Back to the future: targeting the extracellular matrix to treat systemic sclerosis

Fibrosis is the excessive deposition of a stable extracellular matrix (ECM); fibrotic tissue is composed principally of highly crosslinked type I collagen and highly contractile myofibroblasts. Systemic sclerosis (SSc) is a multisystem autoimmune connective tissue disease characterized by skin and organ fibrosis. The fibrotic process has been recognized in SSc for >40 years, but drugs with demonstrable efficacy against SSc fibrosis in ameliorating the lung involvement have only recently been identified. Unfortunately, these treatments are ineffective at improving the skin score in patients with SSc. Previous clinical trials in SSc have largely focused on the cross-purposing of anti-inflammatory drugs and the use of immunosuppressive drugs from the transplantation field, which address inflammatory and/or autoimmune processes. Limited examination has taken place of specific anti-fibrotic agents developed through their ability to directly target the ECM in SSc by, for example, alleviating the persistent matrix stiffness and mechanotransduction that might be required for both the initiation and maintenance of fibrosis, including in SSc. However, because of the importance of the ECM in the SSc phenotype, attempts have now been made to identify drugs that specifically target the ECM, including some drugs that are currently under consideration for the treatment of cancer. The autoimmune disease systemic sclerosis is characterized by fibrosis, which is poorly targeted by the use of anti-inflammatory and immunosuppressive drugs. In this Review, the authors describe the fibrotic mechanisms underlying SSc and attempts to develop drugs to specifically target the fibrotic extracellular matrix. Key points Systemic sclerosis (SSc) is a fibrotic disease, and anti-fibrotic agents deserve consideration as treatments for this disease. Major efforts have been made in the past ~20–25 years to uncover common mechanisms underlying fibrotic disease, including mechanotransductive pathways and enzymes that directly affect extracellular matrix stiffness. Potential SSc targets include collagen prolyl 4-hydroxylase, lysyl oxidase, focal adhesion kinase, TGFβ-activating integrin subunits, TGFβ-activated kinase 1, yes-associated protein 1, myocardin-related transcription factor A and cellular communication network factors. Current efforts are focused on understanding how fibroblast subsets respond excessively to inflammation in fibrosis.