Figure 1. Restoring dermal integrity. A study from Gerber et al. has elucidated potential mechanisms by which mutations in the integrin-binding domain of fibrillin 1 (Fbn1) produce symptoms of stiff skin syndrome and systemic scleroderma. The findings suggest that the biological processes of the two diseases converge on shared signaling pathways that offer common intervention points.

In mouse dermis, mutant Fbn1 induces two distinct pathways that produce activated transforming growth factor-b (Tgfb; Tgfb) and activated (*) integrin b3 (GpIIIa; Cd61), respectively-two components required for collagen expression and consequent skin fibrosis.

Mutant Fbn1 [a(1)] secreted by fibroblasts into the extracellular matrix binds Tgfb [b(1)] normally but forms a large number of
abnormal microfibrillar aggregates, resulting in high levels of latent Tgfb that become activated and upregulate Tgfb*-dependent MAP kinase 3 (Mapk3; Erk-1) and/or Mapk1 (Erk-2) signaling [c(1)].

Also in the dermis, Fbn1 cannot interact normally with infiltrating plasmacytoid dendritic cells (DCs) [a(2)], causing them to upregulate surface expression of integrin b1 (Cd29) [b(2)] and Cd61* [c(2)].

Together, increased Tgfb-dependent Erk-1/2 signaling and high Cd61* levels lead to excessive collagen production and consequent skin fibrosis [d].

The two pathways also may be involved in a feedback loop [e] by which Tgfb* induces infiltrating DCs to produce additional Tgfb.

Fibroblasts from patients with systemic scleroderma also express high levels of TGFb [b(1)], have high surface levels of CD29 [b(2)] and CD61* [c(2)] and upregulate ERK-1/2 signaling [c(1)] to induce collagen production [d].

Inhibition of Tgfb, activation of Cd29, inhibition or deletion of Cd61 or inhibition of Erk1/2 in the mouse models and patient fibroblasts decreased skin fibrosis and collagen production, respectively, compared with controls.