Modulation of αVβ6 integrin in osteoarthritis-related synovitis and the interaction with VTN(381-397 a.a.) competing for TGF-β1 activation

Osteoarthritis is characterized by structural alteration of joints. Fibrosis of the synovial tissue is often detected and considered one of the main causes of joint stiffness and pain. In our earlier proteomic study, increased levels of vitronectin (VTN) fragment (amino acids 381-397) were observed in the serum of osteoarthritis patients. In this work, the affinity of this fragment for integrins and its putative role in TGF-beta 1 activation were investigated. A competition study determined the interaction of VTN(381-397 a.a.) with alpha(V)beta(6) integrin. Subsequently, the presence of alpha(V)beta(6) integrin was substantiated on primary human fibroblast-like synoviocytes (FLSs) by western blot and flow cytometry. By immunohistochemistry, beta(6) was detected in synovial membranes, and its expression showed a correlation with tissue fibrosis. Moreover, beta(6) expression was increased under TGF-beta 1 stimulation; hence, a TGF-beta bioassay was applied. We observed that alpha(V)beta(6) could mediate TGF-beta 1 bioavailability and that VTN(381-397 a.a.) could prevent TGF-beta 1 activation by interacting with alpha(V)beta(6) in human FLSs and increased alpha-SMA. Finally, we analyzed serum samples from healthy controls and patients with osteoarthritis and other rheumatic diseases by nano-LC/Chip MS-MS, confirming the increased expression of VTN(381-397 a.a.) in osteoarthritis as well as in lupus erythematosus and systemic sclerosis. These findings corroborate our previous observations concerning the overexpression of VTN(381-397 a.a.) in osteoarthritis but also in other rheumatic diseases. This fragment interacts with alpha(V)beta(6) integrin, a receptor whose expression is increased in FLSs from the osteoarthritic synovial membrane and that can mediate the activation of the TGF-beta 1 precursor in human FLSs. Rheumatology: A starting point for joint disease Insights into a mechanism underlying the formation of fibrotic tissue within joints in osteoarthritis may also prove relevant to other rheumatological disorders. The general mechanisms underlying fibrosis are reasonably well understood, but it remains unclear what triggers these processes in osteoarthitis. Researchers of the University of Liege in Belgium have uncovered a possible explanation based on experiments with cultured primary synovial fibroblasts from patients. Osteoarthitis is characterized by increased levels of a fragment of the protein vitronectin, and the researchers demonstrated that this in turn binds to a protein called alpha(V)beta(6), potentially promoting initiation of fibrosis. They also observed elevated levels of the same vitronectin fragment in two other rheumatoid disorders, lupus and systemic sclerosis, and concluded that further research is needed to characterize this protein's role in inflammation and fibrosis.

Automated summary

A study revealed that levels of VTN(381-397 a.a.) are increased in osteoarthritis patients, and it has the ability to interact with integrins, potentially promoting TGF-beta 1 activation and fibrosis in human FLSs. This interaction was also observed in other rheumatic diseases, suggesting a potential role of VTN(381-397 a.a.) in these conditions.