Aberrant NF-κB activation in odontoblasts orchestrates inflammatory matrix degradation and mineral resorption

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 factorα(TNF-α)-induced matrix metalloproteinases(Mmps)and Cathepsin K(Ctsk)functions in ODs to enhance matrix degradation and tissue resorption.Furthermore,TNF-αincreases 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.

Wnt/β-catenin signaling in cancers and targeted therapies

Wnt/β-catenin signaling has been broadly implicated in human cancers and experimental cancer models of animals.Aberrant activation of Wnt/β-catenin signaling is tightly linked with the increment of prevalence,advancement of malignant progression,development of poor prognostics,and even ascendence of the cancer-associated mortality.Early experimental investigations have proposed the theoretical potential that efficient repression of this signaling might provide promising therapeutic choices in managing various types of cancers.Up to date,many therapies targeting Wnt/β-catenin signaling in cancers have been developed,which is assumed to endow clinicians with new opportunities of developing more satisfactory and precise remedies for cancer patients with aberrant Wnt/β-catenin signaling.