Dysregulation of cell migration by matrix metalloproteinases in geleophysic dysplasia
Geleophysic dysplasia (GD) is characterized by short stature, brachydactyly, joint limitations, a distinctive facial appearance, as well as cardiac and respiratory dysfunction that can be life-threatening. GD is caused by pathogenic variants in the ADAMTSL2, FBN1, or LTBP3 genes. While dermal fibroblasts derived from affected individuals have shown poor organization of the extracellular matrix (ECM), it remains elusive how the disorganized ECM contributes to GD pathogenesis. To understand the molecular mechanisms in GD, we isolated and characterized primary human dermal fibroblasts from affected individuals with ADAMTSL2 and FBN1 variants. We found that the secretion of ECM proteins including ADAMTSL2, FBN1, and Fibronectin were impaired in GD fibroblasts. Increased cell migration was observed in GD fibroblasts carrying ADAMTSL2 or FBN1 variants, which was associated with up-regulation of MMP-1 and MMP-14, two proteases related to cell mobility. The enhanced cell migration and up-regulation of MMP-1 and MMP-14 were corroborated in mouse primary dermal fibroblasts carrying pathogenic variants in Adamtsl2 and in lung and heart tissues from Adamtsl2-knockout mice. A pan MMP inhibitor, GM6001, inhibited the migration of GD fibroblasts. Overall, our results suggest that MMP-1/-14 up-regulation play a role in the development of GD and may be utilized as a treatment target. Overall design: RNA-Seq profiling of 11x human dermal fibroblasts, including 3x WT, 2x ADAMTSL2 variants (geleophysic dysplasia-1), 4x FBN1 variants (geleophysic dysplasia-2) and 2x FBN1 variants (Marfan syndrome)