<i>MMP20</i>,<i> KLK4,</i> and <i>MMP20/KLK4</i> double null mice define roles for matrix proteases during dental enamel formation

  • Yuanyuan Hu
    Departments of Biologic and Materials Sciences University of Michigan School of Dentistry 1210 Eisenhower Place Ann Arbor Michigan 48108
  • Charles E. Smith
    Departments of Biologic and Materials Sciences University of Michigan School of Dentistry 1210 Eisenhower Place Ann Arbor Michigan 48108
  • Amelia S Richardson
    Departments of Biologic and Materials Sciences University of Michigan School of Dentistry 1210 Eisenhower Place Ann Arbor Michigan 48108
  • John D. Bartlett
    Office of Research College of Dentistry Ohio State University 4139 Postle Hall, 305 W. 12th Ave. Columbus Ohio 43210
  • Jan C.C. Hu
    Departments of Biologic and Materials Sciences University of Michigan School of Dentistry 1210 Eisenhower Place Ann Arbor Michigan 48108
  • James P. Simmer
    Departments of Biologic and Materials Sciences University of Michigan School of Dentistry 1210 Eisenhower Place Ann Arbor Michigan 48108

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<jats:title>Abstract</jats:title><jats:p>Matrix metalloproteinase 20 (MMP20) and kallikrein‐related peptidase 4 (KLK4) are secreted proteinases that are essential for proper dental enamel formation. We characterized and compared enamel formed in wild‐type, <jats:italic>Mmp20</jats:italic><jats:sup>−/−</jats:sup>, <jats:italic>Klk4</jats:italic><jats:sup>−/−</jats:sup>, <jats:italic>Mmp20</jats:italic><jats:sup>+/−</jats:sup><jats:italic>Klk4</jats:italic><jats:sup>+/−</jats:sup>, and <jats:italic>Mmp20</jats:italic><jats:sup>−/−</jats:sup><jats:italic>Klk4</jats:italic><jats:sup>−/−</jats:sup> mice using dissecting and light microscopy, backscattered scanning electron microscopy (bSEM), SEM, microcomputed tomography (<jats:italic>μ</jats:italic>CT), and energy‐dispersive X‐ray analysis (EDX). Following eruption, fractures were observed on <jats:italic>Mmp20</jats:italic><jats:sup>−/−</jats:sup>, <jats:italic>Klk4</jats:italic><jats:sup>−/−</jats:sup>, <jats:italic>Mmp20</jats:italic><jats:sup>+/−</jats:sup><jats:italic>Klk4</jats:italic><jats:sup>+/−</jats:sup>, and <jats:italic>Mmp20</jats:italic><jats:sup>−/−</jats:sup><jats:italic>Klk4</jats:italic><jats:sup>−/−</jats:sup> molars. Failure of the enamel in the <jats:italic>Mmp20</jats:italic><jats:sup>+/−</jats:sup><jats:italic>Klk4</jats:italic><jats:sup>+/−</jats:sup> molars was unexpected and suggested that digenic effects could contribute to the etiology of amelogenesis imperfecta in humans. Micro‐CT analyses of hemimandibles demonstrated significantly reduced high‐density enamel volume in the <jats:italic>Mmp20</jats:italic><jats:sup>−/−</jats:sup> and <jats:italic>Klk4</jats:italic><jats:sup>−/−</jats:sup> mice relative to the wild‐type, which was further reduced in <jats:italic>Mmp20</jats:italic><jats:sup>−/−</jats:sup><jats:italic>Klk4</jats:italic><jats:sup>−/−</jats:sup> mice. bSEM images of 7‐week <jats:italic>Mmp20</jats:italic><jats:sup>−/−</jats:sup> and <jats:italic>Mmp20</jats:italic><jats:sup>−/−</jats:sup><jats:italic>Klk4</jats:italic><jats:sup>−/−</jats:sup> mandibular incisors showed rough, pitted enamel surfaces with numerous indentations and protruding nodules. The <jats:italic>Mmp20</jats:italic><jats:sup>+/−</jats:sup> and <jats:italic>Mmp20</jats:italic><jats:sup>+/−</jats:sup><jats:italic>Klk4</jats:italic><jats:sup>+/−</jats:sup> incisors showed prominent, evenly spaced, horizontal ridges that were more distinct in <jats:italic>Mmp20</jats:italic><jats:sup>+/−</jats:sup><jats:italic>Klk4</jats:italic><jats:sup>+/−</jats:sup> incisors relative to <jats:italic>Mmp20</jats:italic><jats:sup>+/−</jats:sup> incisors due to the darkening of the valleys between the ridges. In cross sections, the <jats:italic>Mmp20</jats:italic><jats:sup>−/−</jats:sup> and <jats:italic>Mmp20</jats:italic><jats:sup>−/−</jats:sup><jats:italic>Klk4</jats:italic><jats:sup>−/−</jats:sup> exhibited three distinct layers. The outer layer exhibited a disturbed elemental composition and an irregular enamel surface covered with nodules. The <jats:italic>Mmp20</jats:italic> null enamel was apparently unable to withstand the sheer forces associated with eruption and separated from dentin during development. Cells invaded the cracks and interposed between the dentin and enamel layers. MMP20 and KLK4 serve overlapping and complementary functions to harden enamel by removing protein, but MMP20 potentially serves multiple additional functions necessary for the adherence of enamel to dentin, the release of intercellular protein stores into the enamel matrix, the retreat of ameloblasts to facilitate thickening of the enamel layer, and the timely transition of ameloblasts to maturation.</jats:p>

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