Koji Yokoyama

Enhanced chondrogenesis of induced pluripotent stem cells from patients with neonatal-onset multisystem inflammatory disease occurs via the caspase 1-independent cAMP/protein kinase A/CREB pathway

Neonatal‐onset multisystem inflammatory disease (NOMID) is a dominantly inherited autoinflammatory disease caused by NLRP3 mutations. NOMID pathophysiology is explained by the NLRP3 inflammasome, which produces interleukin‐1β (IL‐1β). However, epiphyseal overgrowth in NOMID is resistant to anti–IL‐1 therapy and may therefore occur independently of the NLRP3 inflammasome. This study was undertaken to investigate the effect of mutated NLRP3 on chondrocytes using induced pluripotent stem cells (iPSCs) from patients with NOMID.

Understanding the pathophysiology of NOMID arthropathy for drug discovery by iPSCs technology

NOMID, also known as CINCA syndrome, is a dominantly inherited autoinflammatory disease caused by NLRP3 mutations. The pathophysiology of NOMID is explained by gain of function mutation of NLRP3, which activates NLRP3 inflammasome and produce an excess of IL-1β. This mechanism is supported by clinical observation that anti-IL-1 therapy is effective on its systemic inflammation. However, one of its characteristic features, epiphyseal overgrowth, is considered to be resistant to anti-IL-1 therapy, which raises a question that other mechanism than NLRP3 inflammasome may play a role in the epiphyseal overgrowth. In this study, we investigated the effect of mutated NLRP3 on chondrocytes using induced pluripotent stem cells (iPSCs) derived from NOMID patients, and tried to identify drugs to treat the abnormal chondrocytes overgrowth.