Differential expression of secreted factors SOSTDC 1 SOSTDC SOSTDC 1 and ADAMTS 8 ADAMTS ADAMTS 8 cause profibrotic changes in linear morphoea fibroblasts

摘要

Summary Background Linear morphoea ( LM ) is a rare connective tissue disorder characterized by a line of thickened skin and subcutaneous tissue and can also affect the underlying muscle and bone. Little is known about the disease aetiology, with treatment currently limited to immune suppression, and disease recurrence post‐treatment is common. Objectives In order to uncover new therapeutic avenues, the cell‐intrinsic changes in LM fibroblasts compared with site‐matched controls were characterized. Methods We grew fibroblasts from site‐matched affected and unaffected regions from five patients with LM , we subjected them to gene expression analysis and investigation of SMAD signalling. Results Fibroblasts from LM lesions showed increased migration, proliferation, altered collagen processing, and abnormally high basal levels of phosphorylated SMAD 2, thereby rendering them less responsive to transforming growth factor ( TGF )‐β1 and reducing the degree of myofibroblast differentiation, which is a key component of the wound‐healing and scarring process in normal skin. Conditioned media from normal fibroblasts could reverse LM ‐affected fibroblast migration and proliferation, suggesting that the LM phenotype is driven by an altered secretome. Gene array analysis and RNA ‐Seq indicated upregulation of ADAMTS 8 and downregulation of FRAS 1 and SOSTDC 1 . SOSTDC 1 knock‐down recapitulated the reduced TGF ‐β1 responsiveness and LM fibroblast migration, while overexpression of ADAMTS 8 induced myofibroblast markers. Conclusions We demonstrate that cell‐intrinsic changes in the LM fibroblast secretome lead to changes observed in the disease, and that secretome modulation could be a viable therapeutic approach in the treatment of LM .