Abstract
Inflammation-associated proteinase functions are key determinants of inflammatory stromal tissues deconstruction. As a specialized inflammatory pathological process, dental internal resorption (IR) includes both soft and hard tissues deconstruction within the dentin-pulp complex, which has been one of the main reasons for inflammatory tooth loss. Mechanisms of inflammatory matrix degradation and tissue resorption in IR are largely unclear. In this study, we used a combination of Cre-loxP reporter, flow cytometry, cell transplantation, and enzyme activities assay to mechanistically investigate the role of regenerative cells, odontoblasts (ODs), in inflammatory mineral resorption and matrices degradation. We report that inflamed ODs have strong capabilities of matrix degradation and tissue resorption. Traditionally, ODs are regarded as hard-tissue regenerative cells; however, our data unexpectedly present ODs as a crucial population that participates in IR-associated tissue deconstruction. Specifically, we uncovered that nuclear factor-kappa b (NF-κB) signaling orchestrated Tumor necrosis factor α (TNF-α)-induced matrix metalloproteinases (Mmps) and Cathepsin K (Ctsk) functions in ODs to enhance matrix degradation and tissue resorption. Furthermore, TNF-α increases Rankl/Opg ratio in ODs via NF-κB signaling by impairing Opg expression but increasing Rankl level, which utterly makes ODs cell line 17IIA11 (A11) become Trap+ and Ctsk+ multinucleated cells to perform resorptive actions. Blocking of NF-κB signaling significantly rescues matrix degradation and resorptive functions of inflamed ODs via repressing vital inflammatory proteinases Mmps and Ctsk. Utterly, via utilizing NF-κB specific small molecule inhibitors we satisfactorily attenuated inflammatory ODs-associated human dental IR in vivo. Our data reveal the underlying mechanisms of inflammatory matrix degradation and resorption via proteinase activities in IR-related pathological conditions.
Highlights
Dental internal resorption (IR) begins in the dental-pulpal space and extends into surrounding dentin, which includes both dental pulp matrix degradation and dentin resorption.[1,2] IR is a typically pathological resorption, which is usually initiated via continuous inflammation in the pulp.[1]
IHC data clearly showed that 1 d after surgery the level of tumor necrosis factor-α (TNF-α) in ODs was significantly upregulated, and the expression of TNF-α was continuously increased at 3 d postsurgery (Fig. 1a)
Jnk (Fig. 3c), and previous studies have proved that Jnk directly controlled Matrix metalloproteinases (Mmps)[1] transcription in diverse species and types of cells[31, 32], we proposed that under the condition of TNF-α high expressions of Cathepsin K (Ctsk) (Fig. 5b1)
Summary
Dental internal resorption (IR) begins in the dental-pulpal space and extends into surrounding dentin, which includes both dental pulp matrix degradation and dentin resorption.[1,2] IR is a typically pathological resorption, which is usually initiated via continuous inflammation in the pulp.[1]. Except from OCs and ONCs, odontoblasts (ODs) are unexpectedly hypothesized to play a role in IR.[4,5,6] As a specialized population in dentin-pulp complex, ODs are traditionally regarded as hard-tissue regenerative cells.[7]
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