B2 Manuel Koch, Marcus Krüger
Collagen XII as a risk factor for musculoskeletal diseases
Faculty of Medicine, University of Cologne
Joseph-Stelzmann-Str. 52, 50931 Cologne
Prof. Dr. Marcus Krüger
Istitut für Genetik, CECAD
Universität zu Köln
Joseph-Stelzmann Str. 26
50931 Köln
Summary
The collagen family of proteins plays an important role in musculoskeletal homeostasis. The critical functions of collagens are clearly illustrated by a wide spectrum of collagen-related diseases found in humans, e.g., osteogenesis imperfecta, myopathy, and Ehlers-Danlos syndrome. The function of collagen XII was not known until recently. However, since we could show that collagen XII binds to proteins involved in connective tissue diseases, it was no surprise that mutations in collagen XII also cause an Ehlers-Danlos - myopathy overlap syndrome. In collaboration we could identify several families/patients harboring mutations in the COL12A1 gene. To study the molecular mechanism of this syndrome, collagen XII deficient mice were generated. The mice were born but developed kyphosis and muscle weakness. Initial studies revealed that cortical bones were weaker due to the loss of osteoblast polarity and osteocytes had reduced numbers of cytoplasmic/dendritic processes. Furthermore, muscle weakness was observed, which were not caused by the muscle units themselves since physiological measurements on isolated muscles did not show any difference. Our present goal is to elucidate the function of collagen XII in the musculoskeletal system.Publications
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).
Feng C, Chan WCW, Lam Y, Wang X, Chen P, Niu B, Ng VCW, Yeo JC, Stricker S, Cheah KSE, Koch M, Mundlos S, Ng HH, Chan D 2019 Lgr5 and Col22a1 Mark Progenitor Cells in the Lineage toward Juvenile Articular Chondrocytes. Stem Cell Reports 13(4):713-729.
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.
Mohassel P, Liewluck T, Hu Y, Ezzo D, Ogata T, Saade D, Neuhaus S, Bolduc V, Zou Y, Donkervoort S, Medne L, Sumner CJ, Dyck PJB, Wierenga KJ, Tennekoon G, Finkel RS, Chen J, Winder TL, Staff NP, Foley AR, Koch M, Bönnemann CG 2019 Dominant collagen XII mutations cause a distal myopathy. Ann Clin Transl Neurol. 6(10):1980-1988.
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
Jakobsen JR, Mackey AL, Knudsen AB, Koch M, Kjaer M, Krogsgaard MR 2017 Composition and adaptation of human myotendinous junction and neighboring muscle fibers to heavy resistance training. Scand J Med Sci Sports 27(12):1547-1559.
Izu Y, Ezura Y, Koch M, Birk DE, Noda M 2016 Collagens VI and XII form complexes mediating osteoblast interactions during osteogenesis. Cell Tissue Res 364(3):623-635.
Reuten R, Patel TR, McDougall M, Rama N, Nikodemus D, Gibert B, Delcros JG, Prein C, Meier M, Metzger S, Zhou Z, Kaltenberg J, McKee KK, Bald T, Tuting T, Zigrino P, Djonov V, Bloch W, Clausen-Schaumann H, Poschl E, Yurchenco PD, Ehrbar M, Mehlen P, Stetefeld* J, Koch* M 2016 Structural decoding of netrin-4 reveals a regulatory function towards mature basement membranes. Nat Commun 7:13515. *shared last author
Chiquet M, Birk DE, Bonnemann CG, Koch M 2014 Collagen XII: Protecting bone and muscle integrity by organizing collagen fibrils. Int J Biochem Cell Biol 53:51-54.
Hicks D, Farsani GT, Laval S, Collins J, Sarkozy A, Martoni E, Shah A, Zou Y, Koch M, Bonnemann CG, Roberts M, Lochmuller H, Bushby K, Straub V 2014 Mutations in the collagen XII gene define a new form of extracellular matrix-related myopathy. Hum Mol Genet 23(9):2353-2363.
Zou Y, Zwolanek D, Izu Y, Gandhy S, Schreiber G, Brockmann K, Devoto M, Tian Z, Hu Y, Veit G, Meier M, Stetefeld J, Hicks D, Straub V, Voermans NC, Birk DE, Barton ER, Koch* M, Bonnemann* CG 2014 Recessive and dominant mutations in COL12A1 cause a novel EDS/myopathy overlap syndrome in humans and mice. Hum Mol Genet 23(9):2339-2352. *shared last author
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.
Charvet B, Guiraud A, Malbouyres M, Zwolanek D, Guillon E, Bretaud S, Monnot C, Schulze J, Bader HL, Allard B, Koch M, Ruggiero F 2013 Knockdown of col22a1 gene in zebrafish induces a muscular dystrophy by disruption of the myotendinous junction. Development 140(22):4602-4613.
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(27):22549-22559.
Izu Y, Sun M, Zwolanek D, Veit G, Williams V, Cha B, Jepsen KJ, Koch M, Birk DE 2011 Type XII collagen regulates osteoblast polarity and communication during bone formation. J Cell Biol 193(6):1115-1130.