Recent Advances in Fibroblast Signaling & Biology in Scleroderma
Recent Advances in Fibroblast Signaling & Biology in Scleroderma
Purpose of Review: Systemic sclerosis is a complex disease manifesting itself by fibrosis of skin and other internal organs. Fibroblasts isolated from scleroderma lesions and cultured in vitro are characterized by increased synthesis of collagen and other extracellular matrix proteins, consistent with the disease phenotype. Cultured systemic sclerosis fibroblasts therefore serve as a principal experimental model for studying the molecular and cellular mechanisms involved in collagen overproduction in this disease. This review will discuss recent findings related to intracellular signal transduction pathways implicated in deregulated extracellular matrix deposition by systemic sclerosis fibroblasts.
Recent Findings: Recent findings suggest that constitutively elevated synthesis of extracellular matrix by cultured systemic sclerosis fibroblasts is, at least in part, due to the aberrant activation of the autocrine transforming growth factor-β signaling. Enhanced constitutive transforming growth factor-β signaling may result from the elevated levels of transforming growth factor-β receptor type I and/or inappropriate activation of Smad3. These alterations of the transforming growth factor-β signaling in systemic sclerosis fibroblasts may facilitate increased collagen production in vivo even under conditions of low ligand availability. However, there exist many inconsistencies among published reports regarding the detailed mechanisms of this pathway in systemic sclerosis fibroblasts, and additional studies in this area are needed. Other signaling molecules implicated in fibrotic phenotype include several members of the protein kinase C family, mammalian target of rapamycin, mitogen-activated protein kinase, necdin, reactive oxygen species, and sphingolipids. These signaling pathways may work in conjunction with transforming growth factor-β signaling to regulate the behavior of systemic sclerosis fibroblasts.
Summary: Alterations in multiple signaling pathways contribute to elevated extracellular matrix synthesis by systemic sclerosis fibroblasts. Improved understanding of the key signaling molecules may provide a novel avenue for therapeutic interventions.
Fibroblasts cultured from the skin or lungs of patients with systemic sclerosis (scleroderma, SSc) show elevated collagen synthesis and several other phenotypic differences when compared with healthy skin fibroblasts. Earlier findings indicated that the collagen type I gene is upregulated at the transcriptional level in SSc fibroblasts. These findings have been facilitated by the cloning of the regulatory proximal regions of the collagen type I genes. These fruitful studies resulted in characterization of the transcription factors altered in SSc fibroblasts and have been summarized in several recent reviews. In comparison, the signal transduction pathways contributing to SSc in general, and collagen synthesis in particular, until recently, have been largely unexplored. This review will discuss our current knowledge of the signaling molecules involved in the regulation of cell behavior relevant to fibrosis with the emphasis on those pathways that are deregulated in SSc fibroblasts ( Table ). As outlined below, significant progress has been made in characterizing SSc-specific alterations of the transforming growth factor (TGF)-β signaling cascade. The TGF-β signaling pathway is discussed in detail elsewhere, and readers are referred to recent reviews on this topic.
Purpose of Review: Systemic sclerosis is a complex disease manifesting itself by fibrosis of skin and other internal organs. Fibroblasts isolated from scleroderma lesions and cultured in vitro are characterized by increased synthesis of collagen and other extracellular matrix proteins, consistent with the disease phenotype. Cultured systemic sclerosis fibroblasts therefore serve as a principal experimental model for studying the molecular and cellular mechanisms involved in collagen overproduction in this disease. This review will discuss recent findings related to intracellular signal transduction pathways implicated in deregulated extracellular matrix deposition by systemic sclerosis fibroblasts.
Recent Findings: Recent findings suggest that constitutively elevated synthesis of extracellular matrix by cultured systemic sclerosis fibroblasts is, at least in part, due to the aberrant activation of the autocrine transforming growth factor-β signaling. Enhanced constitutive transforming growth factor-β signaling may result from the elevated levels of transforming growth factor-β receptor type I and/or inappropriate activation of Smad3. These alterations of the transforming growth factor-β signaling in systemic sclerosis fibroblasts may facilitate increased collagen production in vivo even under conditions of low ligand availability. However, there exist many inconsistencies among published reports regarding the detailed mechanisms of this pathway in systemic sclerosis fibroblasts, and additional studies in this area are needed. Other signaling molecules implicated in fibrotic phenotype include several members of the protein kinase C family, mammalian target of rapamycin, mitogen-activated protein kinase, necdin, reactive oxygen species, and sphingolipids. These signaling pathways may work in conjunction with transforming growth factor-β signaling to regulate the behavior of systemic sclerosis fibroblasts.
Summary: Alterations in multiple signaling pathways contribute to elevated extracellular matrix synthesis by systemic sclerosis fibroblasts. Improved understanding of the key signaling molecules may provide a novel avenue for therapeutic interventions.
Fibroblasts cultured from the skin or lungs of patients with systemic sclerosis (scleroderma, SSc) show elevated collagen synthesis and several other phenotypic differences when compared with healthy skin fibroblasts. Earlier findings indicated that the collagen type I gene is upregulated at the transcriptional level in SSc fibroblasts. These findings have been facilitated by the cloning of the regulatory proximal regions of the collagen type I genes. These fruitful studies resulted in characterization of the transcription factors altered in SSc fibroblasts and have been summarized in several recent reviews. In comparison, the signal transduction pathways contributing to SSc in general, and collagen synthesis in particular, until recently, have been largely unexplored. This review will discuss our current knowledge of the signaling molecules involved in the regulation of cell behavior relevant to fibrosis with the emphasis on those pathways that are deregulated in SSc fibroblasts ( Table ). As outlined below, significant progress has been made in characterizing SSc-specific alterations of the transforming growth factor (TGF)-β signaling cascade. The TGF-β signaling pathway is discussed in detail elsewhere, and readers are referred to recent reviews on this topic.
Source...