A novel fibrotic disorder associated with increased dermal fibroblast proliferation and downregulation of genes of the microfibrillar network

Abstract

Clinical evaluation of a young woman with subcutaneous fibrotic nodules, progressive distal joint contractures and marfanoid stature revealed a previously unrecognized fibrotic disorder characterized by several unique phenotypic features and some features overlapping with known disorders. Mutational analysis of the FBN1 and FBN2 genes excluded Marfan syndrome and congenital contractural arachnodactyly. MMP2 gene sequence analysis excluded multicentric osteolysis, nodulosis and arthropathy. The lack of mutations within the MAGP2 gene also excluded an MAGP2-associated disorder. In order to establish the mechanistic basis for the severe skin pathology noted in this patient, we performed transcriptional profiling of dermal fibroblasts, and candidate gene expression studies in conjunction with immunocytochemistry and cell-based and functional assays. Data from these experiments have further excluded any previously recognized fibrotic disorder and identified a unique pattern of gene expression in this patient consistent with progressive fibrosis. The pathogenic mechanisms included persistent proliferation of dermal fibroblasts in coexistence with a disarray of the microfibrillar network. Collagen accumulation, moreover, could be linked to extensive crosslinking resulting from increased activities of lysyl oxidases (LOX and LOXL), and lack of remodelling due to deficiencies in collagenolytic matrix metalloproteinases. The disorder may represent a novel syndrome in which transforming growth factor-β1-independent dermal fibrosis, unlike known microfibrillar disorders caused by single gene deficiencies, associates with a disarray of the microfibrillar network.

Microfibrillar-associated protein 5 is linked with markers of obesity-related extracellular matrix remodeling and inflammation

“…19, 20, 21 Expression changes in microfibrillar proteins such as MFAP5, is known to participate in collagen synthesis and accumulation. 22 Lemaire et al 23 have demonstrated that MFAP5 could enhance type I collagen matrix by stabilizing type I procollagen. Furthermore, it has been shown that MAGP-1, which is structurally related molecule to MFAP5, could bind to type VI collagen.…”

LOXL1-associated Candidate Epithelial Pathomechanisms in Exfoliation Glaucoma

“…In cultured cells, LOXL1 synthesis and processing were evaluated by Western blot analysis using LOXL1 polyclonal rabbit primary antibody (Zymed Laboratories, San Francisco), and polyclonal anti-BMP-1 antibody (Affinity Bioreagents). LOXL1 catalytic activity assays were performed in media fractions of cells cultured for 48 hours in phenol red and serum free media using the Amplex Red assay (Life Technologies) as previously described 9 . LOXL1 sub-cellular and ECM localizations were determined in fluorescent immuno-cytochemistryexperiments.…”

Mutation in MMP2 gene may result in scleroderma-like skin thickening

“…It has been involved in different fibrotic disorders and its expression, regulation and activity can play an important role in the initial steps of fibrosis 6. An imbalance in MMP expression pattern, including a downregulation in MMP2, was demonstrated in the fibroblasts of a patient with subcutaneous fibrotic nodules, severe progressive distal joint contractions and marfanoid stature 7. It leads to a disorderly ECM deposition and to a TGF-beta-independent dermal fibrosis.…”