[Ga-68]Ga-Pentixafor and Sodium [F-18]Fluoride PET Can Non-Invasively Identify and Monitor the Dynamics of Orthodontic Tooth Movement in Mouse Model

The cellular and molecular mechanisms of orthodontic tooth movement (OTM) are not yet fully understood, partly due to the lack of dynamical datasets within the same subject. Inflammation and calcification are two main processes during OTM. Given the high sensitivity and specificity of [68Ga]Ga-Pentixafor and Sodium [18F]Fluoride (Na[18F]F) for inflammation and calcification, respectively, the aim of this study is to assess their ability to identify and monitor the dynamics of OTM in an established mouse model. To monitor the processes during OTM in real time, animals were scanned using a small animal PET/CT during week 1, 3, and 5 post-implantation, with [68Ga]Ga-Pentixafor and Na[18F]F. Both tracers showed an increased uptake in the region of interest compared to the control. For [68Ga]Ga-Pentixafor, an increased uptake was observed within the 5-week trial, suggesting the continuous presence of inflammatory markers. Na[18F]F showed an increased uptake during the trial, indicating an intensification of bone remodelling. Interim and end-of-experiment histological assessments visualised increased amounts of chemokine receptor CXCR4 and TRAP-positive cells in the periodontal ligament on the compression side. This approach establishes the first in vivo model for periodontal remodelling during OTM, which efficiently detects and monitors the intricate dynamics of periodontal ligament

A20 Promotes Ripoptosome Formation and TNF-Induced Apoptosis via cIAPs Regulation and NIK Stabilization in Keratinocytes

The ubiquitin-editing protein A20 (TNFAIP3) is a known key player in the regulation of immune responses in many organs. Genome-wide associated studies (GWASs) have linked A20 with a number of inflammatory and autoimmune disorders, including psoriasis. Here, we identified a previously unrecognized role of A20 as a pro-apoptotic factor in TNF-induced cell death in keratinocytes. This function of A20 is mediated via the NF-κB-dependent alteration of cIAP1/2 expression. The changes in cIAP1/2 protein levels promote NIK stabilization and subsequent activation of noncanonical NF-κB signaling. Upregulation of TRAF1 expression triggered by the noncanonical NF-κB signaling further enhances the NIK stabilization in an autocrine manner. Finally, stabilized NIK promotes the formation of the ripoptosome and the execution of cell death. Thus, our data demonstrate that A20 controls the execution of TNF-induced cell death on multiple levels in keratinocytes. This signaling mechanism might have important implications for the development of new therapeutic strategies for the treatment of A20-associated skin diseases