Hiroyuki Nakamura

• DDS, PhD
• Professor at University of the Ryukyus

Introduction Collagen-derived peptides demonstrate diverse biological activities, but their effects on human dental pulp stem cells (hDPSCs) remain unclear. This study investigated the influence of prolyl-hydroxyproline (Pro-Hyp) and hydroxyproline-glycine (Hyp-Gly) on stage-specific embryonic antigen 3 (SSEA3)-positive hDPSCs. Methods SSEA3-posit...

Objective Temporomandibular joint osteoarthritis (TMJ-OA) is painful and causes masticatory dysfunction, but current treatment is limited to symptom relief due to an incomplete appreciation of aetiology. Herein, we develop morphological and histological methods for quantitative evaluation of TMJ-OA severity and examine whether STR/Ort mice, which a...

Background Adult hypophosphatasia is an uncommon inherited disorder of mineral homeostasis affecting bone. It arises from mutations within the Alkaline Phosphatase, Biomineralization Associated (ALPL) gene, which encodes tissue-nonspecific alkaline phosphatase. Because of its low prevalence and non-specific clinical manifestations, underdiagnosis a...

This study investigated the association between oral frailty and regional brain volumes in cognitively unimpaired older adults. We employed a modified version of the Oral Frailty Five-item Checklist (OF-5) and examined its relationship with brain structural changes using magnetic resonance imaging (MRI). A total of 732 participants who were cogniti...

Background Hyposalivation is treated using oral cholinergic drugs; however, systemic side effects occasionally lead to discontinuation of treatment. We aimed to investigate the effects of transdermal pilocarpine on the salivary gland skin on saliva secretion and safety in rats. Methods Pilocarpine was administered to rats orally (0.5 mg/kg) or top...

This study investigated the associations between the number of people eating together and regional brain volumes, nutrient intake, and food and beverage intake in cognitively unimpaired individuals. We found that eating alone was associated with lower total brain volume, particularly in the medial temporal lobe, parietal lobe, occipital lobe, insul...

Background Human dental pulp-derived stem cells (hDPSCs) have emerged as a promising source for adult stem cell-based regenerative medicine. Stage-specific embryonic antigen 3 (SSEA3) is a cell surface marker associated with Multilineage-differentiating stress-enduring (Muse) cells, a subpopulation of human bone marrow-derived stem cells (hBMSCs),...

Odontoma is an odontogenic tumor that occurs relatively frequently and is sometimes seen with calcified odontogenic cysts（COC）. Histopathologically, COC is characterized by calcification of the epithelium and the appearance of ghost cells. In this study, we report a case of maxillary compound odontoma with COC-like changes. The patient was a 3-year...

Several studies have found associations between poor oral health, particularly tooth loss and cognitive decline. However, the specific brain regions affected by tooth loss and the probable causes remain unclear. We conducted a population-based longitudinal cohort study in Nakajima, Nanao City, Japan. Between 2016 and 2018, 2454 residents aged ≥60 p...

Gallbladder cancer (GBC) is an uncommon malignancy that is highly aggressive in the advanced stages. However, it rarely metastasizes to the mandible. Numb chin syndrome (NCS) is a rare neurological manifestation associated with various underlying causes, including occult primary cancers and distant metastases. It is often considered to be a signifi...

Metastatic colorectal carcinoma involving the maxilla is a rare phenomenon, and existing literature regarding the significance of perioperative oral function management (POM) in managing such cases is limited. In the present case report the clinical details of a 58-year-old male referred to the oral and maxillofacial department for POM. The patient...

Despite significant advancements in therapeutic approaches, oral neoplasms remain formidable and life‑threatening conditions that affect a substantial number of individuals worldwide. Within oral malignancies, a subset of cancer stem cells (CSCs) represent a crucial population responsible for tumor initiation and progression. The identification of...

