Phosphoinositide 3-kinase (PI3K) as a New Therapeutic Target for Rheumatoid Arthritis

ABSTRACT

Dysregulated activation of immune and synovial cells and their reciprocal action play a key role in the pathogenesis of rheumatoid arthritis (RA). Various signal transduction molecules regulate cellular responses and small molecular inhibitors targeting the signal molecules, such as Janus kinase (JAK) and spleen tyrosine kinase (Syk) inhibitors, which have been developed for treating RA. Phosphoinositide 3-kinase (PI3K) is one of the signal molecules, which regulates innate and adaptive immune systems and is over-expressed in RA. PI3Ks phosphorylate phosphoinositide-4,5-bisphosphate (PI-4,5-P2) generates phosphoinositide-3,4,5-triphosphate (PI-3,4,5-P3) at the cell membrane. PI3Ks are divided into class I, II and III. Two catalytic subunits, p110gamma and p110delta of PI3K, modulate cellular development, differentiation, proliferation, migration, cytokine synthesis and antibody production in both innate and adaptive immune systems. In RA synovium and synovial fibroblasts, the expression of p110gamma and p110delta is increased, and their up-regulation results in the abnormal activation of cellular immune responses. In preclinical animal models for RA, genetic deletion of p110gamma and p110delta and selective inhibitors decrease the clinical arthritis score, synovial inflammation, cellular infiltration, bone and cartilage erosion and osteoclast activity. There is a synergistic effect for controlling arthritis by dual inhibition of PI3Kgamma and PI3Kdelta. Through reviewing the function of PI3K in the immune system and the effect of PI3K inhibition in preclinical arthritis animal models, we can expect the PI3K inhibition as a new therapeutic target for treatment of RA.