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

Paniagua RT, Chang A, Mariano MM, Stein EA, Wang Q, Lindstrom TM, Sharpe O, Roscow C, Ho PP, Lee DM, Robinson WH - Arthritis Res. Ther. (2010)

Bottom Line: 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.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.

View Article: PubMed Central - HTML - PubMed

Affiliation: 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

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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c-Fms inhibition prevents and treats autoimmune arthritis. Clinical arthritis scores (left panels) and paw thickness measurements (right panels) of arthritic mice treated with imatinib or GW2580. (a, b) Collagen-induced arthritis (CIA) prevention studies in DBA/1 mice; administration of vehicle (n = 12), 30 mg/kg GW2580 (n = 12), 80 mg/kg GW2580 (n = 12), or 80 mg/kg imatinib (n = 12) started 1 day before induction of CIA. (c, d) CIA treatment studies in DBA/1 mice; administration of vehicle (n = 15), 80 mg/kg GW2580 (n = 15), or 80 mg/kg imatinib (n = 15) started once CIA is established as indicated. (e, f) Anti-collagen antibody-induced arthritis (CAIA) prevention studies in BALB/c mice; administration of vehicle (n = 5), 80 mg/kg GW2580 (n = 5), or 80 mg/kg imatinib (n = 5) started 1 day before transfer of anti-collagen type II antibodies. (g, h) K/BxN prevention studies in BALB/c mice; administration of vehicle (n = 5), 80 mg/kg GW2580 (n = 5), or 80 mg/kg imatinib (n = 5) started 1 day before transfer of K/BxN serum. The data shown in (a-h) are representative of three independent experiments. Values are the mean ± standard error of the mean for the representative experiment shown. *P < 0.05, **P < 0.01 compared with vehicle-treated mice.
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Figure 1: c-Fms inhibition prevents and treats autoimmune arthritis. Clinical arthritis scores (left panels) and paw thickness measurements (right panels) of arthritic mice treated with imatinib or GW2580. (a, b) Collagen-induced arthritis (CIA) prevention studies in DBA/1 mice; administration of vehicle (n = 12), 30 mg/kg GW2580 (n = 12), 80 mg/kg GW2580 (n = 12), or 80 mg/kg imatinib (n = 12) started 1 day before induction of CIA. (c, d) CIA treatment studies in DBA/1 mice; administration of vehicle (n = 15), 80 mg/kg GW2580 (n = 15), or 80 mg/kg imatinib (n = 15) started once CIA is established as indicated. (e, f) Anti-collagen antibody-induced arthritis (CAIA) prevention studies in BALB/c mice; administration of vehicle (n = 5), 80 mg/kg GW2580 (n = 5), or 80 mg/kg imatinib (n = 5) started 1 day before transfer of anti-collagen type II antibodies. (g, h) K/BxN prevention studies in BALB/c mice; administration of vehicle (n = 5), 80 mg/kg GW2580 (n = 5), or 80 mg/kg imatinib (n = 5) started 1 day before transfer of K/BxN serum. The data shown in (a-h) are representative of three independent experiments. Values are the mean ± standard error of the mean for the representative experiment shown. *P < 0.05, **P < 0.01 compared with vehicle-treated mice.

Mentions: In the in vitro studies, we used imatinib mesylate that was chemically synthesized and confirmed to be more than 98% pure by the Organic Synthesis Core Facility at Memorial Sloan-Kettering Cancer Center (New York, NY, USA). In the in vivo studies, we used imatinib mesylate tablets (Stanford Inpatient Pharmacy Services, Palo Alto, CA, USA), which were ground and resuspended in the vehicle. GW2580 provided by GlaxoSmithKline (Uxbridge, Middlesex, UK) was used in the studies on prevention of arthritis (Figures 1 and 2). GW2580 purchased from Calbiochem (San Diego, CA, USA) and GW2580 chemically synthesized and confirmed to be more than 99% pure by SRI International (Menlo Park, CA, USA) were used in the studies on the treatment of arthritis (Figures 1 and 2), the experiments shown in Figures 3, 4, 5 and 6, and the experiments shown in Additional file 1. Anti-c-Fms, anti-phospho-c-Fms, and isotype control antibodies were from Santa Cruz Biotechnology, Inc. (Santa Cruz, CA, USA).