Introduction: Temporomandibular joint (TMJ) is one of the common sites developing osteoarthritis (OA). TMJ OA is observed in 8–16% of the population. Major symptoms are joint pain, noise and restricted opening due to structural changes in TMJ, but its pathogenesis remains elusive. In knee OA, cartilage degradation is mediated by collagenases and ag...

Odontogenic keratocysts (OKCs) often occur in the molars in the mandibular ramus; they often progress asymptomatically and are discovered only after widespread development. Some cases of OKC progress to the mandibular condyle; however, very few cases exist only in the condyle. To the best of our knowledge, in all of the previously reported cases, O...

Background: The coexistence of calcium pyrophosphate dihydrate crystal deposition (CPP) and synovial chondromatosis (SC) in the temporomandibular joint (TMJ) is rarely reported. CPP disease (CPPD) is complex arthritis synonymous with excessive pyrophosphate production and variable aberrations in mineral and organic phase metabolism of the joint car...

Oral/dental surgical care in patients with chronic medical comorbidities, such as isovaleric acidemia (IVA), can be challenging. In addition to technical complications, different comorbidities also present a complex range of concerning factors/challenges, which can increase the incidence of morbidity and mortality associated with surgery. IVA, a co...

A dentinogenic ghost cell tumor (DGCT), the rarest locally invasive odontogenic tumor, is considered a solid variant of the calcifying odontogenic cyst. Histopathologically, DGCT is characterized by ameloblastoma-like islands of epithelial cells in a mature connective tissue stroma and aberrant keratinization in the form of ghost cells associated w...

Mixed tumour of the skin or chondroid syringoma (CS) is a rare and mostly benign neoplasm of the sweat glands. Although CS is frequently located on varied parts of the head and neck region, the lower lip is a rarely reported site. The present report describes a case of CS of the lower lip in a 58‑year‑old male as an expository case to further empha...

Apolipoprotein E E4 (APOE4) is a risk factor for cognitive decline. A high blood vitamin C (VC) level reduces APOE4-associated risk of developing cognitive decline in women. In the present study, we aimed to examine the effects of functional variants of VC transporter genes expressed in the brain (SLC2A1, SLC2A3, and SLC23A2) on APOE4-associated ri...

Background Glucose dysmetabolism is an important risk factor for dementia. Objective We investigated the associations of diabetes mellitus, the levels of glycemic measures, and insulin resistance and secretion measures with dementia and its subtypes in a cross-sectional study. Methods In this study, 10,214 community-dwelling participants were enr...

Medication non-adherence in the elderly population is a major problem, preventing them from obtaining optimal therapeutic effects. Identifying the factors affecting medication adherence is crucial for improving and maintaining health among the elderly population and enhance healthcare economy. The purpose of this study was to examine the prevalence...

Temporomandibular joint dysfunction (TMJD) is characterised by clinical symptoms involving both the masticatory muscles and the temporomandibular joint (TMJ). Disc internal derangement and osteoarthritis (OA) are the most common forms of TMJD. Currently, the molecular process associated with degenerative changes in the TMJ is unclear. Our previous...

Malignant peripheral nerve sheath tumors (MPNSTs) are very rare malignant neoplasia that arise from the peripheral nervous system and show nerve sheath differentiation. We report a case of primary malignant peripheral nerve sheath tumor of the mandibular gingiva. A 53-year-old male was referred to our hospital presenting with a mass and pain in the...

Background Pemphigus vulgaris (PV) is an autoimmune blistering disease of the skin and oral mucous membrane. Tongue involvement occurs when most of the other common sites are concurrently affected or when the patient is in remission. PV is an autoimmune disease that may affect the invasive capacity of tongue tumors. An association between PV and ce...

Plunging ranulas are recognized as soft cystic swellings in the submandibular gland area of the upper cervical region. Here, we report the case of a patient who had a large plunging ranula that extended to the inferior lingular segment of the left lung. A surgical excision of the sublingual gland was performed, and a drainage tube inserted in the n...

