D2 Frank Zaucke, Jörg Oliver Semler
The extracellular matrix in non-classical osteogenesis imperfecta
Orthopedic University Hospital Friedrichsheim
Marienburgstr. 2, 60528 Frankfurt
Prof. Dr. Jörg Oliver Semler
University Hospital for Pediatrics and Adolescent Medicine
Faculty of Medicine, University of Cologne
Kerpener Str. 62, 50937 Köln
Summary
In approximately 90% of the cases, the clinical picture of Osteogenesis imperfecta (OI) is caused by mutations in collagen I coding genes. However, pathomechanisms of the remaining non-classical OI types are largely unknown. It is still unclear if structural changes of the ECM directly lead to increased bone fragility or if functional alterations of the ECM cause an impaired stability of the skeletal system. Only a better understanding of underlying mechanisms allows the development of new treatment strategies. Only the elucidation of disease mechanisms in non-classical OI type VI caused by mutations in SERPINF1 paved the way for a new anti-resorptive treatment. The aim of the current project is to decipher mutations in new disease causing genes and analyze their pathogenic effects at the molecular and cellular level. 10 already recruited families will be characterized clinically and genetically using Whole Genome Sequencing. Functional analysis will unravel the influence of mutations on protein stability and localization as well as on collagen folding, transportation and secretion also of other ECM components. The effects on cell proliferation and differentiation and on relevant signaling pathways will be investigated in vitro. In addition to the identification of new pathologies the effects of currently used treatments like bisphosphonates in non-classical OI will be investigated in retrospective analysis. Thereby, we will define criteria for responders and non-responders and aim to develop more efficient therapeutic approaches.Publications
Etich J, Leßmeier L, Rehberg M, Sill H, Zaucke F, Netzer C, Semler O 2020 Osteogenesis imperfecta-pathophysiology and therapeutic options. Mol Cell Pediatr. 7(1):9.
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]
Georgieva VS, Etich J, Bluhm B, Zhu M, Frie C, Wilson R, Zaucke F, Bateman J, Brachvogel B2020 Ablation of the miRNA Cluster 24 Has Profound Effects on Extracellular Matrix Protein Abundance in Cartilage. Int J Mol Sci 21(11):E4112.
Hedderich J, El Bagdadi K, Angele P, Grässel S, Meurer A, Straub RH, Zaucke F, Jenei-Lanzl Z 2020 Norepinephrine Inhibits the Proliferation of Human Bone Marrow-Derived Mesenchymal Stem Cells via β2-Adrenoceptor-Mediated ERK1/2 and PKA Phosphorylation. Int J Mol Sci 21(11):E3924.
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.
Rehberg M, Azim M, Martakis K, Winzenrieth R, Hoyer-Kuhn H, Schoenau E, Semler O, Duran I 2020 Bone microarchitecture assessed by trabecular bone score is independent of mobility level or height in pediatric patients with cerebral palsy. J Bone Miner Res. [Epub ahead of print]
Etich J, Koch M, Wagener R, Zaucke F, Fabri M, Brachvogel B 2019 Gene Expression Profiling of the Extracellular Matrix Signature in Macrophages of Different Activation Status: Relevance for Skin Wound Healing. Int J Mol Sci 20(20).
Hoyer-Kuhn H, Rehberg M, Netzer C, Schoenau E, Semler O 2019 Individualized treatment with denosumab in children with osteogenesis imperfecta - follow up of a trial cohort. Orphanet J Rare Dis 14(1):219.
Jenei-Lanzl Z, Meurer A, Zaucke F 2019 Interleukin-1β signaling in osteoarthritis - chondrocytes in focus. Cell Signal 53:212-223.
Mayorca-Guiliani AE, Willacy O, Madsen CD, Rafaeva M, Heumüller SE, Bock F, Sengle G, Koch M, Imhof T, Zaucke F, Wagener R, Sasaki T, Erler JT, Reuten R 2019 Decellularization and antibody staining of mouse tissues to map native extracellular matrix structures in 3D. Nat Protoc. 14(12):3395-3425.
Moosa S, Yamamoto GL, Garbes L, Keupp K, Beleza-Meireles A, Moreno CA, Valadares ER, de Sousa SB, Maia S, Saraiva J, Honjo RS, Kim CA, Cabral de Menezes H, Lausch E, Lorini PV, Lamounier A Jr, Carniero TCB, Giunta C, Rohrbach M, Janner M, Semler O, Beleggia F, Li Y, Yigit G, Reintjes N, Altmüller J, Nürnberg P, Cavalcanti DP, Zabel B, Warman ML, Bertola DR, Wollnik B, Netzer C 2019 Autosomal-Recessive Mutations in MESD Cause Osteogenesis Imperfecta. Am J Hum Genet 105(4):836-843.
