Collagen-binding integrin α11β1 contributes to joint destruction in arthritic hTNFtg mice

Abstract

Objectives: In rheumatoid arthritis (RA), fibroblast-like synoviocytes (FLS) acquire an aggressive, tumour-like phenotype characterised by increased adhesion to extracellular matrix, contributing to joint degradation. The collagen-binding integrin alpha11beta1 is involved in similar processes in cancer-associated fibroblasts, but its role in RA and arthritic mice remains unclear.

Methods: Integrin α11 expression was analysed in synovial tissue and FLS from RA and osteoarthritis patients and human tumour necrosis factor transgenic (hTNFtg) and wild-type mice supported by Accelerating Medicines Partnership Rheumatoid Arthritis and Pathobiology of Early Arthritis Cohort data. A novel 3-dimensional (3D) organoid coculture model and electron microscopy were used to analyse FLS invasion into cartilage explants, Itga11^-/- were crossed with hTNFtg mice, and disease severity was evaluated using microcomputed tomography (µCT) and histology. Functional assays using FLS included cell morphology, adhesion, degradation, and matrix metalloproteinase expression and were complemented by osteoclast and coculture studies.

Results: In the context of RA, strong α11 expression was detected in the synovium, particularly in sublining clusters of FLS within fibroid-type synovial tissue in vivo and at focal adhesions of arthritic FLS and at invasion sites within the 3D coculture model in vitro. Clinical scores, µCT imaging, and histomorphological analyses revealed significantly reduced cartilage degradation, bone erosions, and FLS attachment to cartilage in Itga11^-/-hTNFtg compared to hTNFtg mice. In vitro studies revealed that α11 deficiency led to a decreased receptor activator of nuclear factor kappa-B ligand/osteoprotegerin ratio along with reduced TNFα-induced proteolytic degradation activity, and signalling pathway activation.

Conclusions: Integrin α11 levels are increased in RA, and its deficiency notably diminishes joint destruction in hTNFtg mice, emphasising its potential as promising therapeutic target.