A critical cellular event in tooth eruption is the formation of osteoclasts that are needed for bone resorption to form an eruption pathway. To analyze molecular regulation of osteoclast formation and activation, we examined the expression of osteoprotegerin (OPG), an inhibitor of osteoclast formation. In vivo, the gene expression of OPG is reduced in the dental follicle of the first mandibular molar of the rat at day 3 post-natally and in the mouse at day 5. This correlates with the days of maximal mononuclear cell influx and osteoclast numbers in the rat and mouse. Thus, inhibition of OPG gene expression on these days might allow osteoclasts to be formed and/or activated. In vitro studies demonstrated that both colony-stimulating factor-1 and parathyroid hormone-related protein reduced OPG gene expression in follicle cells, suggesting that these are candidate molecules for the in vivo inhibition of OPG expression. Osteoclast differentiation factor (ODF) immunolocalizes to the alveolar bone stromal cells adjacent to the follicle, whereby it might act to stimulate fusion of the mononuclear cells in the follicle.

We have recently demonstrated that signal transducers and activators of transcription (STATs) 1, 3, 5A, 5B, and 6 are expressed in both cultured and native adipocytes. Our current studies have focused on the activation of STATs 1 and 3 by leukemia inhibitory factor (LIF), oncostatin-M (OSM), and interferon-␥ (IFN␥) in 3T3-L1 adipocytes. IFN␥ is shown to be a potent activator of STAT 1 as indicated by both tyrosine phosphorylation and nuclear translocation. However, LIF and OSM, which are potent inducers of STAT 3, are less potent activators of STAT 1 as measured by both tyrosine phosphorylation and nuclear translocation. Both STATs 1 and 3 were translocated to the nucleus in a time-dependent fashion following LIF treatment. In addition, IFN␥ resulted in a time-and dose-dependent effect on STATs 1 and 3 nuclear translocation. Growth hormone, a potent activator of STATs 5A and 5B, had a minimal effect on STAT 1 and STAT 3 tyrosine phosphorylation. Preincubation with either insulin or growth hormone had no detectable effects on the tyrosine phosphorylation or nuclear translocation of STATs 1 and 3 induced by LIF, OSM, or IFN␥. The effects of LIF and IFN␥ on STAT 1 and 3 tyrosine phosphorylation and nuclear translocation were confirmed in native rat adipocytes. In 3T3-L1 adipocytes, a low level of serine phosphorylation of STAT 3 on residue 727 was observed and was markedly enhanced by insulin, LIF, or OSM. This increase in STAT 3 Ser 727 phosphorylation was dependent upon the activation of MAPK, since the MAPK kinase inhibitor (PD98059) reduced STAT 3 Ser 727 phosphorylation to basal levels. The inhibition of MAPK had no effect on the ability of STATs 1 and 3 to be tyrosinephosphorylated or translocate to the nucleus. These studies demonstrate the highly specific and quantitative activation of STATs 1 and 3 by LIF, OSM, and IFN␥ in adipocytes and indicate that STAT 3 is a substrate for MAPK in adipocytes.The signal transducer and activator of transcription (STAT) 1 family of transcription factors is composed of seven family members (STATs 1, 2, 3, 4, 5A, 5B, and 6) that, in response to stimulation of various receptors, mainly those for cytokines, are phosphorylated on tyrosine residues, which causes their translocation to the nucleus. Each STAT family member shows a distinct pattern of activation by cytokines and upon nuclear translocation can regulate the transcription of particular genes (1). The order of events for STAT activation can be briefly described as follows: 1) ligand binding of cell surface receptor; 2) receptor association with a Janus kinase family member; 3) Janus kinase tyrosine phosphorylation of STAT proteins; 4) dimerization of the STATs; 5) translocation to the nucleus; and 6) DNA binding. STATs have been shown to bind at least three different DNA consensus sequences, and this binding regulates the transcription of specific genes (1, 2). It has also been demonstrated that STATs can be activated independently of Janus kinases (1, 3) and that serine phosphorylation may also contribute to the abil...

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A requirement for tooth eruption is the resorption of alveolar bone. Because bone resorption is stimulated by dexamethasone both in vivo and in vitro, dexamethasone 21-phosphate, a soluble form of dexamethasone, was injected into rats to determine its effect on tooth eruption. Such dexamethasone injections accelerate the time of intra-osseous eruption in rat incisors but do not accelerate the eruption time of rat molars when injected into rats. The injections of dexamethasone 21-phosphate also accelerate the time of eyelid opening in the postnatal rats, as well as retarding growth, as measured by body weight. These effects of dexamethasone 21-phosphate parallel the effects of epidermal growth factor injections, including the absence of an effect on molar eruption. This suggests that the molecular signals for the initiation of tooth eruption (i.e., onset of bone resorption) differ between rat incisors and molars. Given that rat incisors are teeth of continuous eruption whereas rat molars are teeth of limited eruption, as are human teeth, care must be taken in extrapolating results derived from rat incisors to human dentition. In vitro, dexamethasone has no effect on the gene expression of either osteoprotegerin or epidermal growth factor in dental follicle cells derived from molars. Because osteoprotegerin expression during normal tooth eruption is transitorily inhibited early postnatally in the molar dental follicle to allow osteoclast formation, the absence of inhibition of its expression by dexamethasone could explain why dexamethasone does not accelerate eruption in molars.

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