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

Experimental & Molecular Medicine 2021년 53권 2호 p.210 ~ 222
Ciregia Federica, Deroyer Celine, Cobraiville Gael, Plener Zelda, Malaise Olivier, Gillet Philippe, Fillet Marianne, Malaise Michel G., de Seny Dominique,
소속 상세정보
 ( Ciregia Federica ) - University of Liege Laboratory of Rheumatology
 ( Deroyer Celine ) - University of Liege Laboratory of Rheumatology
 ( Cobraiville Gael ) - University of Liege Laboratory of Rheumatology
 ( Plener Zelda ) - University of Liege Laboratory of Rheumatology
 ( Malaise Olivier ) - University of Liege Laboratory of Rheumatology
 ( Gillet Philippe ) - University Hospital Sart-Tilman Department of Orthopedic Surgery
 ( Fillet Marianne ) - University of Liege Department of Pharmacy
 ( Malaise Michel G. ) - University of Liege Laboratory of Rheumatology
 ( de Seny Dominique ) - University of Liege Laboratory of Rheumatology

Abstract


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-β1 activation were investigated. A competition study determined the interaction of VTN(381?397 a.a.) with αVβ6 integrin. Subsequently, the presence of αVβ6 integrin was substantiated on primary human fibroblast-like synoviocytes (FLSs) by western blot and flow cytometry. By immunohistochemistry, β6 was detected in synovial membranes, and its expression showed a correlation with tissue fibrosis. Moreover, β6 expression was increased under TGF-β1 stimulation; hence, a TGF-β bioassay was applied. We observed that αVβ6 could mediate TGF-β1 bioavailability and that VTN(381?397 a.a.) could prevent TGF-β1 activation by interacting with αVβ6 in human FLSs and increased α-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 αVβ6 integrin, a receptor whose expression is increased in FLSs from the osteoarthritic synovial membrane and that can mediate the activation of the TGF-β1 precursor in human FLSs.

키워드

Cell culture; Osteoarthritis

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