Journal Article

Genetic abrogation of the fibronectin-α5β1 integrin interaction in articular cartilage aggravates osteoarthritis in mice

Kouri, Juan Bautista, Costell, Mercedes, Almonte-Becerril, Maylin, Villarroya, Olga, Gimeno-LLuch, Irene, Benito-Jardón, María

2018

Overview

The balance between synthesis and degradation of the cartilage extracellular matrix is severely altered in osteoarthritis, where degradation predominates. One reason for this imbalance is believed to be due to the ligation of the α5β1 integrin, the classic fibronectin (FN) receptor, with soluble FN fragments instead of insoluble FN fibrils, which induces matrix metalloproteinase (MMP) expression. Our objective was to determine whether the lack of α5β1-FN binding influences cartilage morphogenesis in vivo and whether non-ligated α5β1 protects or aggravates the course of osteoarthritis in mice. We engineered mice (Col2a-Cre;Fn1RGE/fl), whose chondrocytes express an α5β1 binding-deficient FN, by substituting the aspartic acid of the RGD cell-binding motif with a glutamic acid (FN-RGE). At an age of 5 months the knee joints were stressed either by forced exercise (moderate mechanical load) or by partially resecting the meniscus followed by forced exercise (high mechanical load). Sections of femoral articular knees were analysed by Safranin-O staining and by immunofluorescence to determine tissue morphology, extracellular matrix proteins and matrix metalloproteinase expression. The articular cartilage from untrained control and Col2a-Cre;Fn1RGE/fl mice was normal, while the exposure to high mechanical load induced osteoarthritis characterized by proteoglycan and collagen type II loss. In the Col2a-Cre;Fn1RGE/fl articular cartilage osteoarthritis progressed significantly faster than in wild type mice. Mechanistically, we observed increased expression of MMP-13 and MMP-3 metalloproteinases in FN-RGE expressing articular cartilage, which severely affected matrix remodelling. Our results underscore the critical role of FN-α5β1 adhesion as ECM sensor in circumstances of articular cartilage regeneration.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Acids / Animals / Arthritis / Aspartic acid / Binding / Binding sites / Biochemistry / Biocompatibility / Biology and Life Sciences / Biomedical materials / Cartilage / Cartilage (articular) / Cartilage diseases / Cartilage, Articular - cytology / Cartilage, Articular - metabolism / Cartilage, Articular - pathology / Cell adhesion & migration / Cell growth / Chondrocytes / Chondrocytes - metabolism / Chondrocytes - pathology / Collagen / Collagen (type II) / Collagenase 3 / Cytokines / Degradation / Disease Models, Animal / Extracellular matrix / Extracellular Matrix - metabolism / Extracellular Matrix - pathology / Femur / Fibrils / Fibronectin / Fibronectins - genetics / Fibronectins - metabolism / Gene expression / Glutamic acid / Humans / Immunofluorescence / In vivo methods and tests / Integrin alpha5beta1 - metabolism / Kinases / Knee / Knee Joint - metabolism / Knee Joint - pathology / Male / Matrix metalloproteinase / Matrix Metalloproteinase 13 - metabolism / Matrix Metalloproteinase 3 - metabolism / Mechanical properties / Medicine and Health Sciences / Meniscus / Metalloproteinase / Mice / Mice, Transgenic / Molecular biology / Morphogenesis / Morphology / Osteoarthritis / Osteoarthritis - etiology / Osteoarthritis - pathology / Physical Conditioning, Animal - adverse effects / Proteins / Regeneration / Regeneration - physiology / Research and Analysis Methods / Safranin-O / Signal Transduction / Stromelysin 1