Predisposition
Some genes are key drivers of arthrofibrosis
Arthrofibrosis is caused by the interactions of thousands of different genes and their products after an initiating event that causes cell death. The best known and most important gene product involved in fibrosis is transforming growth factor beta 1 (TGF-β1). TGF-β1 is a cytokine (protein) that cells in the body make in response to inflammation and wounding. It regulates many downstream genes involved in wound healing and inflammation, and positive feedback effects between these can become established, resulting in fibrosis [1].
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Genetic variations
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 signaling.
However, TGF-β isn’t the only “game in town”, a large number of cellular signals and processes are involved in fibrosis [1], 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.
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Non-linearity
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
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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.
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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.
Effects of Female Genes & Hormones
The impact that gender and sex hormones have on arthrofibrosis is rarely mentioned despite the fact that hormones significantly affect the immune system [3]. It is well known that women have a heightened inflammatory response to injury and infection that causes “collateral damage” to the body and results in an increased risk of osteoarthritis and autoimmune disease compared to men [4,5]. As a result, 80 % of autoimmune disease occurs in women [4]. However, the stronger immune system also provides better protection from infections [5].
Recent research now indicates that oestrogen can be pro-fibrotic and increases myofibroblast activation and contraction [6]. This may be why women are at an increased risk of developing arthrofibrosis compared to men [2], however, it should be noted that men also have oestrogen. Myofibroblasts (the cells responsible for fibrosis) in capsular tissues express oestrogen receptors, and oestrogen has been linked to capsular contraction [6]. In addition, becoming pregnant after surgery was found to increase fibrotic contractures [6].
The effects of oestrogen and other female hormones on inflammation and fibrosis have implications for the timing of surgery. The effects of oestrogen on fibrosis are not well studied, and its effects on inflammation are complicated and non-linear. In some contexts oestrogen is pro-inflammatory, and in others it is anti-inflammatory. However, we know that oestrogen levels fall just prior to menstruation, and low levels are known to be pro-inflammatory. Supporting this, menstruation is a highly inflammatory event that causes a systemic (whole body) increase in major inflammatory cytokines [7], so this may be a time to avoid surgery. High levels of inflammation are also associated with menstrual disorders [7], particularly endometriosis, and diagnosis and treatment should be a priority for women with arthrofibrosis. Effective treatment will also assist in reducing menstrual pain.
References
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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).
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Usher, K. M. et al. Pathological mechanisms and therapeutic outlooks for arthrofibrosis. Bone Research 7, doi:10.1038/s41413-019-0047-x (2019).
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Desai, M. K. & Brinton, R. D. Autoimmune Disease in Women: Endocrine Transition and Risk Across the Lifespan. Front Endocrinol (Lausanne) 10, 265, doi:10.3389/fendo.2019.00265 (2019).
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Klein, S. L. & Flanagan, K. L. Sex differences in immune responses. Nat Rev Immunol 16, 626-638, doi:10.1038/nri.2016.90 (2016).
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Straub, R. H. The complex role of estrogens in inflammation. Endocr Rev 28, 521-574, doi:10.1210/er.2007-0001 (2007).
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Segreto, F. et al. The role of angiogenesis, inflammation and estrogen receptors in breast implant capsules development and remodeling. J Plast Reconstr Aesthet Surg 71, 637-643, doi:10.1016/j.bjps.2017.12.003 (2018).
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Azlan, A., Salamonsen, L. A., Hutchison, J. & Evans, J. Endometrial inflammasome activation accompanies menstruation and may have implications for systemic inflammatory events of the menstrual cycle. Hum Reprod 35, 1363-1376, doi:10.1093/humrep/deaa065 (2020).
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