RESUMEN
Rheumatoid arthritis (RA) is an autoimmune synovitis characterized by the formation of pannus and the destruction of cartilage and bone in the synovial joints. Although immune cells, which infiltrate the pannus and promote inflammation, play a prominent role in the pathogenesis of RA, other cell types also contribute. Proliferation of synovial fibroblasts, for example, underlies the formation of the pannus, while proliferation of endothelial cells results in neovascularization, which supports the growth of the pannus by supplying it with nutrients and oxygen. The synovial fibroblasts also promote inflammation in the synovium by producing cytokines and chemokines. Finally, osteoclasts cause the destruction of bone. In this study, we show that erlotinib, an inhibitor of the tyrosine kinase epidermal growth factor receptor (EGFR), reduces the severity of established collagen-induced arthritis, a mouse model of RA, and that it does so by targeting synovial fibroblasts, endothelial cells, and osteoclasts. Erlotinib-induced attenuation of autoimmune arthritis was associated with a reduction in number of osteoclasts and blood vessels, and erlotinib inhibited the formation of murine osteoclasts and the proliferation of human endothelial cells in vitro. Erlotinib also inhibited the proliferation and cytokine production of human synovial fibroblasts in vitro. Moreover, EGFR was highly expressed and activated in the synovium of mice with collagen-induced arthritis and patients with RA. Taken together, these findings suggest that EGFR plays a central role in the pathogenesis of RA and that EGFR inhibition may provide benefits in the treatment of RA.
Asunto(s)
Artritis Experimental/tratamiento farmacológico , Artritis Reumatoide/enzimología , Receptores ErbB/fisiología , Inhibidores de Proteínas Quinasas/uso terapéutico , Quinazolinas/uso terapéutico , Animales , Artritis Experimental/enzimología , Becaplermina , División Celular/efectos de los fármacos , Ciclooxigenasa 2/biosíntesis , Ciclooxigenasa 2/genética , Citocinas/biosíntesis , Citocinas/genética , Evaluación Preclínica de Medicamentos , Células Endoteliales/efectos de los fármacos , Células Endoteliales/enzimología , Receptores ErbB/antagonistas & inhibidores , Receptores ErbB/biosíntesis , Receptores ErbB/genética , Clorhidrato de Erlotinib , Fibroblastos/efectos de los fármacos , Fibroblastos/enzimología , Regulación de la Expresión Génica/efectos de los fármacos , Células Endoteliales de la Vena Umbilical Humana/efectos de los fármacos , Células Endoteliales de la Vena Umbilical Humana/enzimología , Humanos , Masculino , Ratones , Ratones Endogámicos DBA , Neovascularización Patológica/tratamiento farmacológico , Neovascularización Patológica/enzimología , Osteoclastos/efectos de los fármacos , Osteoclastos/enzimología , Proteínas Proto-Oncogénicas c-sis/farmacología , Quinazolinas/farmacología , Membrana Sinovial/enzimología , Membrana Sinovial/patologíaRESUMEN
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Asunto(s)
Humanos , Enfermedad de Parkinson/fisiopatología , Evolución Clínica , Progresión de la EnfermedadRESUMEN
El Burgo de Osma (Soria, Spain) offers one of the best preserved medieval structures in Spain. The interior of the building conserves abundant samples of Romanesque art, and the tomb in polychromatic stone of the founder, San Pedro de Osma. We have classified those pieces of art that could represent descriptions of movement disorders. In the main façade of the Cathedral, several statues representing prophets can be seen one of them is clearly different to the rest. This statue represents a man with abnormal cervical posture characterized by right rotation, head tilt and elevation of right shoulder. The tomb includes several statues representing fragments of the life of San Pedro de Osma. Some of these figures show movement disorders. First, a woman with a baby in her arms who has marked head tilt to the left. Second a peasant without hands, perhaps amputated, this man has a head tilt to the right. We suggest that in the latter case ergotism can explain both manifestations: peripheral vascular disease leading to amputation, and cervical dystonia.Finally, a statue of polychromatic wood represents a priest with stooped posture, half open mouth, staring expression and a very notorious anterocollis. The author probably depicted a man with parkinsonism.