IADR Abstract Archives
Embryonic CSF-1 Receptor Inhibition Results in Dental Malformations in Mice
Objectives: Colony stimulating factor-1 and its receptor (CSF-1R) are important in the development, differentiation and survival of macrophage, microglial and osteoclast cells. Mice lacking the ligand or receptor show tooth eruption defects, due to inhibited osteoclast activity. However, a defined role of these molecules in tooth development has not been established. A recent study from our group found that inhibition of CSF-1R in utero resulted in significant dental dysmorphology postnatally. Here we aimed to characterize these defects in detail using μCT scanning and histology.
Methods: A highly specific CSF-1R inhibitor- PLX5622 (Plexxikon), was administered via diet to pregnant CD1 mice beginning at day 3.5 and discontinued postpartum. Pups were sacrificed and crania were collected at postnatal days 21 and 28, followed by high-resolution μCT scanning. Qualitative and quantitative analysis of dental morphology was carried out using routine histology as well as digital segmentation of teeth from μCT scans.
Results: Pups exposed to the PLX5622 diet in utero presented with shorter and wider incisors, with notching at the tips and with facial ectopic enamel ridges. First molars were elongated mesio-distally and constricted bucco-linugally. In some animals, the incisors phenotype resembled that of a branched, geminated tooth. Histology revealed irregular infoldings of the dentin-enamel junction with grossly disorganized dentin and pulp, giving the appearance of multiple small internal germinating centers. Ameloblasts and odontoblasts seemed to maintain their normal columnar shape and polarity. Notably, 100% of pups exposed to the inhibitor exhibited dental malformations, however, with variability in its presentation. Additionally, traditional morphometric analysis revealed subtle differences in craniofacial dimensions in CSF-1R inhibitor exposed animals.
Conclusions: These data provide evidence for a role of CSF-1R during odontogenesis and suggest that signaling through this receptor is likely important during the initiation and morphogenesis stages of tooth development; when the shape of the enamel organ and dentino-enamel junction is being established.
Methods: A highly specific CSF-1R inhibitor- PLX5622 (Plexxikon), was administered via diet to pregnant CD1 mice beginning at day 3.5 and discontinued postpartum. Pups were sacrificed and crania were collected at postnatal days 21 and 28, followed by high-resolution μCT scanning. Qualitative and quantitative analysis of dental morphology was carried out using routine histology as well as digital segmentation of teeth from μCT scans.
Results: Pups exposed to the PLX5622 diet in utero presented with shorter and wider incisors, with notching at the tips and with facial ectopic enamel ridges. First molars were elongated mesio-distally and constricted bucco-linugally. In some animals, the incisors phenotype resembled that of a branched, geminated tooth. Histology revealed irregular infoldings of the dentin-enamel junction with grossly disorganized dentin and pulp, giving the appearance of multiple small internal germinating centers. Ameloblasts and odontoblasts seemed to maintain their normal columnar shape and polarity. Notably, 100% of pups exposed to the inhibitor exhibited dental malformations, however, with variability in its presentation. Additionally, traditional morphometric analysis revealed subtle differences in craniofacial dimensions in CSF-1R inhibitor exposed animals.
Conclusions: These data provide evidence for a role of CSF-1R during odontogenesis and suggest that signaling through this receptor is likely important during the initiation and morphogenesis stages of tooth development; when the shape of the enamel organ and dentino-enamel junction is being established.