D1 Brunhilde Wirth, Anja Niehoff
Unravelling of novel pathomechanisms for bone and cartilage diseases
Faculty of Medicine, University of Cologne
Kerpener Str. 34, 50931 Cologne
Prof. Dr. Anja Niehoff
Cologne Center for Musculoskeletal Biomechanics (CCMB)
Faculty of Medicine, University of Cologne
Joseph-Stelzmann-Str. 9, 50931 Cologne
Institute of Biomechanics and Orthopaedics
German Sport University Cologne
Am Sportpark Müngersdorf 6, 50933 Cologne
Summary
The extracellular matrix (ECM) is connected via cell surface integrins to the actin cytoskeleton of the cell. Thereby, crucial chemical and mechanical signals for tissue morphogenesis, differentiation and homeostasis are transmitted. Plastin 3 (PLS3) is a ubiquitously present actin-binding and -bundling protein that regulates the dynamics of the actin cytoskeleton. Variants in PLS3 cause osteoporosis with fractures and PLS3 overexpression (OE) is a female protective modifier of spinal muscular atrophy (SMA). Recently, it has been shown that PLS3 expression is associated with ECM degeneration in osteoarthritis. However, the exact function of PLS3 for ECM homeostasis in bone and cartilage is still unknown. In our project we want to clarify the role of PLS3 in the pathogenesis of osteoporosis and osteoarthritis. To this end, we generated a conditional PLS3 OE mouse model and purchased a conditional Pls3 knockout (KO) mouse, generated by EUCOMM. Our results will be of highest relevance to develop future therapeutic approaches for these common diseases.Publications
Heilig J, Dietmar H, Brachvogel B, Paulsson M, Zaucke F, Niehoff A 2020 Collagen IX deficiency causes premature vascularization and ossification of murine femoral heads through an imbalance of pro- and antiangiogenic factors. Osteoarthritis Cartilage 28(7):988-999.
Li P, Fleischhauer L, Nicolae C, Prein C, Farkas Z, Saller MM, Prall WC, Wagener R, Heilig J, Niehoff A, Clausen-Schaumann H, Alberton P, Aszodi A 2020 Mice lacking the matrilin family of extracellular matrix proteins develop mild skeletal abnormalities and are susceptible to age-associated osteoarthritis. Int J Mol Sci 21(2).
Wirth B, Karakaya M, Kye MJ, Mendoza-Ferreira N 2020 Twenty-five years of spinal muscular atrophy research: from phenotype to genotype to therapy, and what comes next. Annu Rev Genomics Hum Genet [Epub ahead of print]
Holzer T, Probst K, Etich J, Auler M, Georgieva VS, Bluhm B, Frie C, Heilig J, Niehoff A, Nüchel J, Plomann M, Seeger JM, Kashkar H, Baris OR, Wiesner RJ, Brachvogel B 2019 Respiratory chain inactivation links cartilage-mediated growth retardation to mitochondrial diseases. J Cell Biol 218(6):1853-1870.
Neugebauer J, Heilig J, Hosseinibarkooie S, Ross BC, Mendoza-Ferreira N, Nolte F, Peters M, Hölker I, Hupperich K, Tschanz T, Grysko V, Zaucke F, Niehoff A, Wirth B 2018 Plastin 3 influences bone homeostasis through regulation of osteoclast activity. Hum Mol Genet Sep 10. Epub ahead of print
Riessland M, Kaczmarek A, Schneider S, Swoboda KJ, Löhr H, Bradler C, Grysko V, Dimitriadi M, Hosseinibarkooie S, Torres-Benito L, Peters M, Upadhyay A, Biglari N, Kröber S, Hölker I, Garbes L, Gilissen C, Hoischen A, Nürnberg G, Nürnberg P, Walter M, Rigo F, Bennett CF, Kye MJ, Hart AC, Hammerschmidt M, Kloppenburg P, Wirth B 2017 Neurocalcin delta suppression protects against spinal muscular atrophy in humans and across species by restoring impaired endocytosis. Am J Hum Genet 100(2):297-315.
Hosseinibarkooie S, Peters M, Torres-Benito L, Rastetter RH, Hupperich K, Hoffmann A, Mendoza-Ferreira N, Kaczmarek A, Janzen E, Milbradt J, Lamkemeyer T, Rigo F, Bennett CF, Guschlbauer C, Büschges A, Hammerschmidt M, Riessland M, Kye MJ, Clemen CS, Wirth B 2016 The Power of Human Protective Modifiers: PLS3 and CORO1C Unravel Impaired Endocytosis in Spinal Muscular Atrophy and Rescue SMA Phenotype. Am J Hum Genet 99(3):647-665.
Bleuel J, Zaucke F, Brüggemann G-P, Heilig J, Wolter ML, Hamann N, Firner S, Niehoff A 2015 Effects of moderate cyclic tensile strain on cartilage extracellular matrix proteins. J Biomech Eng 137:061009.
Hamann N, Zaucke F, Heilig J, Oberländer KD, Brüggemann G-P, Niehoff A 2014 Effect of different running modes on the morphological, biochemical, and mechanical properties of articular cartilage. Scand J Med Sci Sport 24(1):179-88.
Niehoff A, Lechner P, Ratiu O, Reuter S, Hamann N, Brüggemann GP, Schönau E, Bloch W, Beccard R 2014 Effect of whole body-vibration and insulin-like growth factor-I (IGF-I) on muscle paralysis-induced bone degeneration after botulinum toxin injection in mice. Calcif Tissue Int 94(4):373-383.
Ackermann B, Krober S, Torres-Benito L, Borgmann A, Peters M, Hosseini Barkooie SM, Tejero R, Jakubik M, Schreml J, Milbradt J, Wunderlich TF, Riessland M, Tabares L, Wirth B 2013 Plastin 3 ameliorates spinal muscular atrophy via delayed axon pruning and improves neuromuscular junction functionality. Hum Mol Genet 22(7):1328-1347.
Hamann N, Zaucke F, Dayakli M, Brüggemann G-P, Niehoff A 2013 Growth-related structural, biochemical, and mechanical properties of the functional bone-cartilage unit. J Anat 222(2):248-59.
van Dijk FS, Zillikens MC, Micha D, Riessland M, Marcelis CL, de Die-Smulders CE, Milbradt J, Franken AA, Harsevoort AJ, Lichtenbelt KD, Pruijs HE, Rubio-Gozalbo ME, Zwertbroek R, Moutaouakil Y, Egthuijsen J, Hammerschmidt M, Bijman R, Semeins CM, Bakker AD, Everts V, Klein-Nulend J, Campos-Obando N, Hofman A, te Meerman GJ, Verkerk AJ, Uitterlinden AG, Maugeri A, Sistermans EA, Waisfisz Q, Meijers-Heijboer H, Wirth B, Simon ME, Pals G 2013 PLS3 mutations in X-linked osteoporosis with fractures. N Engl J Med 369(16):1529-36.
Niehoff A, Offermann M, Dargel J, Schmidt A, Brüggemann G-P, Bloch W 2008 Static and dynamic mechanical compression affects Akt phosphorylation in porcine patellofemoral joint cartilage. J Orthop Res 26(5):616-623.
Oprea GE, Krober S, McWhorter ML, Rossoll W, Muller S, Krawczak M, Bassell GJ, Beattie CE, Wirth B 2008 Plastin 3 is a protective modifier of autosomal recessive spinal muscular atrophy. Science 320(5875):524-7.
