Research
Periodontal Disease and Systemic Health
Periodontitis has been reported to be associated with systemic conditions such as diabetes. We investigate the molecular links between oral bacterial infection and distant organs. Our studies in mouse models have examined how vesicles released by Porphyromonas gingivalis, a major periodontal pathogen, or by macrophages infected with it, reach organs such as the liver, lungs and placenta. We have analyzed how they relate to changes in hepatic glucose metabolism, lung inflammation and fetal development. We aim to identify the molecules that may mediate the effects of oral infection on the body.
Related publications (PubMed): PMID 32088316PMID 34389473PMID 39651617
Extracellular Vesicles from Bacteria and Infected Host Cells
Bacteria release nanosized membrane vesicles, and infected host cells also release extracellular vesicles (EVs). We study how these vesicles are taken up by host cells and tissues and how they influence cellular responses. In mouse models, vesicles from Porphyromonas gingivalis or from infected macrophages reached distant organs and were associated with altered insulin signaling in the liver, lung injury and impaired placental angiogenesis. In cultured cells, vesicles from this bacterium disrupted tight junctions of lung epithelial cells. We are also interested in how host EVs contribute to osteoblast function.
Related publications (PubMed): PMID 32088316PMID 34389473PMID 39651617PMID 32717445PMID 42019871
How Bone Cells Respond to Mechanical Stress
Bone is continuously remodeled in response to mechanical forces. We investigate how bone cells sense and respond to mechanical stress. In cultured osteoblast-like cells, mechanical stretching changed cell alignment and morphology, which in turn affected the direction and speed of cell migration and the orientation of cell division. We also study how cytoskeletal regulators, such as dynamin 2, contribute to osteoblast migration, and how mechanical loading affects osteocyte-like cells. These studies may help explain how mechanical stimulation influences the directional formation of bone tissue.
Related publications (PubMed): PMID 37022568PMID 41714019PMID 33240612
Protein Glycosylation, Osteoblast Differentiation and Live-Cell Imaging
We study O-GlcNAcylation, a sugar modification of intracellular proteins, in osteoblast differentiation. In osteoblast-like cells, O-GlcNAcylation was positively associated with differentiation and interacted with intracellular calcium signaling. Loss of the modifying enzyme OGT reduced osteoblast differentiation and changed the shape of mitochondria, the endoplasmic reticulum and the cytoskeleton. These changes were examined in living cells with an AI model that predicts organelle structures from label-free images. OGT-deficient cells also released extracellular vesicles with lower calcium content, and these vesicles supported osteoblast differentiation less effectively. We use these findings to ask how nutrient-sensing modifications shape bone-forming cells.
Related publications (PubMed): PMID 34418170PMID 39405562PMID 42019871
How Periodontal Pathogens Interfere with Host Immunity
Periodontal pathogens are thought to evade host immune defenses. We investigate how they do so. RNA sequencing of macrophages infected with Porphyromonas gingivalis showed changes in alternative splicing, including a switch in the isoform of the immune checkpoint molecule PD-L1. Gingipain, a protease produced by this bacterium, contributed to this change, and the upregulated isoform was predicted to bind PD-1 more effectively. These findings suggest that P. gingivalis may use gingipain to modulate host immune responses. We are interested in how such mechanisms could relate to the progression of periodontal disease, and we continue to study these host responses in cell models.
Related publication (PubMed): PMID 40140451
Protein Phosphatase PP2A in Osteoblast Differentiation
Protein phosphatase 2A (PP2A) is a major protein phosphatase, and its regulatory subunits are thought to determine where and on which substrates it acts. We asked where these regulators work in bone-forming cells. PTPA, a PP2A regulatory protein, was found mainly in the Golgi apparatus of osteoblast-like cells, and overexpressing it inhibited osteoblast differentiation. Its Golgi localization suggests that it may influence the secretion of bone-related proteins. We also found that inhibiting PP2A changed the localization of O-GlcNAc transferase (OGT), and that high glucose altered OGT localization in early differentiation, in parallel with changes in PP2A activity. These results suggest that phosphorylation and O-GlcNAcylation may interact during osteoblast differentiation.
Related publications (PubMed): PMID 39827549PMID 39800889PMID 36706705
Transcriptional Control of Osteoblast Differentiation: VGLL3 and Autophagy
VGLL3, a transcriptional cofactor, has been identified as a regulator of osteoblast differentiation. In osteoblast-like cells, knocking down Vgll3 reduced autophagic activity, and RNA sequencing identified DAPK2, an autophagy regulator, as a downstream effector. Treatment with rapamycin partially restored autophagy and differentiation in Vgll3-deficient cells, and overexpressing DAPK2 partially rescued them. These findings suggest that VGLL3 may influence osteoblast differentiation through DAPK2-associated autophagy.
Related publication (PubMed): PMID 42052791
Cell–Cell Junctions in the Oral Mucosa
The oral mucosa forms a barrier in which neighboring cells are held together by cell–cell junctions. We study the structure and function of these junctions from a morphological point of view.
