Elsevier BV Acta Medica Okayama 1349-0079 68 1 2026 Roles of the aryl hydrocarbon receptor and its ligands in osteoclast differentiation and temporomandibular joint osteoarthritis 100726 EN Takashi Izawa Department of Orthodontics, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Islamy Rahma Hutami Department of Orthodontics, Universitas Islam Sultan Agung Yuri Yoshikawa Department of Orthodontics, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Gohji Kozaki Department of Orthodontics, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Yusaku Hamada Department of Orthodontics, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Yuki Namba Department of Orthodontics, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Misa Taguchi Department of Orthodontics, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Jiamin Chen Department of Orthodontics, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Janvier Habumugisha Department of Orthodontics, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Hiroshi Kamioka Department of Orthodontics, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Background: The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that plays an essential role in skeletal homeostasis. Increasing evidence indicates that AhR critically regulates osteoclast differentiation and activity, thereby influencing bone mass, bone resorption, and susceptibility to skeletal diseases. Although AhR has also been implicated in osteoblast-lineage cells, its regulatory roles in osteoclasts and immune cells are less well understood but are increasingly recognized as central to bone remodeling. In particular, AhR signaling modulates immune cell subsets relevant to bone metabolism and governs the differentiation of bone marrow-derived macrophages into osteoclasts. Highlight: This review summarizes the recent findings regarding the regulation of osteoclast differentiation by AhR and its ligands under both physiological and pathological conditions. Special emphasis is placed on the interaction between AhR and the RANKL signaling axis in osteoclasts, as well as on how exogenous and endogenous ligands, including benzo[a]pyrene (B[a]P) and 6-formylindolo[3,2-b]carbazole (FICZ), modulate bone resorption and subchondral bone remodeling in temporomandibular joint osteoarthritis. Furthermore, the role of macrophages as osteoclast progenitors and immunomodulators has been highlighted, positioning AhR as a critical intermediary that links environmental exposure, inflammation, and skeletal metabolism. Conclusion: In this review, we outlined the diverse functions of AhR signaling and its ligands in oral and temporomandibular joint osteoarthritis. AhR plays a central role in bone remodeling. The harmful exogenous ligand B[a]P generally promotes bone loss, whereas the endogenous ligand FICZ exerts protective actions. These insights highlight AhR as a key regulatory switch linking the skeletal and immune systems and as a promising therapeutic target for bone-destructive disorders. No potential conflict of interest relevant to this article was reported.

BMC Acta Medica Okayama 1472-6831 25 1 2025 Exploring the relationship between posture-dependent airway assessment in orthodontics: insights from kinetic MRI, cephalometric data, and three-dimensional MRI analysis 745 EN Naoki Oka Department of Orthodontics, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Janvier Habumugisha Department of Orthodontics, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Masahiro Nakamura Department of Orthodontics, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Tomoki Kataoka Division of Oral and Maxillofacial Surgery, Tottori University Atsuro Fujisawa Department of Orthodontics, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Noriaki Kawanabe Department of Orthodontics, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Takashi Izawa Department of Orthodontics, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Hiroshi Kamioka Department of Orthodontics, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Background Previous studies have assessed the upper airway using various examination methods, such as cephalometric imaging and magnetic resonance imaging (MRI). However, there is a significant gap in the research regarding the relationship between these different imaging modalities. This study compares airway assessments using kinetic MRI and cephalometric scans, examining their correlation with three dimensional (3D) MRI data. Materials and methods Kinetic MRI, cephalometric scans, and 3D MRI of forty-seven participants were used in the present study. Airway areas and widths were measured at the retropalatal, retroglossal, and hypopharyngeal levels in both kinetic MRI and cephalometric scans. Airway volumes were calculated from 3D MRI data. Statistical analyses, including the Wilcoxon Signed Rank test, Spearman correlation, and multiple linear regression, were performed to evaluate the data and identify significant differences, correlations, and prediction models, respectively. Results Significant differences were found between kinetic MRI and cephalometric scans. Cephalometric data showed larger airway areas and widths compared to kinetic MRI measurements. Although both cephalometric and kinetic MRI showed a correlation with 3D MRI, kinetic MRI demonstrated stronger correlations with 3D MRI airway volumes than cephalometric scans. According to our linear regression model equations, RPA-Max (maximum retropalatal airway area) and RPA (retropalatal airway area) can elucidate variations in RPV (retropalatal airway volume). RGA-Med (median retroglossal airway area) and RGA-Min (minimum retroglossal airway area) can explain variations in RGV (retroglossal airway volume). HPA (hypopharyngeal airway area) and ULHPAW-Max (maximum upper limit hypopharyngeal airway width) account for variations in HPV (hypopharyngeal airway volume). Additionally, TA-Max (maximum total airway area) can account for variations in TPV (total pharyngeal airway volume).ConclusionBoth cephalometric data and kinetic MRI data showed correlations with 3D MRI data. The shared posture of kinetic MRI and 3D MRI led to stronger correlations between these two modalities. Although cephalometric data had fewer correlations with 3D MRI and predictors for 3D airway volume, they were still significant. Our study highlights the complementary nature of kinetic MRI and cephalometric imaging, as both provide valuable information for airway assessment and exhibit significant correlations with 3D MRI data. No potential conflict of interest relevant to this article was reported.