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

Paniagua RT, Chang A, Mariano MM, Stein EA, Wang Q, Lindstrom TM, Sharpe O, Roscow C, Ho PP, Lee DM, Robinson WH - Arthritis Res. Ther. (2010)

c-Fms inhibition prevents and treats autoimmune arthritis. Clinical arthritis scores (left panels) and paw thickness measurements (right panels) of arthritic mice treated with imatinib or GW2580. (a, b) Collagen-induced arthritis (CIA) prevention studies in DBA/1 mice; administration of vehicle (n = 12), 30 mg/kg GW2580 (n = 12), 80 mg/kg GW2580 (n = 12), or 80 mg/kg imatinib (n = 12) started 1 day before induction of CIA. (c, d) CIA treatment studies in DBA/1 mice; administration of vehicle (n = 15), 80 mg/kg GW2580 (n = 15), or 80 mg/kg imatinib (n = 15) started once CIA is established as indicated. (e, f) Anti-collagen antibody-induced arthritis (CAIA) prevention studies in BALB/c mice; administration of vehicle (n = 5), 80 mg/kg GW2580 (n = 5), or 80 mg/kg imatinib (n = 5) started 1 day before transfer of anti-collagen type II antibodies. (g, h) K/BxN prevention studies in BALB/c mice; administration of vehicle (n = 5), 80 mg/kg GW2580 (n = 5), or 80 mg/kg imatinib (n = 5) started 1 day before transfer of K/BxN serum. The data shown in (a-h) are representative of three independent experiments. Values are the mean ± standard error of the mean for the representative experiment shown. *P < 0.05, **P < 0.01 compared with vehicle-treated mice.
© Copyright Policy - open-access
Related In: Results  -  Collection

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Figure 1: c-Fms inhibition prevents and treats autoimmune arthritis. Clinical arthritis scores (left panels) and paw thickness measurements (right panels) of arthritic mice treated with imatinib or GW2580. (a, b) Collagen-induced arthritis (CIA) prevention studies in DBA/1 mice; administration of vehicle (n = 12), 30 mg/kg GW2580 (n = 12), 80 mg/kg GW2580 (n = 12), or 80 mg/kg imatinib (n = 12) started 1 day before induction of CIA. (c, d) CIA treatment studies in DBA/1 mice; administration of vehicle (n = 15), 80 mg/kg GW2580 (n = 15), or 80 mg/kg imatinib (n = 15) started once CIA is established as indicated. (e, f) Anti-collagen antibody-induced arthritis (CAIA) prevention studies in BALB/c mice; administration of vehicle (n = 5), 80 mg/kg GW2580 (n = 5), or 80 mg/kg imatinib (n = 5) started 1 day before transfer of anti-collagen type II antibodies. (g, h) K/BxN prevention studies in BALB/c mice; administration of vehicle (n = 5), 80 mg/kg GW2580 (n = 5), or 80 mg/kg imatinib (n = 5) started 1 day before transfer of K/BxN serum. The data shown in (a-h) are representative of three independent experiments. Values are the mean ± standard error of the mean for the representative experiment shown. *P < 0.05, **P < 0.01 compared with vehicle-treated mice.
Mentions: In the in vitro studies, we used imatinib mesylate that was chemically synthesized and confirmed to be more than 98% pure by the Organic Synthesis Core Facility at Memorial Sloan-Kettering Cancer Center (New York, NY, USA). In the in vivo studies, we used imatinib mesylate tablets (Stanford Inpatient Pharmacy Services, Palo Alto, CA, USA), which were ground and resuspended in the vehicle. GW2580 provided by GlaxoSmithKline (Uxbridge, Middlesex, UK) was used in the studies on prevention of arthritis (Figures 1 and 2). GW2580 purchased from Calbiochem (San Diego, CA, USA) and GW2580 chemically synthesized and confirmed to be more than 99% pure by SRI International (Menlo Park, CA, USA) were used in the studies on the treatment of arthritis (Figures 1 and 2), the experiments shown in Figures 3, 4, 5 and 6, and the experiments shown in Additional file 1. Anti-c-Fms, anti-phospho-c-Fms, and isotype control antibodies were from Santa Cruz Biotechnology, Inc. (Santa Cruz, CA, USA).

Bottom Line: 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.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.

View Article: PubMed Central - HTML - PubMed

Affiliation: 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

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.

Show MeSH
Related in: MedlinePlus