Ganglioneuroma （GN） is a rare benign neural tumor that is thought to arise from the ganglia of the sympathetic chain or parasympathetic nervous system. A 3-year-old boy presented with tumors in the adrenal gland and the right orbit, and was diagnosed with neuroblastoma （NB） stage Ⅳ After chemotherapy, the tumors were resected and the pathological d...

Background/aim: Oral squamous cell carcinoma (OSCC) is a common malignancy with poor prognosis. Therefore, novel therapeutic options are needed to improve prognosis of OSCC. Recently, microRNAs (miRs) have received increasing attention as a potential therapeutic tool for carcinomas. However, no definitive miR-based drugs for patients with OSCC hav...

A key feature of osteoarthritis is the gradual loss of articular cartilage and bone deformation, resulting in the impairment of joint function. The primary cause of cartilage destruction is considered to be the presence of elevated proteases, such as matrix metalloproteinases (MMPs) and a disintegrin and metalloproteinase with thrombospondin motifs...

Currently, Kaposi’s sarcoma (KS) is treated following the recommendations of international guidelines. These guidelines recommend esophagogastroduodenoscopy/colonoscopy for detecting multicentric KS of visceral lesions. Second primary malignancies (SPMs) are also a common KS complication; however, information on their detection and treatment is unf...

Patients with recurrent and/or metastatic squamous cell carcinoma of the head and neck (R/M SCCHN) have a poor prognosis. Over the past decade, a major development in the first-line treatment of R/M SCCHN was the introduction of cetuximab in combination with platinum plus 5-fluorouracil chemotherapy. Currently, a promising novel treatment option in...

The interaction between cancer cells and the surrounding microenvironment in malignant tumor tissue is known to be closely associated with cancer cell invasion and proliferation. Endothelin (ET) present in the microenvironment surrounding tumors has been reported to play a role in cancer cell invasion and proliferation by binding to receptors on th...

Topical ointment consists of an active ingredient and vehicle, and the vehicle largely comprises the volume of the ointment. During the treatment of chronic wounds, such as pressure ulcers, the vehicle has been considered inactive, only serving as a carrier of the main pharmaceutical. However, recent reports have indicated that the vehicle has dist...

Although several studies have demonstrated a potential correlation of dietary patterns with cognitive function, the relationship between tooth loss and dietary patterns and cognitive function have not been identified. In this cross-sectional study, we used a reduced rank regression (RRR) analysis, a technique used previously to observe dietary patt...

Recurrent and/or metastatic head and neck squamous cell carcinoma (R/M HNSCC) is a devastating malignancy with a poor prognosis. According to recent clinical studies, tumour growth can be effectively reduced and survival can be improved by blocking the programmed death receptor-1 (PD-1)/programmed death-ligand 1 (PD‑L1) pathway. PD-L1 expression ha...

The hyaluronan (HA)-rich extracellular matrix plays dynamic roles during tissue remodeling. Versican and serum-derived HA-associated protein (SHAP) corresponding to the heavy chains of inter-α-trypsin inhibitor (IαI) are major HA-binding molecules in remodeling processes such as wound healing. Versican G1-domain fragment (VG1F) is generated by prot...

Temporomandibular joint dysfunction (TMD) is a collection of clinical symptoms that involve masticatory muscles and the temporomandibular joint (TMJ). Common symptoms include limited jaw motion and joint sound/pain, along with TMJ disc displacement. TMD is frequently associated with synovitis, a chronic inflammation of the synovium. Fibroblast‑like...

Bone development and length relies on the growth plate formation, which is dependent on degradative enzymes such as MMPs. Indeed, deletion of specific members of this enzyme family in mice results in important joint and bone abnormalities, suggesting a role in skeletal development. As such, the control of MMP activity is vital in the complex proces...

