Enamel and dental anomalies in latent‐transforming growth factor beta‐binding protein 3 mutant mice

Abstract

Latent‐transforming growth factor beta‐binding protein 3 (LTBP‐3) is important for craniofacial morphogenesis and hard tissue mineralization, as it is essential for activation of transforming growth factor‐β (TGF‐β). To investigate the role of LTBP‐3 in tooth formation we performed micro‐computed tomography (micro‐CT), histology, and scanning electron microscopy analyses of adult Ltbp3‐/‐ mice. The Ltbp3‐/‐ mutants presented with unique craniofacial malformations and reductions in enamel formation that began at the matrix formation stage. Organization of maturation‐stage ameloblasts was severely disrupted. The lateral side of the incisor was affected most. Reduced enamel mineralization, modification of the enamel prism pattern, and enamel nodules were observed throughout the incisors, as revealed by scanning electron microscopy. Molar roots had internal irregular bulbous‐like formations. The cementum thickness was reduced, and microscopic dentinal tubules showed minor nanostructural changes. Thus, LTBP‐3 is required for ameloblast differentiation and for the formation of decussating enamel prisms, to prevent enamel nodule formation, and for proper root morphogenesis. Also, and consistent with the role of TGF‐β signaling during mineralization, almost all craniofacial bone components were affected in Ltbp3‐/‐ mice, especially those involving the upper jaw and snout. This mouse model demonstrates phenotypic overlap with Verloes Bourguignon syndrome, also caused by mutation of LTBP3, which is hallmarked by craniofacial anomalies and amelogenesis imperfecta phenotypes.

Genotypic Categorization of Loeys-Dietz Syndrome Based on 24 Novel Families and Literature Data

“…Also, in four families the presence of significant craniofacial malformations correlated with a higher risk of vascular manifestations [5,6]. Finally, two children had tooth abnormalities, in particular enamel defects, a possibly underestimated features in LDS in line with the role of TGF-β signaling in dental and enamel formation [15].…”

LTBP3 Pathogenic Variants Predispose Individuals to Thoracic Aortic Aneurysms and Dissections

“…Ltbp3 À/À mice have been extensively documented as being smaller than wild-type or heterozygous littermates and as having dental anomalies and defects in skeletal development; such defects include domed skulls, shortened maxilla, anteriorized foramen magnum, and kyphosis, abnormalities that can result from the reduction of TGF-b bioavailability in mice. 24,25 Neither aortic pathology nor aortic disease has been described in these mice. We investigated these mice for cardiovascular pathology and identified significantly increased elastic lamellar units in Ltbp3 À/À ascending aortas compared to wild-type aortas, a finding that is also observed in another HTAD mouse model, Acta2 À/À mice (Figures 2A and 2B).…”

Fibrillin microfibrils and elastic fibre proteins: Functional interactions and extracellular regulation of growth factors

“…LTBP-2 has also been implicated in wound healing [54]. LTBP-3 deletion in humans produces similar phenotypes to those of LTBP-3 null mice, including short stature, spinal curvature, craniofacial abnormalities and increased bone mass [[55], [56], [57]]. Aberrant LTBP-3-TGFβ complexes may be responsible for aortic dilation and dissection in MFS as MFS mice lacking LTBP-3 had fewer aneurysms and less fragmented elastic fibres [58].…”