C1 Adelheid Korb-Pap, Thomas Pap
Matrix mediated fibroblast activation in rheumatoid arthritis
University Hospital Munster
Albert Schweitzer Campus 1, Geb. D3, 48149 Munster
University Hospital Munster
Albert Schweitzer Campus 1, Geb. D3, 48149 Munster
Faculty of Medicine, University of Cologne
Joseph-Stelzmann-Str. 52, 50931 Cologne
Summary
Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disorder that mainly affects the joints and leads to the progressive destruction of cartilage and bone. Fibroblast-like synoviocytes (FLS) play a central role in the progressive destruction of articular cartilage. In the course of the disease they acquire an invasive, tumour-like phenotype with the formation of actin-based invadopodia-like adhesion structures that protrude into the damaged cartilage. As one key element, these invadopodia-like structures contain b1-integrins that mediate the contact between FLS and the extracellular matrix (ECM) in cartilage. Our previous work has demonstrated a relevant role of the integrins a2b1 and a11b1 in the formation and function of these invadopodia-like adhesion structures. Using samples from RA patients and established RA-specific disease mouse models, we will test the hypothesis that the formation of invadopodia-like structures in arthritic FLS correlates with disease severity, and if and by which mechanisms the loss or inhibition of the integrins a2b1 and a11b1 reduces the transformation of FLS into tumour-like cells and thereby dampens the invadopodia-mediated cartilage destruction. In vivo models will be complemented by high resolution imaging, complex cell culture models and systems biology analysis. Our long-term goal is the identification of target molecules and signalling pathways that may be exploited to prevent formation of the invasive FLS phenotype and their activity in rheumatoid joint destruction.Publications
Etich J, Rehberg M, Eckes B, Sengle G, Semler O, Zaucke F 2020 Signaling pathways affected by mutations causing osteogenesis imperfecta. Cell Signal. [Epub ahead of print]
Godmann L, Bollmann M, Korb-Pap A, König U, Sherwood J, Beckmann D, Mühlenberg K, Echtermeyer F, Whiteford J, De Rossi G, Pap T, Bertrand J 2020 Antibody-mediated inhibition of syndecan-4 dimerisation reduces interleukin (IL)-1 receptor trafficking and signalling. Ann Rheum Dis. 79(4):481-489.
Üstün Y, Reibetanz M, Brachvogel B, Nischt R, Eckes B, Zigrino P, Krieg T 2019 Dual role of laminin‑511 in regulating melanocyte migration and differentiation. Matrix Biol 80:59-71.
Hillen J, Geyer C, Heitzmann M, Beckmann D, Krause A, Winkler I, Pavenstädt H, Bremer C, Pap T, Korb-Pap A 2017 Structural cartilage damage attracts circulating rheumatoid arthritis synovial fibroblasts into affected joints. Arthritis Res Ther 19(1):40.
Ghatak S, Niland S, Schulz JN, Wang F, Eble JA, Leitges M, Mauch C, Krieg T, Zigrino P, Eckes B 2016 Role of integrins α1β1 and α2β1 in wound and tumor angiogenesis in mice. Am J Pathol 186: 3011-3027.
Wehmeyer C, Frank S, Beckmann D, Bottcher M, Cromme C, Konig U, Fennen M, Held A, Paruzel P, Hartmann C, Stratis A, Korb-Pap A, Kamradt T, Kramer I, van den Berg W, Kneissel M, Pap T, Dankbar B 2016 Sclerostin inhibition promotes TNF-dependent inflammatory joint destruction. Sci Transl Med 8(330):330ra335.
Dankbar B, Fennen M, Brunert D, Hayer S, Frank S, Wehmeyer C, Beckmann D, Paruzel P, Bertrand J, Redlich K, Koers-Wunrau C, Stratis A, Korb-Pap A, Pap T 2015 Myostatin is a direct regulator of osteoclast differentiation and its inhibition reduces inflammatory joint destruction in mice. Nat Med 21(9):1085-1090.
Schulz JN, Zeltz C, Sorensen IW, Barczyk M, Carracedo S, Hallinger R, Niehoff A, Eckes B, Gullberg D 2015 Reduced granulation tissue and wound strength in the absence of alpha11beta1 integrin. J Invest Dermatol 135(5):1435-1444.
Stange R, Kronenberg D, Timmen M, Everding J, Hidding H, Eckes B, Hansen U, Holtkamp M, Karst U, Pap T, Raschke MJ 2013 Age-related bone deterioration is diminished by disrupted collagen sensing in integrin alpha2beta1 deficient mice. Bone 56(1):48-54.
Agarwal P, Zwolanek D, Keene DR, Schulz JN, Blumbach K, Heinegard D, Zaucke F, Paulsson M, Krieg T, Koch M, Eckes B 2012 Collagen XII and XIV - new partners of cartilage oligomeric matrix protein in the skin extracellular matrix suprastructure. J Biol Chem 287: 22549-22559.
Korb-Pap A, Stratis A, Mühlenberg K, Niederreiter B, Hayer S, Echtermeyer F, Stange R, Zwerina J, Pap T, Pavenstädt H, Schett G, Smolen JS, Redlich K. 2012 Early structural changes in cartilage and bone are required for the attachment and invasion of inflamed synovial tissue during destructive inflammatory arthritis. Ann Rheum Dis 71(6):1004-1011
Peters MA, Wendholt D, Strietholt S, Frank S, Pundt N, Korb-Pap A, Joosten LA, van den Berg WB, Kollias G, Eckes B, Pap T 2012 The loss of alpha2beta1 integrin suppresses joint inflammation and cartilage destruction in mouse models of rheumatoid arthritis. Arthritis Rheum 64(5):1359-1368.
Kremerskothen J, Stölting M, Wiesner C, Korb-Pap A, van Vliet V, Linder S, Huber TB, Rottiers P, Reuzeau E, Genot E, Pavenstädt H. 2011 Zona occludens proteins modulate podosome formation and function. FASEB J 25(2):505-514.
