Systemic Sclerosis

An Update

Uwe-Frithjof Haustein, MD, PhD


Lab Med. 2011;42(9):562-572. 

In This Article

Fibrogenic Phenotype

One of the most interesting phenomena in the pathophysiology of SSc is the persistence of the fibrogenic phenotype. The protease nexin-1 (PN-1) is over-expressed in SSc. This may play a role in increasing collagen gene transcription.[81] This altered gene expression is due to turning on autocrine signals in the FBs, that, once activated, stimulate a continuous feedback loop.

In addition, altered FBs'susceptibility to apoptosis may play a role in the pathogenesis of FB abnormalities. As a result, SSc FBs are more resistant to Fas-mediated apoptosis than normal FBs.[82] Consistently, there are no data showing apoptosis of FBs in SSc lesions or in culture. This is in agreement with results reporting unchanged numbers of FBs in SSc lesions compared to healthy skin.[83] Therefore, the fibrotic events in SSc seem due to increased synthesis of matrix proteins rather than to increased cell numbers. In addition, endothelin-1, which is over-expressed in SSc, protects FBs from c-myc-dependent apoptosis.[84,85] Finally, hypoxia can also select for apoptosis-resistant cells by inducing apoptosis in c-myc-over-expressing cells.[85] Trans-acting nuclear factors binding to cis-acting elements in enhancer (intronic) and promoter regions of the genes modulate the basal and inducible transcriptional activity of collagen genes.[86]

Fibroblasts subjected to mechanical strain proliferate, elongate, and become bipolar and oriented along the plane of the force.[87] Prominent action stress fibers develop within the cells as in myofibroblasts.

There are several candidates inhibiting the fibrotic process, such as antibodies to TGFβ[88] or lysyl hydroxylase inhibitors that interact with cross-link formation between the collagen chains. An exciting approach might be the direct inhibition of transcription factors by antisense oligonucleotides that interact with specific DNA elements controlling the activity of these genes in FBs. The complexity of FBs in the pathophysiology of SSc is shown in Figure 3.

Figure 3.

Activation of Fibroblasts in SSc. Various ILs, growth factors, chemokines, thrombin, endothelin-1, ROS, activating antibodies (eg, PDGFR-ab) as well as tension trigger signal cascades in FBs: either SMAD signaling pathway or phosphokinase/ERK 1/2 pathway which can modulate transcription factors. As a result, synthesis of ECM protein, cytoskeleton, cytokines and cytokine receptors, as well as growth factors, and the growth factors in an autokrine loop (TGFβ, CTGF) are stimulated, thus maintaining the pathological FB activation. UV activates collagenases (matrix metalloproteinases). The increased lysyl hydroxylase 2 mediates the formation of bone-like collagen.


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