MDPI Acta Medica Okayama 1422-0067 22 16 2021 Macrophage Motility in Wound Healing Is Regulated by HIF-1 alpha via S1P Signaling 8992 EN Islamy Rahma Hutami Department of Orthodontics and Dentofacial Orthopedics, Institute of Biomedical Sciences, Tokushima University Graduate School Takashi Izawa Department of Orthodontics, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Tsendsuren Khurel-Ochir Department of Orthodontics and Dentofacial Orthopedics, Institute of Biomedical Sciences, Tokushima University Graduate School Takuma Sakamaki Department of Orthodontics and Dentofacial Orthopedics, Institute of Biomedical Sciences, Tokushima University Graduate School Akihiko Iwasa Department of Orthodontics and Dentofacial Orthopedics, Institute of Biomedical Sciences, Tokushima University Graduate School Eiji Tanaka Department of Orthodontics and Dentofacial Orthopedics, Institute of Biomedical Sciences, Tokushima University Graduate School Accumulating evidence indicates that the molecular pathways mediating wound healing induce cell migration and localization of cytokines to sites of injury. Macrophages are immune cells that sense and actively respond to disturbances in tissue homeostasis by initiating, and subsequently resolving, inflammation. Hypoxic conditions generated at a wound site also strongly recruit macrophages and affect their function. Hypoxia inducible factor (HIF)-1 alpha is a transcription factor that contributes to both glycolysis and the induction of inflammatory genes, while also being critical for macrophage activation. For the latter, HIF-1 alpha regulates sphingosine 1-phosphate (S1P) to affect the migration, activation, differentiation, and polarization of macrophages. Recently, S1P and HIF-1 alpha have received much attention, and various studies have been performed to investigate their roles in initiating and resolving inflammation via macrophages. It is hypothesized that the HIF-1 alpha/S1P/S1P receptor axis is an important determinant of macrophage function under inflammatory conditions and during disease pathogenesis. Therefore, in this review, biological regulation of monocytes/macrophages in response to circulating HIF-1 alpha is summarized, including signaling by S1P/S1P receptors, which have essential roles in wound healing. No potential conflict of interest relevant to this article was reported.

