La vía JAK/STAT y su inhibición en la patogenia de la artritis reumatoide

• Autores: Sandra Pérez Baos
• Directores de la Tesis: Gabriel Herrero-Beaumont Cuenca (dir. tes.), Raquel Largo Carazo (dir. tes.)
• Lectura: En la Universidad Autónoma de Madrid ( España ) en 2018
• Idioma: español
• Número de páginas: 192
• Programa de doctorado: Programa de Doctorado en Biociencias Moleculares por la Universidad Autónoma de Madrid
• Materias:
  • Ciencias de la vida
    • Biología molecular
  • Ciencias médicas
    • Medicina interna
      • Reumatología
• Enlaces
  • Tesis en acceso abierto en: Biblos-e Archivo
• Resumen

  • Rheumatoid Arthritis (RA) is a chronic, systemic, inflammatory autoimmune disorder affecting 1% of the world population. Although it primarily targets synovial joints, around 40% of RA patients also show extra-articular manifestations. These include high cardiovascular risk –paradoxically concomitant with decreased serum lipids that increase with the treatment– and sarcopenia, among others. Until recently, conventional therapy only relied on anti-inflammatory agents as well as biologic and non-biologic disease modifying antirheumatic drugs (DMARDs). However, targeting intracellular pathways has emerged as a promising approach for RA therapeutics. This is the case of tofacitinib, an oral inhibitor of the Janus kinase (JAK) family recently approved for the treatment of RA.

    This thesis, which has been organized in three sections, delves into the role of the JAK/STAT (Signal Transducer and Activator of Transcription) pathway in the above-mentioned articular and extra-articular consequences of RA.

    In order to gain insight into the early effects drawn by tofacitinib on intra-joint JAK/STAT-dependent cytokine signaling, we first sought modulation of synovial STATs and their end-products at flare-up in a rabbit model of antigen induced arthritis (AIA). Our findings point to phospho-STAT1 and metalloproteinases (MMP-1, -3 and -13) as early molecular readouts of response to this JAK inhibitor.

    On the other hand, and aiming to unravel the mechanisms underlaying the so-called lipid paradox during RA and with the treatment, we further studied this phenomenon in vivo, in a rabbit model of AIA, and in vitro, in THP-1 macrophages. We found a link between active inflammation and cholesterol accumulation within synovial macrophages and a direct effect of tofacitinib on restoring the impaired cholesterol release from these cells. This mechanism would justify the increases in serum cholesterol after the treatment of RA patients with JAK/STAT inhibitors.

    Finally, we characterized the pattern of muscular injury and response during arthritis-related sarcopenia in AIA rabbits. Here, we propose that the skeletal muscle itself contributes to the sarcopenic process through a mechanism of autocrine atrophy triggered by the release of muscle-derived, pro-inflammatory mediators. In this scenario, we also described the existence of a compensatory anabolic activation in parallel with a striking reduction in phospho-STAT3 and myostatin levels.

    Altogether, results of this thesis add knowledge to the current understanding of the role of the JAK/STAT pathway in RA pathogenesis and suggest that early inhibition of this intracellular cascade will improve the management of both articular and extra-articular manifestations of the disease in RA patients.