Psoriasis is characterized by red, scaly patches that are itchy and painful; it is chronic, incurable and affects 2% to 3% of the population worldwide. The associated psoriatic arthritis can cause disabling damage to bones and joints. Because that damage also is irreversible, study researchers said it is critical to identify patients with psoriatic arthritis early to prevent further destruction to their bones, tendons and joints. A team led by Case Western Reserve University School of Medicine researchers has made two major discoveries involving psoriasis. The researchers found that an overabundance of a protein known as KLK6 can produce and worsen the skin inflammation characteristic of psoriasis, and, even more significant, that KLK6 can play a key role in damaging the joints and bones of people with the disorder. The research also revealed that normalizing the level of KLK6 can eliminate skin inflammation and lessen the arthritis-like damage. The research, which used mouse models and patient skin samples, appeared this spring in The Journal of Clinical Investigation.
While scientists had known that about a third of people diagnosed with psoriasis also develop psoriatic arthritis (PsA), the reason wasn’t clear. Nicole Ward, study’s lead investigator and a professor of Nutrition and Dermatology, explained: “To discover that turning down KLK6 eliminated the skin “inflammation and even improved the arthritis-like changes, that was unbelievable. 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 study is the latest in a series Dr. Ward and her colleagues have conducted involving psoriasis and Kallikrein-related peptidase 6, or KLK6. They undertook the current research to understand how the cellular and molecular mechanisms of KLK6 and another protein, known as protease-activated receptors (PAR)1, promote skin inflammation.
Until now, little was known about the connections between KLK6 and psoriasis or psoriatic arthritis, and even less was known about PAR1 and psoriasis. KLK6 controls reactions either within and outside cells. Increasing scientific evidence suggests it also may have a role in certain inflammatory skin diseases as well as multiple sclerosis, Parkinson’s and Alzheimer’s diseases. PAR1 is a receptor protein that has been extensively studied in the cardiovascular system, mainly for congestive heart failure. PAR‐1 belongs to the G‐protein‐coupled receptor superfamily and is widely expressed in the vascular tissue and the heart, including heart cells and cardiac fibroblasts. Thrombin is a principal protease of the coagulation cascade that converts soluble fibrinogen into an insoluble clot. In addition to its important role in thrombosis, thrombin and Factor Xa can induce multiple cellular responses through PAR‐1.
This explains the interest of PAR1 in blood circulation. However, this receptor is actively working also in brain cells together with several other surface receptors for hormones and neurochemicals. PAR1 appears to have a role also in skin where it controls keratinocyte stability and wound repair. Previously, Ward and colleagues found the skin of psoriasis patients contained 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 theorized that KLK6 might drive inflammation by signaling through PAR1. To address the latest question, genetic engineering was used to overproduce KLK6, which resulted in the development of a psoriasis-like skin disease as well as bone and joint disease. They also found that “knocking out,” or deleting, PAR1 led to a reduction in skin inflammation and, more profoundly, a significant improvement in bone and joint problems.
These findings suggest that chronic inflammation originating in the skin has the capacity to cause distant joint and bone destruction seen in arthritis. The researchers then took psoriasis skin from patients, treated it with an FDA-approved PAR1 antagonist in culture and showed significant decreases in several psoriasis markers. Next, the researchers aim to study how skin inflammation causes arthritis-like damage and translate those findings to benefit patients. They also plan to study and compare models that do and don’t develop arthritis to identify biomarkers that can predict the development of psoriatic arthritis. According to the researchers, if successful, this would be paradigm-shifting and would lead to a more personalized method for identifying which psoriasis patient will go on to develop PsA so we can modify their treatment accordingly.
- Edited by Dr. Gianfrancesco Cormaci, PhD, specialist in Clinical Biochemistry
Billi AC et al., Ward NL. J Clin Invest. 2020 Jun 1; 130(6):3151-3157.
Xue M, Lin H, Zhao R et al. J Dermatol Sci 2017 Mar; 85(3):178-185.
Fischer J, Meyer-Hoffert U. Thromb Haemost. 2013 Sep; 110(3):442.
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