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A fibroblast mitogen present in scleroderma but not control sera: inhibition by proteinase inhibitors
Abstract:
Fibroblast mitogenic activity (MA) has been identified in scleroderma (SD) sera. Control and scleroderma skin fibroblasts in early passage were observed for replication (cell counts) after 72 h of serum exposure. SD sera at 15% concentration induced a significant increase in control fibroblast numbers when compared with control sera; this effect was not seen with SD cells while at higher serum concentrations (30%); SD cells were slightly responsive to the MA. MA was completely abrogated by the proteinase inhibitors STI and TLCK which did not affect mitogens in healthy sera. Circulating mitogenic proteinases selective for fibroblasts could play a role in the fibrosis of SD by modulating fibroblast replication.
Insights
Scleroderma (SD) sera contain fibroblast mitogenic activity (MA) that increases fibroblast replication. Proteinase inhibitors block this MA, suggesting circulating proteinases may contribute to SD fibrosis.
Area of Science:
- Connective tissue diseases
- Dermatology
- Immunology
Background:
- Scleroderma (SD) is a fibrotic disease characterized by abnormal extracellular matrix deposition.
- Fibroblast mitogenic activity (MA) has been observed in the sera of patients with scleroderma.
Purpose of the Study:
- To investigate the role of fibroblast MA in scleroderma pathogenesis.
- To determine if MA in scleroderma sera is mediated by proteinases.
Main Methods:
- Human skin fibroblasts from control and scleroderma subjects were cultured.
- Fibroblast replication was assessed after exposure to control or scleroderma sera.
- The effect of proteinase inhibitors (STI and TLCK) on MA was evaluated.
Main Results:
- Scleroderma sera significantly increased control fibroblast replication at 15% concentration.
- Scleroderma fibroblasts showed only slight responsiveness to MA, even at 30% serum concentration.
- Proteinase inhibitors completely abrogated the MA in scleroderma sera but not in control sera.
Conclusions:
- Circulating proteinases with selective fibroblast mitogenic activity may contribute to the fibrotic process in scleroderma.
- These findings suggest a potential mechanism for fibroblast dysregulation in scleroderma pathogenesis.