Blockade of the programmed-death 1 receptor (PD-1)/programmed-death ligand (PD-L1) pathway efficiently reduces tumour growth and improves survival. Durable tumour regression with blockade of the PD-1/PD-L1 checkpoint has been demonstrated in recent clinical studies. Oral squamous cell carcinoma (OSCC) is highly immunosuppressive, and PD-L1 expressi...

Inhibition of epidermal growth factor receptor (EGFR) signalling has emerged as a new treatment strategy for oral squamous cell carcinoma (OSCC). Previously, we found that loss of EGFR expression in OSCC was associated with epithelial-mesenchymal transition (EMT), and may have functional implications with regard to resistance to cetuximab, a monocl...

IL-6 is a cytokine that is involved in various physiological and pathological conditions, and approaches using gain-of-function transgenic animals have contributed in elucidating IL-6 function. However, studies of the multiple functions of IL-6 in vivo are very time consuming because they require the generation of transgenic mice that harbor the ge...

Inhibition of epidermal growth factor receptor (EGFR) signaling has emerged as a novel therapeutic strategy for the treatment of oral squamous cell carcinoma (OSCC). The EGFR-directed inhibitor cetuximab is currently the only approved targeted therapy for the treatment of OSCC. EGFR status may affect the patient response to cetuximab treatment. In...

Background Vascular endothelial growth factor (VEGF) family members play a major role in angiogenesis and vascularization. VEGF-A promotes tumor angiogenesis by stimulating the growth of tumor vascular endothelial cells. In addition, VEGF-C has been identified as a potent inducer of lymphangiogenesis in tumor and lymph node metastasis. Previous stu...

We have used an aggrecan gene enhancer to generate a transgenic murine line (Acan-CreER-Ires-Luc) expressing firefly luciferase and tamoxifen activatable Cre recombinase (Cre-ER(T2) ). The expression and efficiency of the inducible Cre recombinase activity were tested in double transgenic mice created by crossing the Acan-CreER-Ires-Luc line with a...

Biomodification of dentin by a natural crosslinker has been recommended to improve a mechanical property of demineralized dentin. This study investigated the effect of various plant-derived agents (hesperidin, proanthocyanidin, epigallocatechin gallate and genipin) on the stability of dentin collagen matrix to resist collagenase degradation. The de...

Matrix metalloproteinases (MMPs) are involved in extracellular matrix degradation and the modulation of cell behavior. These proteinases have also been implicated in tissue repair and regeneration. Our previous studies have demonstrated that MMP-3 elicits stimulatory effects on the proliferation and the migration of endothelial cells as well as ant...

We measured the production levels of seven different matrix metalloproteinases (MMP-1, 2, 3, 7, 8, 9 and 13) and two tissue inhibitors of metalloproteinases (TIMP-1 and 2) in the homogenates of human oral squamous cell carcinomas and control normal squamous epithelia by the corresponding sandwich enzyme immunoassay systems. The levels of MMP-1, 2,...

Fetal cells enter the maternal circulation from the early first trimester of pregnancy, where they persist in tissue decades later. We investigated in mice whether fetal microchimeric cells (FMCs) can be detected in maternal kidney, and whether they play a role in kidney homeostasis. FMCs were identified in vivo in two models: one an adaptive model...

Connective tissue growth factor (CTGF) is a cysteine-rich secreted matricellular protein involved in wound healing and tissue repair. Enhanced and prolonged expression of CTGF has been associated with tissue fibrosis in humans. However, questions remain as to whether CTGF expression alone is sufficient to drive fibrosis. This study was undertaken t...

We investigated whether the affinity of tissue inhibitor of metalloproteinases (TIMP)-3 for adamalysins with thrombospondin motifs (ADAMTS)-4 and ADAMTS-5 is affected by the non-catalytic ancillary domains of the enzymes. For this purpose, we first established a novel method of purifying recombinant FLAG-tagged TIMP-3 and its inhibitory N-terminal...

