Lasp1 regulates adherens junction dynamics and fibroblast transformation in destructive arthritis

Abstract

The LIM and SH3 domain protein 1 (Lasp1) was originally cloned from metastatic breast cancer and characterised as an adaptor molecule associated with tumourigenesis and cancer cell invasion. However, the regulation of Lasp1 and its function in the aggressive transformation of cells is unclear. Here we use integrative epigenomic profiling of invasive fibroblast-like synoviocytes (FLS) from patients with rheumatoid arthritis (RA) and from mouse models of the disease, to identify Lasp1 as an epigenomically co-modified region in chronic inflammatory arthritis and a functionally important binding partner of the Cadherin-11/β-Catenin complex in zipper-like cell-to-cell contacts. In vitro, loss or blocking of Lasp1 alters pathological tissue formation, migratory behaviour and platelet-derived growth factor response of arthritic FLS. In arthritic human TNF transgenic mice, deletion of Lasp1 reduces arthritic joint destruction. Therefore, we show a function of Lasp1 in cellular junction formation and inflammatory tissue remodelling and identify Lasp1 as a potential target for treating inflammatory joint disorders associated with aggressive cellular transformation.

Suppression of inflammatory arthritis by the parasitic worm product ES-62 is associated with epigenetic changes in synovial fibroblasts

“…This identified a gene signature panel representing an interactive biological network of hub (STAT1, RAC2 and KYNU) proteins and effector molecules (PEPD receptor and NR4A1, MEOX2, KLF4, IRF1 and MYB transcription factors and miRs-146a, -299, -3659, -6882 and -8078) that provides a platform for validation of pathogenic mechanisms and potentially, a predictive tool for diagnosis and development of effective treatment strategies for RA: apart from KYNU and miR-299 (miRs-3659, -6882 and -8078 were not identified in our methylome study), our proof-of-concept methylome analysis suggests that these “signature” genes may be differentially methylated in naïve-, CIA- and ES-62-CIA-SFs. Likewise, very recently [ 82 ], an integrated epigenetic study (histone marks, open chromatin, transcriptomics and DNA methylation) identified 8 epigenetic clusters that differentially modified in healthy and hyper-responsive SFs (from both humans and mouse models). Although different mouse models to CIA (hTNFtg and G6PI-induced arthritis models) were analysed, essentially all of the 52 genes exhibiting differential DNA methylation, and clustered on the basis of their involvement in the proliferation, migration and cell-cell interaction processes involved in the pathogenic transformation of RA SFs, appeared to be differentially methylated amongst our Naïve, CIA and CIA-ES-62 groups, albeit in some cases these changes were subtle and all require statistical validation.…”

Synovial fibroblasts as potential drug targets in rheumatoid arthritis, where do we stand and where shall we go?

“…However, the treatment with a humanized monoclonal antibody against cadherin-11 (RG6125) failed to show efficacy in patients with RA inadequately responding to anti-TNFα therapy in a phase 2 clinical trial and led to the withdrawal of this synovial fibroblast-selective intervention from the list of potential future therapies of RA 75. Meanwhile, in a recent article, the LIM and SH3 domain protein 1 (Lasp1) was found to be upregulated in the RA synovium and was described as an important mediator of the cell responses (eg, migration) of arthritic FLS 5. Further studies revealed that the loss of Lasp1 resulted in abrogated cadherin-11-containing cell-cell contacts and decreased the severity of experimental arthritis in mice, pointing at its target potential in the therapy of RA 5…”

“…Meanwhile, in a recent article, the LIM and SH3 domain protein 1 (Lasp1) was found to be upregulated in the RA synovium and was described as an important mediator of the cell responses (eg, migration) of arthritic FLS 5. Further studies revealed that the loss of Lasp1 resulted in abrogated cadherin-11-containing cell-cell contacts and decreased the severity of experimental arthritis in mice, pointing at its target potential in the therapy of RA 5…”

“…This is due to a peculiarity of the synovial membrane that unlike other border membranes lacks an organised basement membrane, and thus, the classical architecture of an epithelium. Several studies have demonstrated that although cellular contacts between the fibroblast-like synoviocytes lack tight junctions and desmosomes, there are specific adhesion molecules such as cadherin-11, which mediate a strong homophilic adhesion between synoviocytes through interaction with organisers of the cytoskeleton and that are largely responsible for their organisation into a tissue 4 5…”

“…These changes have been described in detail in a number of reviews and comprise a complex set of cellular changes that eventually result in the proliferation and differentiation into distinct subpopulations 8 9. During this process, some FLS acquire invasive, tumour cell-like destructive characteristics through epigenetic and metabolic changes as well as through interaction with both themselves and different immune cells like lymphocytes or macrophages 5 10. As a consequence of their transformation, some FLS subsets contribute prominently to the destruction of articular structures while others have been hypothesised to exert more regulatory functions 6.…”