CCN2 Inhibition Reverses Fibrosis in Overuse Injury

Fibrosis is a characteristic feature of aging, degrading tissue and organ function in the lungs, kidneys, heart, and elsewhere. It is a failure of regeneration and tissue maintenance, involving the inappropriate formation of scar-like collagen structures. Fibrosis is also found in overuse injury in muscle. In the case of aging, recent research has shown that cellular senescence has a prominent role in fibrosis, most likely mediate by inflammatory signaling. Removal of senescent cells reverses fibrosis in animal models, making senolytic therapies interesting in this context. Here researchers do not discuss senescent cells, but do show that inhibition of CCN2 reverses muscle fibrosis due to overuse injury. CCN2 inhibition underwent a successful human trial for lung fibrosis, which in turn suggests that perhaps senolytic therapies would usefully treat overuse injuries.

Overuse-induced musculoskeletal disorders are widely understood to be injuries and disorders affecting the musculoskeletal system. Tissue fibrosis is a pathological hallmark of overuse-induced muscle injuries and is considered to play key roles in associated motor dysfunction. Such fibrosis is thought to distort dynamic properties of tissue and contribute to functional declines due to adherence of adjacent structures. We have shown that inflammation is a key driver of further fibrosis, and that early use of anti-inflammatory drugs, ergonomic task reduction and manual therapy treatments are able to prevent their development. However, treatments aimed at reducing established muscle and other tissue fibrosis have proved to be more difficult, because once deposited and cross-linked, the extracellular matrix becomes resistant to degradation.

Blocking CCN2 signaling has shown promise for many fibrotic disorders. Downregulation of CCN2 reduces liver fibrosis and limits hypertrophic scarring without affecting wound healing. We recently found that CCN2 is critical to the early progression of chronic overuse-induced muscle fibrosis and grip strength declines in rats that performed an operant reaching, grasping, and lever-pulling task at high repetition high force (HRHF) levels for three weeks. CCN2 inhibition reduced this early progression of fibrosis and improved motor declines. However, continued performance of the HRHF task for 18 weeks, untreated, induces even greater muscle fibrosis and motor declines than at earlier weeks. Therefore, we examined for the first time whether inhibition of CCN2 using this antibody is able to reduce established skeletal muscle fibrosis in our operant rat model of overuse injury.

We show here that 6 weeks of rest combined with systemic inhibition of CCN2 significantly reduced established skeletal muscle fibrosis and improved motor function, compared to control rat levels. We again show that increased muscle fibrosis was mirrored by increased serum levels of CCN2, adding further support to its use as a serum biomarker of underlying tissue fibrosis occurring with overuse injuries as well as other diseases associated with enhanced fibrogenic activity.

Link: https://doi.org/10.1096/fj.202000240RR

Comments

For some time fibrosis was considered more or less one-way. After all, the scar tissue is a perfectly valid connective tissue that replaces the specialized tissues and thus impairing their function, and in some cases might even make the scarred tissue mechanically stronger.
Even minor reversal of fibrosis is a big deal. Of course, if it can be reversed 100% then we have the original more-or-less intact organ...

Posted by: cuberat at April 7th, 2020 2:26 PM

This has implications far beyond organ renewal. For the past 50 years, we have been manually reversing fibrosis in the connective tissue surrounding the muscles in athletes. The result has been that 17 Olympic athletes won 44 Gold Medals and set 11 World Records. But more interestingly, when we doubled chest flexibility, lung capacity increased up to 33% and school grades, pay and promotions also improved.

Since 2000, the major source of overuse and reduction of chest flexibility for our student athletes was carrying a heavy backpack to school every day. This could account for the 40% drop in freshmen STEM majors between 1996 and 2008, as well as the doubling of mental health problems among teens and young adults in this century (testing of a group of ten of our runners after we doubled their chest expansion by two psychologists with the Adjective Check List found an unprecedented improvements in feelings of self-esteem, self-confidence, autonomy, perseverance, self-control, nurturance and dominance and equally large drops in abasement, deference and sympathy-seeking). In other words, fibrosis in the connective tissue surrounding the chest also affects the brain by reducing lung capacity and oxygen intake. Some of the mental decline seen in the elderly may be a result of this fibrosis.

The most alarming study we have found is one that describes what happens to the brains of rats born to pregnant mothers kept in a low oxygen environment. Their brains had less GABA, the calming neurotransmitter that helps us deal with stress. This may account for the 'snowflake' phenomena where students today demand 'safe places' to be protected from ideas or people differing from themselves.

Posted by: Bob Prichard at April 12th, 2020 9:43 AM

What about fibrosis due to medical radiation exposure? This is a big problem for thousands of people who have been blasted by this barbaric and dangerous "treatment". Will senolytics reverse that brand of fibrosis, or is that somehow a different tissue?

Posted by: Dean at April 13th, 2020 8:01 PM
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