Integrins link chondrocytes to the surrounding extracellular matrix (ECM), mediating chondrocyte development and differentiation and controlling catabolic pathways that cause cartilage destruction. New research has revealed a role for integrin β-like protein 1 (ITGBL1) in modulating integrin-mediated chondrocyte activity, suggesting that blocking integrins with ITGBL1 could reduce cartilage damage in osteoarthritis (OA).

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“ITGBL1 is a secreted protein that possesses a dual function in inhibiting inflammation and promoting chondrogenesis,” explains corresponding author Tae Joo Park. “Our data suggest that ITGBL1 might function as a secreted inhibitor for a broad range of integrins.”

Fragments of ECM molecules such as fibronectin are produced via proteolytic cleavage of the ECM by catabolic enzymes during cartilage degeneration. These fragmented ECM molecules can themselves trigger the production of catabolic enzymes by chondrocytes in a positive feedback loop. “Integrins are known to be receptors for fragmented ECM molecules and to promote chondrolysis in models of arthritis,” says Park.

In vitro studies showed that overexpression of ITGBL1 reduced the binding of fragmented ECM molecules to human chondrocytes via integrins. Similarly, stimulation of human chondrocytes with fragmented ECM molecules caused an upregulation of catabolic enzymes that could be reduced by the overexpression of ITGBL1.

In mice, knockdown of Itgbl1 using intra-articular adenoviral delivery of short hairpin RNA caused cartilage damage similar to that seen in patients with OA. Interestingly, expression of ITGBL1 was also greatly reduced in cartilage from patients with OA compared with undamaged control cartilage. Furthermore, in the destabilization of the medial meniscus mouse model of OA, intra-articular adenoviral delivery of Itgbl1 reduced cartilage damage and osteophyte formation.

intra-articular adenoviral delivery of Itgbl1 reduced cartilage damage and osteophyte formation

“As a long-term goal, we are trying to identify the minimal domain of ITGBL1 that could be used to treat various integrin-mediated diseases,” states Park. “Ultimately, we hope to develop peptide drugs based on the ITGBL1 sequence.”