C-Fms-mediated differentiation and priming of monocyte lineage cells play a central role in autoimmune arthritis

Ricardo T. Paniagua, Anna Chang, Melissa M. Mariano, Emily A. Stein, Qian Wang, Tamsin M. Lindstrom, Orr Sharpe, Claire Roscow, Peggy P. Ho, David M. Lee, William H. Robinson

Research output: Contribution to journalArticle

47 Citations (Scopus)

Abstract

Introduction: 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.

Original languageEnglish (US)
Article numberR32
JournalArthritis Research and Therapy
Volume12
Issue number1
DOIs
StatePublished - Feb 24 2010

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Arthritis
Monocytes
Rheumatoid Arthritis
Experimental Arthritis
Macrophage Colony-Stimulating Factor
Macrophages
Osteoclasts
Synovial Fluid
Psoriatic Arthritis
Fc Receptors
Bone Resorption
Osteoarthritis
Protein-Tyrosine Kinases
Tumor Necrosis Factor-alpha
Joints
Platelet-Derived Growth Factor Receptors
Synovitis
Synovial Membrane
United States Food and Drug Administration
Antineoplastic Agents

ASJC Scopus subject areas

  • Rheumatology
  • Immunology
  • Immunology and Allergy
  • Medicine(all)

Cite this

Paniagua, R. T., Chang, A., Mariano, M. M., Stein, E. A., Wang, Q., Lindstrom, T. M., ... Robinson, W. H. (2010). C-Fms-mediated differentiation and priming of monocyte lineage cells play a central role in autoimmune arthritis. Arthritis Research and Therapy, 12(1), [R32]. https://doi.org/10.1186/ar2940

C-Fms-mediated differentiation and priming of monocyte lineage cells play a central role in autoimmune arthritis. / Paniagua, Ricardo T.; Chang, Anna; Mariano, Melissa M.; Stein, Emily A.; Wang, Qian; Lindstrom, Tamsin M.; Sharpe, Orr; Roscow, Claire; Ho, Peggy P.; Lee, David M.; Robinson, William H.

In: Arthritis Research and Therapy, Vol. 12, No. 1, R32, 24.02.2010.

Research output: Contribution to journalArticle

Paniagua, RT, Chang, A, Mariano, MM, Stein, EA, Wang, Q, Lindstrom, TM, Sharpe, O, Roscow, C, Ho, PP, Lee, DM & Robinson, WH 2010, 'C-Fms-mediated differentiation and priming of monocyte lineage cells play a central role in autoimmune arthritis', Arthritis Research and Therapy, vol. 12, no. 1, R32. https://doi.org/10.1186/ar2940
Paniagua, Ricardo T. ; Chang, Anna ; Mariano, Melissa M. ; Stein, Emily A. ; Wang, Qian ; Lindstrom, Tamsin M. ; Sharpe, Orr ; Roscow, Claire ; Ho, Peggy P. ; Lee, David M. ; Robinson, William H. / C-Fms-mediated differentiation and priming of monocyte lineage cells play a central role in autoimmune arthritis. In: Arthritis Research and Therapy. 2010 ; Vol. 12, No. 1.
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abstract = "Introduction: 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.",
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AU - Paniagua, Ricardo T.

AU - Chang, Anna

AU - Mariano, Melissa M.

AU - Stein, Emily A.

AU - Wang, Qian

AU - Lindstrom, Tamsin M.

AU - Sharpe, Orr

AU - Roscow, Claire

AU - Ho, Peggy P.

AU - Lee, David M.

AU - Robinson, William H.

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N2 - Introduction: 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.

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