Individuals with psoriasis have an increased risk of developing psoriatic arthritis (PsA), but the exact mechanisms that link skin inflammation and joint disease are unclear. The results of a new study suggest that in mice, signalling between the serine proteinase kallikrein-related peptidase 6 (KLK6) and proteinase-activated receptor 1 (PAR1) in the skin alone might be sufficient to trigger joint disease.

“The idea that overexpressing a serine protease in the epidermis could be sufficient to cause damage to the joints and bones at distant sites was what got us really excited,” enthuses corresponding author Nicole Ward. “Preclinical reports have shown that skin-initiated inflammation can lead to arthritis-like changes, so our findings support the idea that chronic inflammation in the skin has the capacity to promote distant damage to the joints and bone, and that eliminating the skin inflammation can reduce that damage.”

To investigate the role of KLK6 in psoriasis and PsA, Ward and colleagues developed transgenic mice with overexpression of Klk6 in their keratinocytes. This overexpression of Klk6 could be switched off by the administration of doxycycline. These mice, known as Klk6+ transgenic mice, developed dermatitis that histologically and transcriptionally mirrored human psoriatic skin lesions. Interestingly, the mice also spontaneously developed dactylitis, enthesitis, synovitis, kyphosis and had reduced vertebral bone mineral density, suggestive of a disease similar to that seen in patients with PsA.

Reduction of the Klk6 expression in these mice to wild-type levels with doxycycline ameliorated the skin inflammation and caused a reversal of at least some of their joint disease, suggesting that the skin inflammation was necessary for the arthritis to persist.

Knockout experiments revealed a role for PAR1, but not for PAR2, in KLK6 signalling, and follow-up experiments on human psoriatic skin explants showed a reduction in the production of pro-inflammatory cytokines upon treatment with the PAR1 inhibitor vorapaxar.

the skin inflammation was necessary for the arthritis to persist

“We are focused on taking this work forward by using the Klk6+ transgenic mice to study the mechanisms of action by which skin inflammation causes arthritis-like damage and by translating these findings back into mechanisms that are relevant to patients with PsA,” concludes Ward.