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/ß-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.
Subject(s)
Adaptor Proteins, Signal Transducing/metabolism , Adherens Junctions/metabolism , Arthritis/metabolism , Cell Transformation, Neoplastic/metabolism , Cytoskeletal Proteins/metabolism , Fibroblasts/metabolism , LIM Domain Proteins/metabolism , Adaptor Proteins, Signal Transducing/genetics , Animals , Arthritis/pathology , Arthritis, Rheumatoid/metabolism , Arthritis, Rheumatoid/pathology , Cadherins/metabolism , Cytoskeletal Proteins/genetics , Female , Homeodomain Proteins , LIM Domain Proteins/genetics , Mice , Mice, Inbred C57BL , Mice, Knockout , Osteoblasts , beta Catenin/metabolismABSTRACT
Cannabinoids represent a promising class of compounds for developing novel therapeutic agents. Since the isolation and identification of the major psychoactive component Δ(9)-THC in Cannabis sativa in the 1960s, numerous analogues of the classical plant cannabinoids have been synthesized and tested for their biological activity. These compounds primarily target the cannabinoid receptors 1 (CB1) and Cannabinoid receptors 2 (CB2). This chapter focuses on CB1. Despite the lack of crystal structures for CB1, protein-based homology modeling approaches and molecular docking methods can be used in the design and discovery of cannabinoid analogues. Efficient synthetic approaches for therapeutically interesting cannabinoid analogues have been developed to further facilitate the drug discovery process.