Systemic sclerosis (SSc) is a clinically heterogeneous fibrotic disease with no effective treatment. Myofibroblasts are responsible for unresolving synchronous skin and internal organ fibrosis in SSc, but the drivers of sustained myofibroblast activation remain poorly understood. Using unbiased transcriptome analysis of skin biopsies, we identified downregulation of SPAG17 in multiple independent SSc patient cohorts, and by orthogonal approaches observed significant negative correlation between SPAG17 and fibrotic gene expression. Fibroblasts and endothelial cells explanted from SSc skin biopsies showed reduced chromatin accessibility at the SPAG17 locus. Remarkably, mice lacking Spag17 demonstrated spontaneous skin fibrosis with increased dermal thickness, collagen deposition and stiffness, and altered collagen fiber alignment. Knockdown of SPAG17 in human and mouse fibroblasts and microvascular endothelial cells was accompanied by spontaneous myofibroblast transformation and markedly heightened sensitivity to profibrotic stimuli. These responses were accompanied by constitutive transforming growth factor-β (TGF-β) pathway activation. Thus, we discovered impaired expression of SPAG17 in SSc and identified a new cell-intrinsic role for SPAG17 in negative regulation of fibrotic responses. These findings shed fresh light on the pathogenesis of SSc, and may inform the search for innovative therapies for SSc and other fibrotic conditions via SPAG17 signaling.
Keywords: SPAG17; Systemic sclerosis; morphogen signaling; myofibroblast.
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