ADAMTS-4 (aggrecanase-1) and ADAMTS-5 (aggrecanase-2) are multidomain metalloproteinases belonging to the ADAMTS family. We have previously reported that human ADAMTS-5 has much higher aggrecanolytic activity than human ADAMTS-4. To investigate the different proteolytic activity of the two enzymes, we generated a series of chimeras by exchanging va...

To investigate whether matrix metalloproteinases (MMPs) and/or aggrecanase in synovial fluid can be used as biochemical markers in the diagnosis of internal derangement (ID) of the temporomandibular joint (TMJ). Forty-four samples of synovial fluid were obtained from 35 patients with ID and osteoarthritis (OA) and 15 normal samples from 10 asymptom...

To determine whether or not aggrecanase in synovial fluid can be used as a biochemical marker in the diagnosis of temporomandibular joint disorder (TMJD). Forty-four samples of synovial fluid were obtained from 35 patients with internal derangement or osteoarthritis and 15 control samples from 10 asymptomatic volunteers. Aggrecanase in the synovial...

CD44 is a receptor for hyaluronan and mediates signaling that regulates complex cell behavior including cancer cell migration and invasion. Shedding of the extracellular portion of CD44 is the last step in the regulation of the molecule-releasing interaction between the ligand and cell. However, highly glycosylated forms of CD44 have hampered the i...

Gastric carcinomas can be classified into scirrhous carcinomas (SC), i.e. 'linitis plastica' or Borrmann 4 gastric cancer, and non-scirrhous carcinomas (NSC). SC are characterized by diffuse invasive growth patterns with marked fibrosis, frequent peritoneal dissemination and lymph-node metastases and poor prognosis, while NSC show medullary growth...

Publisher Summary This chapter examines the structural chemistry and the biological aspects of membrane-type matrix metalloproteinase 3 (MT3-MMP). A recombinant MT3-MMP having the catalytic and hemopexin-like domains was expressed as a soluble form and used to study its enzymatic activity. The rMT3-MMP is capable of digesting type III collagen, car...

CD44 is an enigmatic cell adhesion molecule acting as a major receptor for hyaluronan and playing roles in many biological and pathological processes such as lymphocyte homing, T-cell activation, wound healing, angiogenesis, and metastatic spread of tumor cells. However, the complexity of the molecule, with its alternatively spliced variants, exten...

Vascular endothelial growth factor (VEGF) is a strong angiogenic mitogen and plays important roles in angiogenesis under various pathophysiological conditions. The in vivo angiogenic activity of secreted VEGF may be regulated by extracellular inhibitors, because it is also produced in avascular tissues such as the cartilage. To seek the binding inh...

ADAMTS4 (aggrecanase-1) is considered to play a key role in the degradation of aggrecan in arthritides. The inhibitory activity of tissue inhibitors of metalloproteinases (TIMPs) to ADAMTS4 was examined in an assay using aggrecan substrate. Among the four TIMPs, TIMP-3 inhibited the activity most efficiently with an IC(50) value of 7.9 nM, which wa...

Brevican is a member of the lectican family of chondroitin sulfate proteoglycans that is predominantly expressed in the central nervous system. The susceptibility of brevican to digestion by matrix metalloproteinases (MMP-1, -2, -3, -7, -8, -9, -10, and -13 and membrane type 1 and 3 MMPs) and aggrecanase-1 (ADAMTS4) was examined. MMP-1, -2, -3, -7,...

A disintegrin-like and metalloproteinase with thrombospondin type I motifs-1 (ADAMTS-1) is an extracellular matrix-anchored metalloproteinase. In this study we have demonstrated that ADAMTS-1 is able to cleave a major cartilage proteoglycan, aggrecan. N-terminal sequencing analysis of the cleavage product revealed that ADAMTS-1 cleaves the Glu(1871...

Matrix metalloproteinases (MMPs) are expressed in joint tissues of patients with rheumatoid arthritis (RA) and osteoarthritis (OA). The objective of this study was to define the steady state levels of seven different MMPs and two tissue inhibitors of metalloproteinases (TIMPs) as well as the potential metalloproteinase activity in the synovial flui...

