Regulation of cytokine-dependent calcification of cartilage tissue by NPP1 and syndecan-4
Final Report Abstract
Pathological tissue calcification with basic calcium phosphate (BCP) crystals occurs prominently in osteoarthritis (OA) and is linked to chondrocyte differentiation. The nucleotide pyrophosphatase phosphodiesterase NPP1 has been implicated in this process, and there is evidence that inflammatory factors such as interleukin (IL)-1 promote tissue calcification through suppression of NPP1. In this project, we have used NPP1 mutant (ttw/ttw) mice to study the role of excessive BCP production on the course of OA-like changes in mice. Through in vitro experiments on isolated chondrocytes as well as in vivo studies in wild type and NPP1-mutant (ttw/ttw) mice, we could demonstrate that articular calcification is not only an epiphenomenon of OA-like cartilage degeneration but is by itself sufficient to induce and promote such OA-like changes. In close collaboration with related projects at the IEMM, we could show that BCP crystals produced by articular chondrocytes promote their loss of phenotype stability and can induce canonical Wnt signalling. We could also show that syndecan-4 promotes IL-1 signalling most likely through direct binding of IL-1 to syndecan-4 with subsequent dimerization of syndecan-4, which in turn regulates IL-1 receptor expression on the cell surface. The project will be continued by Jessica Bertrand, who formerly worked at the IEMM in Münster, Professor of Experimental Orthopaedics at Magdeburg University.
Publications
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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. 2012;71:1004-11
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
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Stressinduced cartilage degradation does not depend on the NLRP3 inflammasome in human osteoarthritis and mouse models. Arthritis Rheum. 2012;64:3972-81
Bougault C, Gosset M, Houard X, Salvat C, Godmann L, Pap T, Jacques C, Berenbaum F
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Syndecan 4 supports bone fracture repair, but not fetal skeletal development, in mice. Arthritis Rheum. 2013; 65:743-52
Bertrand J, Stange R, Hidding H, Echtermeyer F, Nalesso G, Godmann L, Timmen M, Bruckner P, Dell'Accio F, Raschke MJ et al.
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Critical role for syndecan-4 in dendritic cell migration during development of allergic airway inflammation. Nat Commun. 2015;6:7554
Polte T, Petzold S, Bertrand J, Schütze N, Hinz D, Simon JC, Lehmann I, Echtermeyer F, Pap T, Averbeck M
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Articular cartilage calcification of the humeral head is highly prevalent and associated with osteoarthritis in the general population. J Orthop Res. 34,11, November 2016, Pages 1984-1990
Hawellek T, Hubert J, Hischke S, Vettorazzi E, Wegscheider K, Bertrand J, Pap T, Krause M, Püschel K, Rüther W, Niemeier A
