Partial protection against collagen antibody-induced arthritis in PARP-1 deficient mice

Rheumatoid arthritis (RA) is characterized by inflammation, synovial hyperplasia, pannus formation and progressive destruction of cartilage and bone [1,2]. In RA, inflammatory cytokines, chemokines, growth factors and adhesion molecules are produced by leukocytes and resident synoviocytes. These factors perpetuate chronic inflammation by the recruitment of additional inflammatory cells into the sublining region that, in turn, lead to continuous production of inflammatory mediators and enzymes, resulting in destruction of joint structures [3-8]. The efficacy of treatments with tumor necrosis factor (TNF) and IL-1 inhibitors strongly support the key role of inflammatory cytokines in the pathogenesis of RA [9,10] and points to therapeutic approaches directed toward regulation of cytokine networks involved in RA.Poly(ADP-ribose) polymerase (PARP)-1 is a highly conserved nuclear zinc-finger protein involved in maintenance of genomic integrity. PARP-1 detects DNA breakage generated by several genotoxic agents and synthesizes and transfers ADP ribose units (poly(ADPribosyl)ation activity) into acceptor proteins involved in the conservation of chromatin structure and DNA metabolism, modulating in this way DNA repair and cell survival [11,12]. Studies with PARP-1 deficient mice or with chemical inhibitors have enlarged the physiological role of this protein. In these situations, lack of PARP-1 function protects against several disorders with an inflammatory component, such as endotoxic shock [13], streptozotocin induced diabetes [14], chronic colitis [15] and uveitis [16]. Two mechanisms have been proposed to explain the role of PARP-1 in these diseases. One mechanism is related to massive PARP-1 activation induced by genotoxic injury developed during the inflammatory process. In this case, hyperactivated PARP-1 would lead to ATP depletion and cell dysfunction [17]. The other proposed mechanism is related to a functional link between PARP-1 and inflammation-related transcrip