Heterogeneity of collagen synthesis in normal and systemic sclerosis skin fibroblasts. Increased proportion of high collagen‐producing cells in systemic sclerosis fibroblasts

Abstract

Objective. The goal of this study was to quantitatively analyze the distribution of collagen synthesis in normal and systemic sclerosis (SSc) fibroblast populations in order to determine the extent of activation in SSc populations.Methods. We used quantitative in situ hybridization to assess the population distribution of type I collagen synthesis. Fibroblast cultures were derived from both clinically involved and uninvolved skin regions of patients with SSc, and from healthy adults, and assessed for levels of cyl(1) procollagen messenger RNA (mRNA).Results. Dermal fibroblasts from both patients with SSc and normal adults were heterogeneous for distribution of d ( I ) procollagen mRNA when assessed by in situ hybridization, with a wide range of grains per cell. In contrast, clones of neonatal fibroblasts showed a relatively homogeneous distribution of grain counts. Involved SSc skin fibroblasts had a larger proportion of cells in the high collagen-producing mRNA subpopulation (mean f SEM 28.4 f 6.85%), compared with normal fibroblasts (1.75 f 1.44%) and uninvolved fibroblasts (9.6 f 6.73%). Conversely, within the low collagen- Submitted for publication August 9, 1995; acceptcd in revised form March 4, 1996. producing mRNA subpopulation, involved fibroblasts had a smaller proportion of cells (mean f SEM 14.0 f 5.63%) than did uninvolved fibroblasts (37.8 2 13.690/0), while normal fibroblasts had a majority of the cells in this subpopulation (53.5 f 8.68%).Conclusion. These results suggest that only a specific subset of fibroblasts are activated in SSc, as evidenced by an increased proportion of cells with high levels of al(1) procollagen mRNA. Differences between the SSc and normal fibroblast populations appeared to be quantitative rather than qualitative. This may be a result of either clonal selection or selective activation in the pathogenesis of SSc.

Increased Expression of Integrin αvβ3 Contributes to the Establishment of Autocrine TGF-β Signaling in Scleroderma Fibroblasts

“…Dermal fibroblast activation is one of the important processes in the pathogenesis of SSc (2)(3)(4)(5). We have reported that the activation of SSc fibroblasts may be a result of the stimulation by autocrine TGF-␤1, and the up-regulated expression of TGF-␤ receptors may contribute to this process (6 -9).…”

“…Previous findings indicate that the pathogenesis of this disorder includes inflammation, autoimmune attack, and vascular damage, leading to fibroblast activation (2). However, cultured SSc fibroblasts, which are free from such environmental factors, continue to produce the excessive amount of extracellular matrix (ECM) proteins (3,4), suggesting that SSc fibroblasts establish a constitutive self-activation system once activated. One of major cytokines that may be involved in this process is TGF-␤1 (5), and the principal effect of this cytokine on mesenchymal cells is the stimulation of ECM deposition.…”

Impaired IL-17 Signaling Pathway Contributes to the Increased Collagen Expression in Scleroderma Fibroblasts

“…Although the pathogenesis of this disease is unclear, it includes inflammation, autoimmune attack, and vascular damage, leading to the activation of fibroblasts and abnormal accumulation of extracellular matrix (ECM) (1,2). Therefore, the abnormal SSc fibroblasts responsible for fibrosis may develop from a subset of cells that have escaped from normal control mechanisms (3,4).…”

Increased Expression of Integrin αvβ5 Induces the Myofibroblastic Differentiation of Dermal Fibroblasts

“…TGF-␤ increases the expression of various ECM components, such as collagen types I, III, VI, VII, and X, fibronectin, and proteoglycans. [2][3][4][5][6][7][8] It also inhibits the production of proteolytic enzymes that catalyze ECM degradation, while enhancing the expression of protease inhibitors. 9 As a result of these multifaceted effects, TGF-␤ is believed to play a critical role in a variety of biological processes, such as wound healing and tissue remodeling.…”