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

Bone homeostasis is maintained primarily by the coordinated activities of two main cellular processes: osteoblast- mediated bone formation; and osteoclast-mediated bone resorption. Perturbation of these coordinated activities can lead to profound alterations in bone mass that have clinical relevance (1, 2). For example, osteoporosis is a common cause of vertebral and compression fractures among the elderly. In addition, rare disorders of increased bone mass caused by the absence or dysfunction of osteoclasts, namely osteopetrosis, can cause death during childhood as a result of ablation of the bone marrow space and skeletal abnormalities caused by the absence of normal bone-remodeling activity (3). The elevated osteoclast function is also associated with many other disorders of the skeleton, including periodontal disease, rheumatoid arthritis, and the metastatic spread of cancer to bone (4). Studies in animal models of osteopetrosis, and particularly in mutant mice, have provided significant new insights regarding the fundamental biology of osteoclasts (1, 5, 6). For example, some mutants completely lack osteoclasts, implying the involvement of the mutated genes in the early stages of osteoclast differentiation (7–10); other mutants produce osteoclasts with an immature appearance, highlighting the important roles of these mutated genes in terminal differentiation (11, 12); other mutants produce osteoclasts that appear normal but are defective in their ability to resorb bone, indicating that these genes are required for the maturation of the osteoclast and their normal bone-resorption capacity (13–17). These three different types of osteopetrosis mutants are phenotypically quite similar, except that the first appears to have reduced bone formation, suggesting that the absence of osteoclasts may also affect the activity of osteoblasts in these mice (18). This group of mutants is phenotypically reminiscent of human autosomal-recessive osteopetrosis. The mouse genes Atp6i, Gl, Traf-6, c-Src, and Clcn-7, respectively, when mutated, give rise to osteopetrosis with abnormal osteoclasts (13–17, 19). The human homologues for three of these genes (GL, ATP6i, and CLCN-7, respectively) are in fact disease genes for human autosomal-recessive osteopetrosis (13, 14, 19). However, mutations in these three genes alone do not appear to account for all cases of this disease in humans (13, 14, 19), indicating the existence of additional disease-causing genes for autosomal-recessive osteopetrosis. Osteoclasts are also vital for tooth eruption, a process that requires two highly coordinated processes: the formation of an eruption pathway; and the vertical movement of the developing tooth bud into the oral cavity (20). To form the eruption pathway, active alveolar bone resorption and the recruitment of numerous osteoclasts are required (21). Furthermore, recent studies have shown that a number of genes contribute to this process (21). Interestingly, we know very little about tooth root formation, an important physiological process. There are numerous osteopetrosis models but it is, in fact, not known whether or not these animals have defects in tooth root formation, and whether osteoclasts play any role in this developmental event. In this work, we have characterized a new mouse model of osteopetrosis that is caused by a spontaneous mutation: it is referred to as ntl (‘new toothless’) mouse. First, we investigated whether, how, and why odontomas were developed in this mutant. Second, we attempted to identify, by genetic mapping, the gene that is responsible for this osteopetrosis animal model. Third, we considered whether this model and other similar osteopetrosis models interfere with tooth root formation. Our results support the hypotheses that defects in osteoclasts disrupt the development and growth of the tooth root, and that homeostatic perturbation of the odontogenic precursors that are central to the root formation of mouse incisors is the primary cause of odontoma-like proliferations in this new mutant.