Abstract
Hutchinson-Gilford progeria syndrome (HGPS) is a rare accelerated senescence disease, manifesting dental abnormalities and several symptoms suggestive of premature aging. Although irregular secondary dentin formation in HGPS patients has been reported, pathological mechanisms underlying aberrant dentin formation remain undefined. In this study, we analyzed the mandibular molars of a tissue-specific mouse model that overexpresses the most common HGPS mutation (LMNA, c.1824C > T, p.G608G) in odontoblasts. In the molars of HGPS mutant mice at postnatal week 13, targeted expression of the HGPS mutation in odontoblasts results in excessive dentin formation and pulp obliteration. Circumpulpal dentin of HGPS mutants was clearly distinguished from secondary dentin of wild-type (WT) littermates and its mantle dentin by considering the irregular porous structure and loss of dentinal tubules. However, the dentin was significantly thinner in the molars of HGPS mutants at postnatal weeks 3 and 5 than in those of WT mice. In vitro analyses using MDPC-23, a mouse odontoblastic cell line, showed cellular senescence, defects of signaling pathways and consequential downregulation of matrix protein expression in progerin-expressing odontoblasts. These results indicate that expression of the HGPS mutation in odontoblasts disturbs physiological secondary dentin formation. In addition, progerin-expressing odontoblasts secrete paracrine factors that can stimulate odontogenic differentiation of dental pulp cells. Taken together, our results suggest that the aberrant circumpulpal dentin of HGPS mutants results from defects in physiological secondary dentin formation and consequential pathologic response stimulated by paracrine factors from neighboring progerin-expressing odontoblasts.
Highlights
Dentin is produced by odontoblasts, differentiated cells derived from ectomesenchyme[12]
Deposited dentin of Hutchinson-Gilford progeria syndrome (HGPS) mice differs from primary dentin by its discontinuous dentinal tubules and porous structure, which is similar to tertiary dentin
Based on the chronological analysis of dental tissues from HGPS mutant mice, it appears that normal development of dentin underlies primary dentin formation, but irregular circumpulpal dentin is deposited beneath mantle dentin beginning at postnatal week 5 and gradually obliterates almost the entire pulp cavity by postnatal week 20
Summary
Dentin is produced by odontoblasts, differentiated cells derived from ectomesenchyme[12]. Previous results showed that tissue-specific inducible expression of human lamin A, carrying the HGPS mutation, during skeletal development in mice caused bone abnormalities with poor biomechanical properties and widespread loss of osteocytes and osteoblasts[17]. It was reported that expression of the HGPS mutation during tooth development resulted in irregular dentin formation and polarization defects in the same mutant mouse strain[17]. It remains to be clarified how the HGPS mutation operates in the process of dentin formation during tooth development. Different age groups of transgenic mice with tissue-specific expression of the HGPS mutation were histologically analyzed, and in addition in vitro techniques were used to uncover the underlying molecular mechanisms following expression of the HGPS mutation in odontoblasts
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