A new osteopetrosis mutant mouse strain (ntl) with odontoma‐like proliferations and lack of tooth roots

Abstract

A new spontaneous mouse mutant (ntl) with autosomal-recessive osteopetrosis was characterized. These mice formed tartrate-resistant acid phosphate (TRAP)-positive osteoclasts but their osteoclasts had no ruffled border and did not resorb bone. These mice displayed no tooth eruption or tooth root formation. Adult mutant mice developed odontoma-like proliferations near the proximal ends of the incisors. Intraperitoneal injection of progenitor cells from the liver of 16.5 days postcoitum wild-type embryos into newborn mutants rescued the osteopetrosis phenotype, indicating that the defects were intrinsic to the osteoclasts. Our findings not only provide further support for a critical role of osteoclasts in tooth eruption and tooth root development, but also suggest that the perturbation of the homeostasis of the odontogenic precursors of the incisors is primarily responsible for the development of the odontoma-like proliferations in this osteopetrosis mutant. Genetic mapping has narrowed down the location of the mutant allele to a genetic interval of 3.2 cM on mouse chromosome 17.

Osteoclasts in the Dental Microenvironment: A Delicate Balance Controls Dental Histogenesis

“…WT = Wild-type. mouse lines [for review, see Helfrich, 2005], the dental phenotype has been established as being a direct consequence of osteoclast dysfunction [Yoshino et al, 2003;Lu et al, 2009]. Taken together, these experiments and the present study lend support to the concept that osteoclasts exert a 'microenvironmental' action on dental cells, although the underlying mechanisms are currently unknown.…”

“…This phenotype was moderate here in Msx2-/-mice where the third molar was principally affected. In a more variable pattern, alterations to odontogenesis have been described; the defects include a complete lack of root formation, as observed in several mouse mutants [Lu et al, 2009], and/or, as shown in Msx2-/-mice in the present study, late growth of odontogenic tumor-like structures [Nakajima et al, 1996;Tiffee et al, 1999], the occurrence of which is frequently reported. It may involve continuously erupting incisors and/or limited growth of molars.…”

Microscopic analysis of molar–incisor malformation

“…Recent animal testing revealed that a specific gene variation in root odontoblasts is able to affect root formation. 34 The genes Nfic, 35 Msx2, 36 Shh, 37 Sp6, 38 Noggin, 39 b-catenin, 40 smadd4, 41 Ntl, 42 and Rankl 43,44 are related to the shape, length, and number of roots. Among these, the most relevant to the present study is the Wnt/b-catenin signaling associated with root and cementum formation.…”

Report of two Chinese patients suffering from CLCN7-related osteopetrosis and root dysplasia

“…However, tooth eruption is a complex process that also requires the combined influences of dental follicle, periodontal ligament, hydrostatic pressure and root formation (Helfrich, 2005;Tiffee et al,1999). So far, lack of tooth root formation has been observed in four osteopetrosis models, namely ntl mice (spontaneous mutant mice), Rank À/À mice, Rankl À/À mice, and c-src À/À mice (Lu et al, 2009;Tiffee et al, 1999). A clinical report described an ARO patient with some teeth without root development (Jalevik et al, 2002).…”

“…We suspected that ClC-7 has a spatial and temporal distribution during mouse tooth development and might contribute to the mouse tooth development (Su et al, 2008). It is widely believed that the Hertwig's epithelial root sheath probably initiates differentiation of odontoblasts from the peripheral mesenchymal cells followed by tooth root formation (Lu et al, 2009). Recently it was demonstrated that osteoclasts play an essential role in root formation (Lu et al, 2009) and it is possible that ClC-7 in different tooth cells could contribute directly to the root formation.…”