Elastic fiber assembly is disrupted by excessive accumulation of chondroitin sulfate in the human dermal fibrotic disease, keloid

Abstract

Keloid is a fibrotic disease characterized by abnormal accumulation of extracellular matrix in the dermis. The keloid matrix contains excess collagen and glycosaminoglycans (GAGs), but lacks elastic fiber. However, the roles of these matrix components in the pathogenesis of keloid are largely unknown. Here, we show that elastin and DANCE (also known as fibulin-5), a protein required for elastic fiber formation, are not deposited in the extracellular matrix of keloids, due to excess accumulation of chondoitin sulfate (CS), although the expression of elastin and DANCE is not affected. Amount of CS accumulated in the keloid legion was 6.9-fold higher than in normal skin. Fibrillin-1, a scaffold protein for elastic fiber assembly, was abnormally distributed in the keloid matrix. Addition of purified CS to keloid fibroblast culture resulted in abnormal deposition of fibrillin-1, concomitant with significantly decreased accumulation of elastin and DANCE in the extracellular matrix. We propose that CS plays a crucial role in the development of keloid lesions through inhibition of elastic fiber assembly.

Protective effects of an extract from Citrus bergamia against inflammatory injury in interferon-gamma and histamine exposed human keratinocytes

“…GAGs and PGs are known to interact selectively with various growth factors, eventually resulting in an imbalance between cell proliferation and cell death, and to modulate the viscoelastic properties of extracellular matrix of tissues. In inflammatory skin disorders the over-secretion of inflammatory cytokines triggers the uncontrolled manifestation of an abnormal accumulation of extracellular matrix components, so that, in inflammatory diseases, the skin shows excessive GAG accumulation (Gasser et al, 2008;Ikeda et al, 2009). Our data demonstrated that CBE added to the cells determined strong inhibition of GAG synthesis from IFN-γ and H.…”

“…In particular, interferon-gamma (IFN-γ) is an essential cytokine in amplifying inflammatory reactions, as it stimulates the synthesis of chemokines that attract inflammatory cells and induces the expression of molecules important as inducible inter-cellular adhesion molecule-1 (ICAM-1) for the retention and activation of T cells (Albanesi et al, 1999). Moreover the over-secretion of inflammatory cytokines triggers an abnormal accumulation of extracellular matrix components such as glycosaminoglycans (GAGs) (Gasser et al, 2008;Ikeda et al, 2009).…”

Ultraviolet Irradiation Induces the Accumulation of Chondroitin Sulfate, but Not Other Glycosaminoglycans, in Human Skin

“…Regarding structural effects, recent studies demonstrated that CS can inhibit elastogenesis [29], [30]. Proteins involved in elastic fiber synthesis, including fibrillin and DANCE, are strongly decreased after addition of C4S and after addition of C6S to cultured fibroblasts [30].…”

“…Proteins involved in elastic fiber synthesis, including fibrillin and DANCE, are strongly decreased after addition of C4S and after addition of C6S to cultured fibroblasts [30]. Because CS accumulates after intermediate-term UV exposure (Figure 3), short-term UV exposure (Figure 6), and in late-stage, solar elastotic lesions [4], its early and sustained induction may contribute to the lack of normal elastic fibers in chronically irradiated skin.…”

Elastin in the Liver

“…Heparan sulfate proteoglycans regulate microfibril assembly and elastin deposition on microfibrils (Cain et al, 2008). Chondroitin sulfate proteoglycans in excess cause abnormal deposition of fibrillin-1 and decreased production of TE and fibulin-5 (Ikeda et al, 2009). Small leucine-rich chondroitin sulfate proteoglycans biglycan and decorin may have a role in the formation of elastic fiber.…”