Control of Fibrosis in Systemic Scleroderma.

Abstract

Scleroderma is characterized by an excessive deposition of collagen in all involved organs. This is due to an overproduction of extracellular matrix (ECM) molecules following induction of gene expression, whereas there is no evidence that the composition of the connective tissue matrix is altered. Several in vivo studies and in vitro experiments suggest that a close interaction between inflammatory cells and fibroblasts is required for the initial activation of fibroblasts. TGF-beta presumably plays an important role, but other cytokines, e.g., PDGF or FGF, may also be involved. Many of the ECM molecules have been shown to interact closely with fibroblasts and provide signals that regulate fibroblast metabolism. The cellular response towards those signals is a further aspect of fibrosis that has attracted attention during recent years. The altered expression of receptor proteins on the cell surface of scleroderma fibroblasts for example might explain in part the lack of down-regulation of collagen synthesis in late phases of the disease. This review summarizes the alterations of connective tissue in scleroderma, and discusses the role of cytokines as well as the ECM for the regulation of fibroblast function and their implication for the development of fibrosis.

Expression of a dominant-negative type II transforming growth factor β (TGF-β) receptor in the epidermis of transgenic mice blocks TGF-β-mediated growth inhibition

“…Other unanswered questions center on TGF-␤ and diseases of connective tissue. Although TGF-␤ is thought to play a critical role in normal wound healing by regulating connective tissue deposition, its inappropriate expression has been implicated in the pathogenesis of fibrotic diseases such as hypertrophic scarring, superficial types of scleroderma, and keloids (37). Our initial attempt to make a transgenic animal model to determine whether expression of TGF-␤ in the epithelial compartment of the skin might contribute to the development of fibrosis in the superficial dermis resulted in neonatal lethality due to growth arrest of the epidermis (3).…”

Vascular changes in autoimmunological connective tissue diseases

“…It is now accepted that systemic sclerosis is a disease in which certain environmental factors (toxic), within the group of patients with genetic predisposition, damage the blood vessels and cause immune cell activation, which leads to non-specific stimulation of fibroblasts and other connective tissue cells that produce components of an extracellular matrix [5].…”

Chemokines and Chemokine Receptors in Scleroderma

“…Since lymphocytes are not only immunological effector cells but also capable of producing a number of cytokines/growth factors, they are considered to play an important role in cutaneous fibrotic reaction. Mononuclear cell infiltrates in the skin belong to the most characteristic histological features in early scleroderma [2], which is suggested to secret cytokines stimulating ECM production. Moreover, infiltrating T cells, predominately CD4+, are the major lymphocytes seen in the involved skin of scleroderma.…”

“…In particular, type I and III collagen, fibronectin and proteoglycans are highly produced by activated fibroblasts in the affected dermis [2]. In vitro, activated scleroderma fibroblasts continue to synthesize increased amounts of collagen, as compared with control fibroblasts [3, 4].…”