Combined application of geranylgeranylacetone and amelogenin promotes angiogenesis and wound healing in human periodontal ligament cells

Abstract

Amelogenin directly binds to glucose‐regulated protein 78 (Grp78). Cell migration activity is expected to increase when human periodontal ligament cells (hPDLCs) overexpressing Grp78 are treated with amelogenin. Geranylgeranylacetone (GGA) is a drug that induces the expression of heat shock protein and is routinely used to treat gastric ulcers. Here, we investigated the changes in the properties and behavior of hPDLCs in response to treatment with GGA and the synergistic effects of amelogenin stimulation in hPDLCs pretreated with GGA for the establishment of a novel periodontal tissue regenerative therapy. We observed that GGA treatment increased Grp78 protein expression in hPDLCs and enhanced cell migration. Microarray analysis demonstrated that increased Grp78 expression triggered the production of angiopoietin‐like 4 and amphiregulin, which are involved in the enhancement of angiogenesis and subsequent wound healing via the activation of hypoxia‐inducible factor 1α and peroxisome proliferator‐activated receptors as well as the phosphorylation of cAMP response element‐binding protein and protein kinase A. Moreover, the addition of recombinant murine amelogenin (rM180) further accelerated hPDLC migration and tube formation of human umbilical vein endothelial cells due to the upregulation of interleukin‐8 (IL‐8), monocyte chemotactic protein 1, and IL‐6, which are also known as angiogenesis‐inducing factors. These findings suggest that the application of GGA to gingival tissue and alveolar bone damaged by periodontal disease would facilitate the wound healing process by inducing periodontal ligament cells to migrate to the root surface and release cytokines involved in tissue repair. Additionally, supplementation with amelogenin synergistically enhanced the migratory capacity of these cells while actively promoting angiogenesis. Therefore, the combined application of GGA and amelogenin may establish a suitable environment for periodontal wound healing and further drive the development of novel therapeutics for periodontal tissue regeneration.

MZB1 targeted by miR‐185‐5p inhibits the migration of human periodontal ligament cells through NF‐κB signaling and promotes alveolar bone loss

“…Liu et al 22 found that 2 transcripts of FBXO5 (transcripts a and b) promoted migration of hPDLSCs and then facilitated periodontal tissue regeneration. Yamato et al 23 indicated that geranylgeranylacetone treatment increased the expression of GRP78 protein in hPDLCs, and GRP78 could induce the migration of hPDLCs to the root surface and release cytokines involved in tissue repair, thus promoting wound healing. In our study, wound healing and transwell assays confirmed that migratory capacity of hPDLCs was significantly suppressed after overexpression of MZB1, while knockdown of MZB1 performed the opposite way, suggesting the negative role of MZB1 in periodontal tissue regeneration.…”

LIPUS can promote osteogenesis of hPDLCs and inhibit the periodontal inflammatory response via TLR5

“…In this process, hPDLCs play an important role in mechanosensing and mechanotransduction (Sun et al, 2021). Since the periodontal ligament is adjacent to the alveolar bone, the biological activity of periodontal ligament cells is likely to affect the metabolism of alveolar bone (Yamato et al, 2021).…”

Synthetic Hydrogels with Entangled Neutrophil Extracellular Traps Influence Tumor Progression in MDA-MB-231 Cells

“…They were treated with media containing 5 mM PMA (positive control), normal media (negative control), or reserved conditioned media from cells encapsulated in gels with varying concentrations of NETs (Section 5.2.9). An IL-8 neutralizing antibody previously used by Yamato et al [46] (15 µg/mL, AHC0881, Thermofisher) was added to half the wells.…”

“…They were treated with media containing 5 mM PMA (positive control), normal media (negative control), or reserved conditioned media from cells encapsulated in gels with varying concentrations of NETs (Section 5.2.9). An IL-8 neutralizing antibody previously used by Yamato et al [46] (15 µg/mL, AHC0881, Thermofisher) was added to half the wells. After 3 hr, the media was collected and stored at -80 o C for later analysis, and cells were fixed in 4% paraformaldehyde (Electron Microscopy Services) for 15 min at room temperature.…”