Whether any particular individual develops arthrofibrosis (or other fibrotic condition) depends on a large number of factors. Some of these are under our control and can be altered. For example, poor diet, smoking and stress.
Other factors are not under our control – these include injury, infection and our genetic predisposition. Arthrofibrosis is caused by the interactions of thousands of different genes after an initiating event that causes cell death.
Some of these genes are key drivers of arthrofibrosis, and perhaps the best known of these is transforming growth factor beta 1 TGF-β1. TGF-β1 is a cytokine (protein) that many cells in the body make in response to inflammation and wounding. It regulates many downstream genes involved in wound healing and inflammation, and there are many feedback effects between these processes1.
Genetic variations that cause changes in the way that TGF-β1 is produced, or in the way it signals to cells are well known to underlie a number of diseases including fibrosis, autoimmune and connective tissue diseases and cancer. However, suppressing the actions of TGF-β entirely can’t be done safely because it an essential protein. Some medications such as Losartan and Metformin down-regulate it’s production or signalling.
However, TGF-β isn’t the only “game in town”, a large number of cellular signals and processes are involved in fibrosis1, and people with typical TGF-β genes can develop arthrofibrosis. An individual may have variations in genes for wound healing (other than TGF-β), immune system function, collagen production or destruction, serotonin production, the vascular system and a number of other processes.
There are thousands of genes, each of which has an influence on the risk of developing arthrofibrosis. However, the total risk is not the sum of these genes, since some regulate others and there are feedback effects. That is, the response is non-linear. And some genes reduce the risk of fibrosis.
Genetic testing is advancing at a rapid pace, and the understanding of how individual genetic variations impact risk is also advancing. Next generation sequencing can now examine a great many genes at once, and provide an indication of individual risk.
The results of comprehensive genetic testing will also indicate which specific therapies should be the most effective for an individual. For example, a monoclonal antibody that targets one particular cytokine, such as TNF-α may not work for another individual who has elevated IL-1.
In the absence of genetic testing, testing the levels of TGF-β and the major inflammatory cytokines such as TNF-α, IL-1, IL-6, and others is helpful and can indicate the best therapeutic approaches. There are a number of laboratories that offer these tests, but they are typically not offered by clinicians, who tend to use traditional test for severe inflammation (CRP, ESR). These often don’t work well for detecting the chronic low-grade inflammation that is involved in fibrosis.
Figure from Usher et. al. 20192.
1. Weiskirchen, R., Weiskirchen, S. & Tacke, F. Organ and tissue fibrosis: Molecular signals, cellular mechanisms and translational implications. Mol Aspects Med 65, 2-15, doi:10.1016/j.mam.2018.06.003 (2019).
2. Usher, K. M. et al. Pathological mechanisms and therapeutic outlooks for arthrofibrosis. Bone Research 7, doi:10.1038/s41413-019-0047-x (2019).