The reduced progression of skin sclerosis in PGRN-deficient mice was associated with down-regulation of transforming growth factor (TGF)-β receptor I (TβR I) and decreased level of phosphorylated Smad3, with correspondingly impaired expression of its downstream target gene connective tissue growth factor (CTGF) in skin lesion.
Constitutive activation of the c-Abl/PKC-δ/Fli1 pathway at least partially contributes to the establishment of the profibrotic phenotype in LSc dermal fibroblasts, which provides a novel molecular basis to explain the efficacy of imatinib against skin sclerosis in a certain subset of LSc.
In contrast to healthy skin, Fli1 protein is consistently absent from fibroblasts and significantly reduced in endothelial cells in clinically involved scleroderma skin, which correlates with enhanced collagen synthesis in systemic sclerosis skin.
Finally, the anti-CD154 antibody inhibited the bleomycin-induced skin sclerosis by suppressing fibroblast proliferation and down-regulating MCP-1 expression.
Moreover, detailed analysis of CD226 revealed that CD226(high)CD8(+) T cells were increased in SSc patients (mean, 50.7%) compared with healthy controls (32.9%) and were appreciably associated with the severity of skin sclerosis and interstitial lung disease.
The skin of mice with bleomycin-induced skin sclerosis, a model for systemic sclerosis (SSc), was assessed for CD40 and CD154 expression, in vivo fibroblast proliferation, and the expression of specific genes.
We previously reported an elevated level of circulating periostin in patients with systemic sclerosis (SSc) and its association with the severity of skin sclerosis.
Reflecting the critical role of interleukin (IL)-6 in systemic sclerosis (SSc), tocilizumab, an anti-IL-6 receptor antibody, is currently under a global phase III trial against skin sclerosis of this disease.
The reduced progression of skin sclerosis in PGRN-deficient mice was associated with down-regulation of transforming growth factor (TGF)-β receptor I (TβR I) and decreased level of phosphorylated Smad3, with correspondingly impaired expression of its downstream target gene connective tissue growth factor (CTGF) in skin lesion.
Our findings reinforce a correlation between CTGF gene expression and skin sclerosis and support the hypothesis that transforming growth factor-beta plays an important role in the pathogenesis of fibrosis, as it is the only inducer for CTGF identified to date.
Our findings indicate a correlation between CTGF gene expression and skin sclerosis and support the hypothesis that transforming growth factor-beta plays an important role in the pathogenesis of SSc, because transforming growth factor beta is the only inducer for CTGF identified to date.
Finally, the anti-CD154 antibody inhibited the bleomycin-induced skin sclerosis by suppressing fibroblast proliferation and down-regulating MCP-1 expression.