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.