Nature Portfolio Acta Medica Okayama 2045-2322 11 1 2021 Roles for B[a]P and FICZ in subchondral bone metabolism and experimental temporomandibular joint osteoarthritis via the AhR/Cyp1a1 signaling axis 14927 EN Yuri Yoshikawa Department of Orthodontics, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Takashi Izawa Department of Orthodontics, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Yusaku Hamada Department of Orthodontics, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Hiroko Takenaga Department of Orthodontics, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Ziyi Wang Department of Orthodontics, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Naozumi Ishimaru Department of Oral Molecular Pathology, Tokushima University Graduate School of Biomedical Sciences Hiroshi Kamioka Department of Orthodontics, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Bone loss due to smoking represents a major risk factor for fractures and bone osteoporosis. Signaling through the aryl hydrocarbon receptor (AhR) and its ligands contributes to both bone homeostasis and inflammatory diseases. It remains unclear whether the same AhR signaling axis affects the temporomandibular joint (TMJ). The aim of this study was to investigate possible mechanisms which mediate bone loss in the TMJ due to smoking. In particular, whether benzo[a]pyrene (B[a]P), a carcinogen of tobacco smoke, induces expression of the AhR target gene, Cyp1a1, in mandibular condyles. Possible functions of an endogenous ligand of FICZ, were also investigated in a TMJ-osteoarthritis (OA) mouse model. B[a]P was administered orally to wild-type and AhR(-/-) mice and bone metabolism was subsequently examined. TMJ-OA was induced in wild-type mice with forceful opening of the mouth. Therapeutic functions of FICZ were detected with mu CT and histology. Exposure to B[a]P accelerated bone loss in the mandibular subchondral bone. This bone loss manifested with osteoclastic bone resorption and upregulated expression of Cyp1a1 in an AhR-dependent manner. In a mouse model of TMJ-OA, FICZ exhibited a dose-dependent rescue of mandibular subchondral bone loss by repressing osteoclast activity. Meanwhile, in vitro, pre-treatment with FICZ reduced RANKL-mediated osteoclastogenesis. B[a]P regulates mandibular subchondral bone metabolism via the Cyp1a1. The AhR ligand, FICZ, can prevent TMJ-OA by regulating osteoclast differentiation. No potential conflict of interest relevant to this article was reported.

Wiley Acta Medica Okayama 1354-523X 28 4 2021 HIF‐1α controls palatal wound healing by regulating macrophage motility via S1P/S1P1 signaling axis 1157 1169 EN Islamy Rahma Hutami Department of Orthodontics and Dentofacial Orthopedics Institute of Biomedical Sciences Tokushima University Graduate School Tokushima Japan Takashi Izawa Department of Orthodontics, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University Tsendsuren Khurel‐Ochir Department of Orthodontics and Dentofacial Orthopedics Institute of Biomedical Sciences Tokushima University Graduate School Tokushima Japan Takuma Sakamaki Department of Orthodontics and Dentofacial Orthopedics Institute of Biomedical Sciences Tokushima University Graduate School Tokushima Japan Akihiko Iwasa Department of Orthodontics and Dentofacial Orthopedics Institute of Biomedical Sciences Tokushima University Graduate School Tokushima Japan Shuhei Tomita Department of Pharmacology Osaka City University Graduate School of Medicine Osaka Japan Eiji Tanaka Department of Orthodontics and Dentofacial Orthopedics Institute of Biomedical Sciences Tokushima University Graduate School Tokushima Japan Objectives To investigate the role of hypoxia-inducible factor 1 alpha (HIF-1 alpha) signaling, the expression profile of M1 and M2 macrophages, and the role of the sphingosine 1-phosphate (S1P)/S1P receptor system in palatal wound healing of heterozygous HIF-1 alpha-deficient (HIF-1 alpha HET) mice. Materials and methods HIF-1 alpha HET and wild-type (WT) littermates underwent palatal tissue excision at the mid-hard palate. Histological analysis, immunostaining, real-time PCR, Western blotting (WB), and cellular migration assays were performed to analyze wound closure and macrophage infiltration. Results DMOG pretreatment showed an acceleration of palatal wound closure in WT mice. In contrast, the delayed palatal wound closure was observed in HIF-1 alpha HET mice with diminished production of Col1a1, MCP-1, and MIP-1 alpha, compared with WT mice. Decreased infiltration of M1 macrophage (F4/80(+)TNF-alpha(+), F4/80(+)iNOS(+)) and M2 macrophage (F4/80(+)Arginase-1(+), F4/80(+)CD163(+)) was observed. The numbers of F4/80(+)S1P(1)(+) macrophages of HIF-1 alpha HET wounded tissues were significantly lower compared with WT tissues. S1P treatment of bone marrow macrophages (BMMs) significantly upregulated expression of S1P(1) in WT mice compared with HIF-1 alpha HET. Phosphorylation of MAPK rapidly decreased in BMMs of HIF-1 alpha HET mice than in BMMs of WT mice by S1P stimulation. Moreover, S1P enhanced HIF-1 alpha expression via S1P(1) receptors to affect macrophage migration. Conclusions HIF-1 alpha deficiency aggravates M1 and M2 macrophage infiltration and controls macrophage motility via S1P/S1P(1) signaling. These results suggest that HIF-1 alpha signaling may contribute to the regulation of palatal wound healing. No potential conflict of interest relevant to this article was reported.