Cellular and Molecular Mechanisms of Fibrosis in Systemic Sclerosis

Fibrogenesis is a sequential pathological process culminating in the scarring of virtually any organ. Fibrosis is characterized by disruption of normal tissue architecture and its replacement with stiff, paucicellular, and collagen-rich connective tissue. The process results in progressive functional impairment and ultimately organ failure. Fibrosis is the hallmark of systemic sclerosis (SSc, scleroderma), as well as a large and heterogeneous collection of human fibrotic diseases. In SSc, synchronous fibrosis occurs in the skin and multiple internal organs. Fibrosis is the end result of chronic tissue injury characterized by vascular damage, inflammation, and mesenchymal stromal cell activation in a genetically predisposed individual. Injury-activated vascular, epithelial, and immune cells generate profibrotic soluble mediators that serve as paracrine cues to induce sustained activation, differentiation, and survival of stromal cells, leading to excessive extracellular matrix (ECM) deposition, tissue stiffness, and ultimately fibrosis. Fibrosis progression is driven by multiple self-sustaining amplification mechanisms including mechanical feedback loops, epigenetic modifications, matrikines, metabolic alterations, cellular aging, and senescence. Advances in deciphering the pathophysiology of fibrosis in SSc are paving the way for innovative therapeutic approaches that not only prevent progression of tissue scarring, but also have the potential to reverse established fibrosis. Current approved antifibrotic treatments are modestly slow, but do not reverse fibrosis.