Dental malformations associated with biallelic MMP20 mutations

Abstract

Background Matrix metallopeptidase 20 (MMP20) is an evolutionarily conserved protease that is essential for processing enamel matrix proteins during dental enamel formation. MMP20 mutations cause human autosomal recessive pigmented hypomaturation‐type amelogenesis imperfecta (AI2A2; OMIM #612529). MMP20 is expressed in both odontoblasts and ameloblasts, but its function during dentinogenesis is unclear. Methods We characterized 10 AI kindreds with MMP20 defects, characterized human third molars and/or Mmp20 −/− mice by histology, Backscattered Scanning Electron Microscopy (bSEM), µCT, and nanohardness testing. Results We identified six novel MMP20 disease‐causing mutations. Four pathogenic variants were associated with exons encoding the MMP20 hemopexin‐like (PEX) domain, suggesting a necessary regulatory function. Mutant human enamel hardness was softest (13% of normal) midway between the dentinoenamel junction (DEJ) and the enamel surface. bSEM and µCT analyses of the third molars revealed reduced mineral density in both enamel and dentin. Dentin close to the DEJ showed an average hardness number 62%–69% of control. Characterization of Mmp20 −/− mouse dentin revealed a significant reduction in dentin thickness and mineral density and a transient increase in predentin thickness, indicating disturbances in dentin matrix secretion and mineralization. Conclusion These results expand the spectrum of MMP20 disease‐causing mutations and provide the first evidence for MMP20 function during dentin formation.

Manifestation and Mechanisms of Abnormal Mineralization in Teeth

“…Consequently, atypical calcified nodules form on the surface of enamel (Figure 5B,C). 71 Apart from cleaving of cadherins by MMP-20, "a disintegrin and metalloproteinase" (ADAM)-10 also cleaves cadherins, tight junctions, and desmosome proteins. 80 preameloblast from preodontoblast depends on the degradation of the basement membrane by ADAM10, and AI occurs when such a process is abnormal.…”

“…(A) Maxillary occlusal view of a patient with Mmp20 mutation. Reproduced with permission from ref . Copyright 2020 Hu, Y.; Smith, C. E.; Richardson, A. S.; Bartlett, J. D.; Hu, J. C. C.; Simmer, J. P. (B) Scanning electron microscopy of mandibular molar crowns.…”

“…(PD, predentin; PDL, periodontal ligament). Reproduced with permission from ref . Copyright 2020 Hu, Y.; Smith, C. E.; Richardson, A. S.; Bartlett, J. D.; Hu, J. C. C.; Simmer, J. P. (D) Schematic diagram showing molar enamel organ organization in WT, MMP20-overexpressing, and Mmp20 null mice.…”

Loss of BMP2 and BMP4 Signaling in the Dental Epithelium Causes Defective Enamel Maturation and Aberrant Development of Ameloblasts

“…From the onset of the transition stage of amelogenesis onwards, ameloblasts express and secrete high levels of kallikrein-related peptidase 4 (KLK4) [ 11 , 33 , 34 ], a serine protease which degrades EMPs [ 35 ]. Mmp20 expression levels decline in ameloblasts during the transition and early maturation stages, and Mmp20 mRNA is barely detectable in late maturation-stage ameloblasts [ 11 , 36 ].…”

“…The importance of EMPs, MMP20, and KLK4 for normal enamel formation has been revealed by genetic studies both in humans [ 9 , 36 , 37 ] and in mouse models [ 26 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 ].…”