Overabundance of a protein known as KLK6 worsens the skin inflammation of psoriasis and also plays a key role in the joint and bone damage in psoriatic arthritis, US researchers have shown.
Using in vitro skin samples from animals and humans, Case Western Reserve University School of Medicine scientists in Cleveland showed that normalising the level of KLK6 eliminates psoriasis skin inflammation and – in a novel finding – lessens the arthritis-like damage seen in PsA.
The research is the latest attempt to evaluate the cellular and molecular mechanisms of Kallikrein-related peptidase 6, or KLK6 and another protein, known as protease-activated receptors (PAR)1, in skin inflammation.
Lead investigator Dr Nicole Ward (PhD) a professor in the department of dermatology, said that KLK6 was emerging as significant biomarker of inflammatory and malignant diseases, with evidence showing it may promote inflammation and autoimmunity via cleavage of the G protein–coupled protease-activated receptor 1 (PAR1) and PAR2.
In previous studies Dr Ward and colleagues have found the skin of psoriasis patients contains as much as six times more KLK6 than normal. They also found that the PAR1 receptor was overproduced in skin and immune cells. Based on that, they theorised that KLK6 might drive inflammation by signalling through PAR1.
To address the latest question, genetic engineering was used to overproduce KLK6, which resulted in generalised, severe psoriasiform dermatitis with spontaneous development of debilitating psoriatic arthritis-like joint disease.
The new research also found that “knocking out,” or deleting, PAR1 led to a normalisation of skin KLK6 levels and attenuated the psoriatic skin and joint phenotypes.
The mechanism involving this regulatory pathway was confirmed in human psoriasis by using vorapaxar, an FDA-approved PAR1 antagonist, on explanted lesional skin from patients with psoriasis.
“Beyond defining a critical role for KLK6/PAR1 signalling in promoting psoriasis, our results demonstrate that KLK6/PAR1-mediated inflammation in the skin alone is sufficient to drive inflammatory joint disease. Further, we identify PAR1 as a promising cytokine-independent target in therapy of psoriasis and psoriatic arthritis.” said Dr Ward.
“This suggests that clinicians need to aggressively treat patients with psoriasis to prevent the arthritis changes, which generally occur after the skin disease presents itself. Since the joint and bone damage are largely irreversible in patients, prevention becomes critical.”
The research, is published in The Journal of Clinical Investigation.