In vitro, membrane-type matrix metalloproteinases (MT-MMP) are known to activate the zymogen of MMP-2 (proMMP-2, progelatinase A), which is one of the key MMP in joint destruction in rheumatoid arthritis. In the present study, we examined the production and activation of proMMP-2, and the expression of MT1-MMP, MT2-MMP, and MT3-MMP, their correlati...

To determine the effects of calcium pentosan polysulfate (CaPPS) on the production of matrix metalloproteinases (MMPs) and their endogenous inhibitors, tissue inhibitors of metalloproteinases (TIMP), in cultures of rheumatoid synovial fibroblasts. The production of MMP-1, -2, -3, -7, -8, -9, and -13 and of TIMP-1, -2, -3, and -4 in cultured rheumat...

Membrane type 3 matrix metalloproteinase (MT3-MMP), an activator for the zymogen of MMP-2 (proMMP-2, or progelatinase A), is known to be expressed in human placenta, brain, lung and rat vascular smooth muscle cells, but information about its biochemical properties is limited. In the present study, we expressed and purified a truncated form of MT3-M...

Three different membrane-type matrix metalloproteinases (MT1-, MT2-, and MT3-MMPs) are known to activate in vitro the zymogen of MMP-2 (pro-MMP-2, progelatinase A), which is one of the key MMPs in invasion and metastasis of various cancers. In the present study, we have examined production and activation of pro-MMP-2, expression of MT1-, MT2-, and...

Matrix metalloproteinases (MMPs) are believed to be involved in the invasion and metastasis of various human carcinomas. In the present study, the production levels of seven different MMPs (MMP-1, -2, -3, -7, -8, -9, and -13), the activation of the zymogen of MMP-2 (proMMP-2), the expression of membrane-type MMPs (MT1-, MT2-, and MT3-MMPs), and the...

Matrix metalloproteinases (MMP) are synthesized as inactive zymogens (proMMP) and subsequently activated by many factors to degrade the extracellular matrix (ECM). In the present study, we have examined the intermolecular activation mechanisms of proMMP by MMP-10 (stromelysin 2). ProMMP-10 was purified from the culture media of OSC-20 human oral sq...

Activation of the zymogen of matrix metalloproteinase 2 (proMMP-2, progelatinase A) possibly is one of the key steps in invasion and metastasis of various human carcinomas. Three different membrane-type MMPs (MT-MMPs), MT1-, MT2-, and MT3-MMPs are thought to be activators of proMMP-2 in the tissues. MT4-MMP is structurally different from the other...

最近, 膜型マトリックスメタロプロテアーゼ (MT-MMP) がMMP-2 (ゼラチナーゼA) の活性化因子としてクローニングされ, さらにヒト肺癌および胃癌におけるこのMT-MMPの発現がMMP-2の活性化とよく相関していたことから, MT-MMPによるMMP-2の活性化が癌の浸潤や転移における一つの重要な鍵を握っている可能性が示唆されるようになった。そこで本研究では, ヒトロ腔扁平上皮癌におけるMT-MMPの発現と癌の浸潤・転移との関係を明らかにする目的で, 33例の口腔扁平上皮癌組織におけるMT1-MMP, MT3-MMPおよびMMP-2の免疫組織化学的発現と癌浸潤様式およびリンパ節転移との関係について検討を行った。その結果, MT1-MMP, MT3-MMPおよびMMP-2の陽性例は...

Activation of the zymogen of matrix metalloprotelnase 2 (proMMP-2, progelatinase A) possibly is one ofthe key steps In Invasion and metastasis of varioushumancarcinomas. Threedifferentmembrane-type MMPS (MT-MMPs), MT1., MT2-, and MT3-MMPSare thought to be activators of proMMP-2 Inthetissues.MT4.MMP Isstructurally differentfromthe other three enzyme...