Novel approaches to identify biomechanisms in systemic sclerosis

Systemic sclerosis is a severe connective tissue disease in which inflammation and autoimmunity are associated with progressive tissue remodeling and fibrosis of the skin and internal organs. Complex genetic backgrounds contribute to susceptibility and the disease can be triggered by environmental factors. It is proposed that based on the genetic susceptibility an immune inflammatory disease microenvironment is initiated leading to overexpression of cytokines and growth factors and the development of a fibrotic disease process. Analysis of copy number variation in candidate genes was performed using DNA from patients and controls. This identified a possible association between disease susceptibility and one candidate factor, LEPREL1, a prolyl 3- hydroxylase involved in collagen alignment in the endoplasmic reticulum. Deletion of the LEPREL1 gene led to resistance to dermal fibrosis in mice, whereas levels of the encoded enzyme were increased in disease fibroblasts, all consistent with an important role in the fibrotic process. Furthermore, profiling of tissue fluid from the dermal lesions revealed the presence of an inflammatory, pro-fibrotic microenvironment. When candidate factors present in the tissue fluid (e.g. PDGF), were applied to fibroblasts on aligned collagen matrices, fibroblast orientation and migration was enhanced, modeling the effect on spread of the disease. In contrast, the use of inhibitors (e.g. heparin, imatinib), particularly in combination, attenuated fibroblast alignment and migration. Finally, since this disease has proved resistant to current non-specific therapies, a novel anti-inflammatory peptide was evaluated using a mouse model of systemic sclerosis-like inflammation and fibrosis. Treatment with the peptide suppressed the pattern of inflammatory changes seen in this model of systemic sclerosis, and significantly reduced tissue fibrosis and the replacement of the normal tissue architecture with scar tissue. This approach using antiinflammatory peptides could be potentially relevant for the treatment of individuals with systemic sclerosis in order to attenuate the pathological inflammatory fibrotic process