Rehberg M, Winzenrieth R, Hoyer-Kuhn H, Duran I, Schoenau E, Semler O 2019 TBS as a Tool to Differentiate the Impact of Antiresorptives onCortical and Trabecular Bone in Children With OsteogenesisImperfecta. J Clin Densitom 22(2):229-235.
Gebauer JM, Köhler A, Dietmar H, Gompert M, Neundorf I, Zaucke F, Koch M, Baumann U 2018 COMP and TSP-4 interact specifically with the novel GXKGHR motif only found in fibrillar collagens. Sci Rep 8(1):17187
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 27(24):4249-426.
Hoyer-Kuhn H, Franklin J, Allo G, Kron M, Netzer C, Eysel P, Hero B, Schoenau E, Semler O 2016 Safety and efficacy of denosumab in children with osteogenesis imperfect--a first prospective trial. J Musculoskelet Neuronal Interact 16(1):24-32.
Kamper M, Hamann N, Prein C, Clausen-Schaumann H, Farkas Z, Aszodi A, Niehoff A, Paulsson M, Zaucke F 2016 Early changes in morphology, bone mineral density and matrix composition of vertebrae lead to disc degeneration in aged collagen IX -/- mice. Matrix Biol 49:132-143
Oecal S, Socher E, Uthoff M, Ernst C, Zaucke F, Sticht H, Baumann U, Gebauer JM 2016 The pH-Dependent Client Release From the Collagen-Specific Chaperone Hsp47 is Triggered by a Tandem Histidine Pair. J Biol Chem 291(24):12612-12626.
Schulz J, Nüchel J, Niehoff A, Bloch W, Schönborn K, Kamper M, Brinckmann J, Plomann M, Paulsson M, Krieg T, Zaucke F*, Eckes B* 2016 COMP assisted collagen secretion - a novel intracellular function required for fibrosis. J Cell Sci 129(4):706-716 *shared last author
Garbes L, Kim K, Rieß A, Hoyer-Kuhn H, Beleggia F, Bevot A, Kim MJ, Huh YH, Kweon HS, Savarirayan R, Amor D, Kakadia PM, Lindig T, Kagan KO, Becker J, Boyadjiev SA, Wollnik B, Semler O, Bohlander SK, Kim J, Netzer C 2015 Mutations in SEC24D, encoding a component of the COPII machinery, cause a syndromic form of osteogenesis imperfecta. Am J Hum Genet 96(3):432-439.
Brachvogel B*, Zaucke F*, Dave K, Norris EL, Stermann J, Dayakli M, Koch M, Gorman JJ, Bateman JF, Wilson R 2013 Comparative proteomic analysis of normal and collagen IX null mouse cartilage reveals altered extracellular matrix composition and novel components of the collagen IX interactome. J Biol Chem 288(19):13481–13492.* shared first author
Keupp K, Beleggia F, Kayserili H, Barnes AM, Steiner M, Semler O, Fischer B, Yigit G, Janda CY, Becker J, Breer S, Altunoglu U, Grünhagen J, Krawitz P, Hecht J, Schinke T, Makareeva E, Lausch E, Cankaya T, Caparrós-Martín JA, Lapunzina P, Temtamy S, Aglan M, Zabel B, Eysel P, Koerber F, Leikin S, Garcia KC, Netzer C, Schönau E, Ruiz-Perez VL, Mundlos S, Amling M, Kornak U, Marini J, Wollnik B 2013. Mutations in WNT1 cause different forms of bone fragility. Am J Hum Genet 92(4):565-74.
Semler O, Netzer C, Hoyer-Kuhn H, Becker J, Eysel P, Schoenau E 2012 First use of the RANKL antibody denosumab in osteogenesis imperfecta type VI. J. Musculoskelet. Neuronal Interact 12(3):183-188.
Widmer C, Gebauer J, Brunstein E, Rosenbaum S, Zaucke F, Drögemüller C, Loeb T, Baumann U 2012 A molecular basis for the action of the collagen-specific chaperone Hsp47/SerpinH1 and its structure-specific client recognition. Proc Natl Acad Sci 109(33):13243-13247.
Becker J, Semler O, Gilissen C, Li Y, Bolz HJ, Giunta C, Bergmann C, Rohrbach M, Koerber F, Zimmermann K, de Vries P, Wirth B, Schoenau E, Wollnik B, Veltman JA, Hoischen A, Netzer C 2011 Exome sequencing identifies truncating mutations in human SERPINF1 in autosomal-recessive osteogenesis imperfecta. Am J Hum Genet 88(3):362-371.
