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Transcriptomic profile of Lin negative, LEPR positive cells of human peri-implant fibrous tissue and peri-implant bone

ABSTRACT: Peri-implant fibrosis is one of the most common reasons for implant failure and surgical revision after prosthetic joint replacement. This type of surgical revisionis associated with substantial additional morbidity and healthcare costs. However, the cellular and molecular mediators of peri-implant fibrosis remain unclear. Here, we show that peri-implant fibrotic tissue in mice and humans is largely composed of a specific population of leptin receptor-expressing(LEPR+) cells and that these LEPR+cells are necessary and sufficient to both generate and maintain peri-implant fibrotic tissue. Genetic ablation of LEPR+cells prevents peri-implant fibrosis, and implantation of LEPR+cells from peri-implant fibrotic tissue is sufficient to induce fibrosis in secondary hosts. We further identify adhesion G protein-coupled receptorF5 (ADGRF5) as a crucial mediator of the fibrotic response by LEPR+cells, as conditional deletion of ADGRF5 in LEPR+cells attenuates peri-implant fibrosis while augmenting peri-implant bone formation. Finally, we demonstrate that inhibition of ADGRF5 by intra articular or systemic administration of neutralizing anti-ADGRF5prevents and reverses peri-implant fibrosis. Thus, pharmaceutical agents that inhibit the ADGRF5 pathway inLEPR+cells may represent a new approach to prevent and treat peri-implant fibrosis.

ORGANISM(S): Homo sapiens

PROVIDER: GSE227128 | GEO | 2024/03/10

REPOSITORIES: GEO

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Project description:Oral health is associated with a symbiotic microbial community and host-microbe homeostasis is maintained by the controlled immune response. Various factors can disrupt this homeostasis. Dysbiosis, which is characterized by increased immune response and a shift in the microbiome, contributes the pathogenesis of peri-implantitis. Peri-implant mucosa and commensal bacteria play important roles in the maintenance of host-microbe homeostasis, but little is known about how they interact. We have therefore investigated the early host-microbe interaction between a commensal multispecies biofilm (Streptococcus oralis, Actinomyces naeslundii, Veillonella dispar, Porphyromonas gingivalis) and peri-implant mucosa at 24 and 48 h. Our in vitro peri-implant mucosa-biofilm model contained organotypic oral mucosa, implant material and biofilm. After 24 h, the biofilm induced a modest innate immune response in the peri-implant mucosa by the upregulation of 5 genes related to immune and inflammatory response and the increased secretion of IL-6 and CCL20. This controlled immune response protected tissue integrity and the peri-implant mucosa remained intact. The secreted antibacterial proteins human β-Defensins-1, -2, and CCL20 controlled the overgrowth of the biofilm by reducing its volume - without affecting the live/dead ratio or bacterial distribution. Thus, host-microbe homeostasis was established within the first 24 h. In contrast, host-microbe homeostasis was disrupted after 48 h. The mucosa was damaged and detached from the implant, due to the induced downregulation of cell adhesion related genes. The immune response was enhanced by upregulation of additional genes related to the immune and inflammatory response and increased secretion of IL-1β, TNF-α, and CCL20. Moreover, bacterial distribution was altered, with an increased proportion of V. dispar. The disrupted host-microbe homeostasis could lead to incipient dysbiosis. This deeper understanding of the early host-microbe interaction at the peri-implant site may provide the basis for new strategies to improve the prevention and therapy of peri-implant diseases.

Project description:The goal of this study was to compare the gene expression profiles of chronically inflamed human peri-implant and chronically inflamed human periodontal tissues in order to elucidate potential changes at the molecular level. Cells out of the pocket depth of the inflamed peri-implant and periodontal ligament as well as from the middle third of healthy periodontal ligament were applied. Genome-wide gene expression was compared with the help of microarray analysis, and the data were validated by real-time RT-PCR. The expression rates of 14,239 genes were investigated and 2,079 of them were found differentially expressed by at least two-fold; the expression rates of 1,093 genes were significantly up-regulated and the expression rates of 986 genes were significantly down-regulated in inflamed peri-implant cells compared to inflamed periodontal cells. We focused on genes coding for extracellular matrix components and those that degrade them. Only genes of non-fibril-forming collagens (types IV, VI, VII, and XVII) were increased in inflamed peri-implant tissue, whereas only the genes of two fibril-forming collagens (types III and XVII) were decreased, suggesting that peri-implant tissue re-models faster than periodontal tissue. Furthermore, cathepsin D and cathepsin S might participate to a greater extent in connective tissue destruction of peri-implant tissue. The present investigation demonstrated that, despite their clinical similarities, periimplantitis and periodontitis are two different diseases at the genetic level. Keywords: inflammation, peri-implant, periodontal ligament cells The peri-implant tissue was scraped of the implant and the periodontal tissue was scraped off the roots of the teeth. Both tissue probes were treated with the RNeasy mini Kit (Qiagen, Hilden, Germany) to isolate total RNA from chronically inflamed peri-implant and chronically inflamed PDL cells, according to the manufacturer’s instructions. Healthy PDL cells were taken from the middle third of the root clearly avoiding sampling the gingiva. The chronically inflamed peri-implant and periodontal cells were taken directly out of the depth of the pocket again avoiding the ingrown gingiva. Quality control and quantitation of total RNA samples were determined prior to the microarray experiments (Agilent 2100 Bioanalyzer, Agilent Technologies, Palo Alto, CA, USA). Equal amounts of total RNA were pooled into an inflamed peri-implant and an inflamed and healthy periodontal cell pool. To monitor the relative abundance of mRNA for full-length human genes, the Affymetrix GeneChip HG_U133A was used, representing 22,283 probe sets (14,239 unique human genes). Labelled cRNA, fragmented to an average size of 100–150 bases, was hybridized to the GeneChips. For each pool of cRNA, two GeneChips were hybridized. Chronically inflamed peri-implant as well as healthy and chronically inflamed periodontal tissue was collected from 48 patients at the Dental Medical School of the University of Goettingen (21 men, 27 women, aged between 18 and 72 years) from March 2005 to August 2006, as already described by Gersdorff et al. (2007). The peri-implant tissue probes were taken from endosteal implants (Astra Tech®, ITI Bonefit®, or Brånemark®) with chronic peri-implant lesions (Schwarz et al. 2007). The periodontal tissue probes were taken from teeth, either extracted for orthodontic reasons or due to carious lesions (healthy periodontium) or from teeth with generalized chronic periodontitis (Armitage 2004). Teeth with healthy PDL had no clinical signs of inflammation (no bleeding on probing), exhibited a probing depth of ?3,5 mm and had no radiographic detectable bone loss. In contrast, implants and teeth with generalized chronic inflammation exhibited obvious clinical signals of inflammation (bleeding on probing), exhibited a probing depth of >4 mm and had radiographic evidence of bone loss (1 to 7 mm). A detailed anamnesis of each patient was explored. All patients were without a medical history, i.e. heart diseases or diabetes, and were not on medication. In addition, the tissue samples used in our study were only taken from non-smokers. The explanted implants and extracted teeth were immediately frozen and stored at -80 °C. All patients who participated in the study were informed about the nature and aim of this project and gave their written informed consent. The study was approved according to the regulations of the Ethics Committee of the Medical Faculty of the University of Goettingen.

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Transcriptomic profile of Lin negative, LEPR positive cells of human peri-implant fibrous tissue and peri-implant bone

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