RESUMO
Systemic sclerosis (SSc) is an autoimmune disease characterized by fibrosis of skin and internal organs. Protein tyrosine phosphatases have received little attention in the study of SSc or fibrosis. Here, we show that the tyrosine phosphatase PTP4A1 is highly expressed in fibroblasts from patients with SSc. PTP4A1 and its close homolog PTP4A2 are critical promoters of TGFß signaling in primary dermal fibroblasts and of bleomycin-induced fibrosis in vivo. PTP4A1 promotes TGFß signaling in human fibroblasts through enhancement of ERK activity, which stimulates SMAD3 expression and nuclear translocation. Upstream from ERK, we show that PTP4A1 directly interacts with SRC and inhibits SRC basal activation independently of its phosphatase activity. Unexpectedly, PTP4A2 minimally interacts with SRC and does not promote the SRC-ERK-SMAD3 pathway. Thus, in addition to defining PTP4A1 as a molecule of interest for TGFß-dependent fibrosis, our study provides information regarding the functional specificity of different members of the PTP4A subclass of phosphatases.
Assuntos
Proteínas Imediatamente Precoces/metabolismo , Sistema de Sinalização das MAP Quinases , Proteínas Tirosina Fosfatases/metabolismo , Escleroderma Sistêmico/enzimologia , Fator de Crescimento Transformador beta/fisiologia , Animais , Linhagem Celular , Derme/patologia , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Feminino , Fibroblastos/enzimologia , Fibroblastos/metabolismo , Humanos , Proteínas Imediatamente Precoces/antagonistas & inibidores , Proteínas Imediatamente Precoces/genética , Proteínas Imediatamente Precoces/fisiologia , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteínas Tirosina Fosfatases/antagonistas & inibidores , Proteínas Tirosina Fosfatases/genética , Proteínas Tirosina Fosfatases/fisiologia , Proteínas Proto-Oncogênicas pp60(c-src)/metabolismo , Escleroderma Sistêmico/metabolismo , Escleroderma Sistêmico/patologia , Proteína Smad3/metabolismoRESUMO
Psoriatic arthritis (PsA) is an inflammatory arthritis that occurs in individuals with psoriasis. The primary goals in the treatment of PsA are reduction of pain; improvement in the other signs and symptoms of disease, including skin and nail involvement; optimization of functional capacity and quality of life; and inhibition of the progression of joint damage. These goals should be achieved while minimizing potential toxicities from treatment. The management of PsA should simultaneously target arthritis, skin disease, and other manifestations of PsA, including involvement of the axial skeleton, dactylitis, enthesitis, and eye inflammation. In this respect targeted biological agents, primarily tumor necrosis factor inhibitors, have emerged as generally well tolerated and highly effective alternatives to traditional disease modifying antirheumatic drugs. Herein we review the evidence regarding the treatment of PsA arthritis with biological agents.