzyl)oxy)benzyl)pyrimidine-2,4-diamine; D000840:Anisoles; D018501:Antirheumatic Agents; D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D016173:Macrophage Colony-Stimulating Factor; D000068877:Imatinib Mesylate; D016186:Receptor, Macrophage Colony-Stimulating Factor