Effect of Laminin‐A4 inhibition on cluster formation of human osteoarthritic chondrocytes

Abstract

Formation of chondrocyte clusters is not only a morphological sign of osteoarthritis but it is also observed in cell culture. Active locomotion of chondrocytes is controlled by integrins in vitro. Integrins bind to Laminin-A4 (LAMA4), a protein that is highly expressed in vivo in clusters of hypertrophic chondrocytes. We tested if LAMA4 is relevant for cluster formation. Human chondrocytes were cultured in a 2D matrigel model and treated with different concentrations of a monoclonal inhibitory anti-LAMA4-antibody. Migration and cluster formation was analysed using live cell imaging technique. Full genome gene expression analysis was performed to assess the effect of LAMA4 inhibition. The data set were screened for genes relevant to cell motility. F-actin staining was performed to document cytoskeletal changes. Anti-LAMA4 treatment significantly reduced the rate of cluster formation in human chondrocytes. Cells changed their surface morphology and exhibited fewer protrusions. Expression of genes associated with cellular motility and migration was affected by anti-LAMA4 treatment. LAMA4-integrin signalling affects chondrocyte morphology and gene expression in vitro, thereby contributing to cluster formation in human osteoarthritic chondrocytes.

The tendon interfascicular basement membrane provides a vascular niche for CD146+pericyte cell subpopulations

“…The colocalisation of CD146 and LAMA4 in the current study further reinforces the putative ligand-receptor interaction that CD146 and LAMA4 share, which has been demonstrated in previous studies [49,50]. In chondrocytes, blockading LAMA4 inhibited cluster formation, which is typical of pathological cartilage, and also resulted in downregulation of Claudin-1 (previously identified as a tendon IFM protein) and MMP3 [51,52]. Recent studies have already established that loss of LAMA4 results in reduced CD146 cell expression and loss of basement membrane/niche maintenance in both mesenchymal and haematopoietic environments [53].…”

RETRACTED ARTICLE: Down-regulated LAMA4 inhibits oxidative stress-induced apoptosis of retinal ganglion cells through the MAPK signaling pathway in rats with glaucoma

“…It has also been reported that LAMA4 is greatly increased on tumor blood vessels in colorectal and renal malignancies [23]. Furthermore, the overexpressed LAMA4 has been observed in vivo in clusters of hypertrophic chondrocytes, and it has been demonstrated to be associated with cellular motility and migration [24]. Zhi-Xue Yang et al demonstrated that LAMA4 expression elevated in triple-negative breast cancer tissues (TNBC), and the downregulated LAMA4 can suppress the proliferation, migration, and invasion of TNBC cells [25].…”

Genetic variation of aggrecanase-2 (ADAMTS5) in susceptibility to osteoarthritis

“…The five genes most related to ADAMTS5 were ADAM metallopeptidase with thrombospondin type 1 motif 1 (ADAMTS1), fibrillin 1 (FBN1), laminin alpha 4 (LAMA4), protocadherin 18 (PCDH18), and decorin (DCN). LAMA4-integrin signaling contributes to clustering in human osteoarthritic chondrocytes, which is a morphological sign of OA (17). Figure 2 shows the GO enrichment results of these genes.…”