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A discoidin domain receptor 1 knock-out mouse as a novel model for osteoarthritis of the temporomandibular joint

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Abstract

Discoidin domain receptor 1 (DDR-1)-deficient mice exhibited a high incidence of osteoarthritis (OA) in the temporomandibular joint (TMJ) as early as 9 weeks of age. They showed typical histological signs of OA, including surface fissures, loss of proteoglycans, chondrocyte cluster formation, collagen type I upregulation, and atypical collagen fibril arrangements. Chondrocytes isolated from the TMJs of DDR-1-deficient mice maintained their osteoarthritic characteristics when placed in culture. They expressed high levels of runx-2 and collagen type I, as well as low levels of sox-9 and aggrecan. The expression of DDR-2, a key factor in OA, was increased. DDR-1-deficient chondrocytes from the TMJ were positively influenced towards chondrogenesis by a three-dimensional matrix combined with a runx-2 knockdown or stimulation with extracellular matrix components, such as nidogen-2. Therefore, the DDR-1 knock-out mouse can serve as a novel model for temporomandibular disorders, such as OA of the TMJ, and will help to develop new treatment options, particularly those involving tissue regeneration.

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Acknowledgments

The authors would like to thank the staff of the animal facilities at the MPI Experimental Medicine, Goettingen and the Medical Faculty of the University of Goettingen for animal care, Dr. Bunt, Molecular & Live Cell Imaging (MOLCI), central imaging facility of the UMG, for the confocal microscopy work, Dr. Salinas-Riester for performing the microarray and Mr. Opitz for statistical evaluation, and Dr. Dullin for help with the micro-CT. We would also like to thank Mr. Hoehne, as parts of the results were taken from his doctoral thesis. We also wish to thank Mr. Menrath for professional assistance with the figure layout.

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Authors and Affiliations

  1. Oral Biology and Tissue Regeneration Work Group, Department of Prosthodontics, Medical Faculty, Georg-August-University, Robert Koch Straße 40, 37075, Goettingen, Germany

    Boris Schminke, Hayat Muhammad, Christa Bode, Boguslawa Sadowski, Regina Gerter, Nikolaus Gersdorff, Ralf Bürgers & Nicolai Miosge

  2. Robert H. Smith Faculty of Agriculture, Food and Environment, Institute of Biochemistry, Food Science and Nutrition, The Hebrew University of Jerusalem, P.O. Box 12, 76100, Rehovot, Israel

    Efrat Monsonego-Ornan

  3. Developmental Biology, Harvard School of Dental Medicine, 188 Longwood Avenue, Boston, MA, 02115, USA

    Vicki Rosen

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  1. Boris Schminke
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  2. Hayat Muhammad
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Correspondence to Vicki Rosen or Nicolai Miosge.

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B. Schminke and H. Muhammad contributed equally to this work.

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18_2013_1436_Fig8_ESM.jpg

Supplemental Fig. 1 The role of runx-2 as a transcription factor in the osteoblastic lineage. a DAPI staining of a chondrocytes nucleus, b immunocytochemistry of runx-2, localization in the cytoplasm and nucleus of the same chondrocyte was observed. c Merged image of a and b for better visualization of runx-2 in the nucleus. Overexpression of runx-2. Lane 1 control with the vector without insert; lane 2 page ruler; and lane 3 overexpressed runx-2. Coomassie blue staining was performed to determine the overall protein pattern and to confirm equal loading, as observed in d. Western blot of runx-2, as observed in e. Measured mRNA expression levels of osteogenic markers of the cells after overexpression of runx-2. We observed enhanced gene expression of f runx-2, g Col1A1, h SPP1 and i IBSP. *Significant differences (p ≤ 0.05); data are mean values with SD from three individual experiments (JPEG 2551 kb)

18_2013_1436_Fig9_ESM.jpg

Supplemental Fig. 2 Preliminary investigation of primary cilia in TMJ chondrocytes. a Microarray results of genes associated with primary cilia. b DAPI staining (left) of the nuclei of the chondrocytes and acetylated α-tubulin staining (red for better visualization) of the primary cilia (right) are shown. c The quantification of the results indicated a tendency towards a reduction of the percentage of cells with primary cilia in DDR-1 KO chondrocytes. Data are mean values with SD of three individual experiments. (n = 6, including three KO mice and three WT mice, for cilia staining) (JPEG 5676 kb)

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Schminke, B., Muhammad, H., Bode, C. et al. A discoidin domain receptor 1 knock-out mouse as a novel model for osteoarthritis of the temporomandibular joint. Cell. Mol. Life Sci. 71, 1081–1096 (2014). https://doi.org/10.1007/s00018-013-1436-8

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