JNK Linked to Joint Destruction in RA
Mitogen-activated protein (MAP) kinases regulate various cellular activities, such as gene expression, cell replication and division, cellular differentiation, and cell survival and apoptosis. Dr. Firestein and his team have been studying MAP kinases and how their activities affect rheumatoid arthritis (RA) for a number of years.
Stimuli from outside the cell lead to activation of MAP kinases via a series of chemical reactions inside cells (a signaling cascade). Three major families of MAP kinases have been implicated in the development and perpetuation of RA: c-Jun N-terminal kinase (JNK), extracellular regulating kinase (ERK), and p38 MAP kinase. Each of these families regulates genes involved in inflammation, including cytokines and metalloproteinases.
During previous studies performed by Dr. Firestein’s team, they found that JNK activity is greater in the synovium of people with RA than those of people with osteoarthritis (OA). They also found that JNK activity correlated with increased matrix metalloproteinase (MMP) expression. Matrix metalloproteinases are known to play a critical role in joint destruction (degradation of the matrix on which bone is formed).
What Problem Was Studied?
It was hypothesized that MMP production, and therefore joint destruction, might be regulated by JNK. A series of experiments was devised to test this theory.
What Was Done in the Study?
Using a selective JNK inhibitor as well as novel strains of mice that lack JNK genes, Firestein and colleagues tested the effects of JNK blockade on MMP activation and bone destruction. They used human fibroblast-like synoviocytes obtained during joint replacement surgeries for in vitro experiments and rats with adjuvant-induced arthritis (an animal model of RA) for in vivo experiments.
What Were the Study Results?
They found that the JNK inhibitor reduced MMP levels in laboratory-cultured synoviocytes and that cultured synoviocytes from the mice with deficient JNK expression behaved similarly. The JNK inhibitor significantly decreased JNK activity in arthritic rats treated with the compound. Paw swelling decreased modestly, but animals treated with the inhibitor showed “significantly less joint damage and remodeling than controls.” Firestein concluded that JNK activation is a primary mediator of joint destruction in arthritis.
What Do These Results Mean to People with RA?
Dr. Firestein identified JNK inhibition as a potential therapeutic target for preventing matrix destruction, and hence joint deterioration, in RA. This therapy, combined with approaches that suppress inflammatory pathways, could suppress both inflammation and joint damage in RA. The goal is to develop the next generation of therapies that can match or exceed the benefits of the anti-cytokine antibodies using less expensive oral drugs. Several of these agents are now in clinical development in RA as well as other inflammatory diseases.