Biomedical subjects

Sakae Tanaka

Publications and source records attributed to Sakae Tanaka.

At least 19 recordsLinked to original sources

PubMed2026

PDGFRA amplification could be a poor prognostic factor of advanced undifferentiated pleomorphic sarcoma in a comprehensive genomic profiling cohort.

BACKGROUND: Undifferentiated pleomorphic sarcoma (UPS) is the most common pleomorphic sarcoma, and its genomic landscape has been analysed, albeit in small numbers. This study aimed to clarify the relationship between gene variants and the prognosis of patients with advanced UPS. METHODS: This retrospective cohort study was conducted to analyse the data of patients with advanced UPS using a registry of the Center for Cancer Genomics and Advanced Therapeutics (C-CAT) database up to Oct 2025 in Japan, analysed using comprehensive genomic profiling assay. RESULTS: A total of 233 patients with advanced UPS were identified in the C-CAT database; 151 men (64.8%), median age: 60.2 years. TP53 variant (55%) was the most frequent event and the rate of Platelet-derived growth factor receptor alpha (PDGFRA) and KDR amplification were 9% and 6%, respectively. PDGFRA amplification co-occurred with KDR amplification (P < 0.001). Survival from the initiation of chemotherapy was analysed by adjusting for length bias inherent in the database using the Kaplan-Meier estimator, an established method of adjustment. Patients with PDGFRA amplification (11 patients) had a worse prognosis than those without PDGFRA amplification [hazard ratio 2.9, 95% confidence interval 1.2-6.9 (P = 0.02)]. TP53 alterations (P = 0.24) were not associated with prognosis. In addition, treatment time with pazopanib with PDGFRA amplification [4 patients, 2.3 months (1.2-11.2 months)] was not different with those without PDGFRA amplification [28 patients, 3.8 months (0.9 months-not reached)] (P = 0.52). CONCLUSIONS: For patients with advanced UPS, PDGFRA amplification was a poor prognostic factor and is not related to the efficacy of pazopanib treatment.

PDGFRA amplification↗

PubMed2026

Distinct periarticular muscle transcriptomes: inflammation in rheumatoid arthritis versus metabolic dysregulation in osteoarthritis.

OBJECTIVES: Periarticular skeletal muscle abnormalities are recognised in rheumatoid arthritis (RA) and osteoarthritis (OA), but their divergent molecular pathologies are poorly defined. This study aimed to elucidate and directly compare the transcriptomic profiles of periarticular muscle in patients with RA and OA. METHODS: We performed bulk RNA sequencing of periarticular skeletal muscle samples collected during total joint arthroplasty from RA (n=6) and OA (n=4) patients. Differential gene expression analysis, weighted gene co-expression network analysis (WGCNA), pathway enrichment, and gene set variation analyses were conducted to identify disease-specific molecular features and their clinical associations. RESULTS: The two conditions showed fundamentally distinct profiles. RA muscle exhibited a pronounced inflammatory signature, characterised by upregulation of cytokine-responsive genes including FOS, EGR1, and CXCL2, and enrichment of tumour necrosis factor-α and interleukin-6 (IL-6)/JAK-STAT3 signalling. In contrast, OA muscle was characterised by metabolic dysregulation, with upregulation of genes linked to adipogenesis (PCK1, SFRP4) and significant enrichment of epithelial-to-mesenchymal transition (EMT) signalling. These divergent profiles were further supported by WGCNA, which identified distinct modules reflecting heightened innate immune and complement activation in RA, and disrupted metabolic processes in OA. Notably, in RA, the IL-2-STAT5 signalling pathway was unique among those tested in showing a strong positive correlation with DAS28-ESR (r=0.94, p=0.019). CONCLUSIONS: This study reveals distinct molecular pathologies in the periarticular muscle of RA and OA. RA muscle shows an intense inflammatory profile potentially linked to cachexia, whereas OA muscle displays features of metabolic disease and pro-fibrotic remodelling.

Humans↗

PubMed2005

RANK-mediated amplification of TRAF6 signaling leads to NFATc1 induction during osteoclastogenesis.

RANK and CD40 activate NF-kappaB and MAPKs to similar levels via TRAF6. Even though overexpression of TRAF6 results in osteoclast formation, RANK but not CD40 promotes osteoclastogenesis. To understand the molecular basis for RANK-specific activity in osteoclastogenesis, we created an osteoclast formation system driven by anti-human CD40 antibody-mediated stimulation of a chimeric receptor, h40/mRK, which consists of the extracellular domain of human CD40 and the transmembrane and cytoplasmic domains of mouse RANK. By introducing mutations into three TRAF6-binding sites of RANK, we found that h40/mRK with a single TRAF6-binding site efficiently induced Ca2+ oscillation and expression of NFATc1, a master switch in osteoclastogenesis, whereas CD40 carrying a single TRAF6-binding site did not. However, expression of CD40 that was approximately 100 times greater than that of h40/mRK resulted in osteoclast formation, indicating that the RANK-TRAF6 signal is more potent than the CD40-TRAF6 signal in terms of NFATc1 activation and osteoclastogenesis. These results suggest that RANK may harbor a specific domain that amplifies TRAF6 signaling.

Animals↗

PubMed2005

[Involvement of osteoclasts in cartilage and bone destruction in rheumatoid arthritis].

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Animals↗

PubMed2005

[Disorder of bone quality in osteopetrosis].

Osteopetrosis is a genetic disorder characterized by increased bone mass due to the reduced bone resorption. It is also characterized by the discrepancy between bone mass and bone strength. In this review, I would like to introduce the up-to-date of the research and treatment of osteopetrosis.

Adult↗

PubMed2005

[A novel therapeutic vaccine approach against RANKL that prevents pathological bone destruction].

The vaccination method is used to induce antibody response against disease-related proteins by immunization with modified pathological antigen as preventive therapy to acquire disease resistance. A RANKL vaccine was developed by modifying the soluble TNF-like domain of murine RANKL to incorporate a promiscuous Th epitope. Immunization with RANKL vaccine prevented pathological bone resorption in arthritic mice or ovariactomized mice.

Animals↗

PubMed2004

Essential role of synoviolin in embryogenesis.

We recently reported the importance of Synoviolin in quality control of proteins through the endoplasmic reticulum (ER)-associated degradation (ERAD) system and its involvement in the pathogenesis of arthropathy through its anti-apoptotic effect. For further understanding of the role of Synoviolin in vivo, we generated in this study synoviolin-deficient (syno(-/-)) mice by genetargeted disruption. Strikingly, all fetuses lacking syno died in utero around embryonic day 13.5, although Hrd1p, a yeast orthologue of Synoviolin, is non-essential for survival. Histologically, hypocellularity and aberrant apoptosis were noted in the syno(-/-) fetal liver. Moreover, definitive erythropoiesis was affected in non-cell autonomous manner in syno(-/-) embryos, causing death in utero. Cultured embryonic fibroblasts derived from syno(-/-) mice were more susceptible to endoplasmic reticulum stress-induced apoptosis than those from syno(+/+) mice, but the susceptibility was rescued by overexpression of synoviolin. Our findings emphasized the indispensable role of the Synoviolin in embryogenesis.

Adenoviridae↗

PubMed2004

Monokine induced by interferon-gamma is induced by receptor activator of nuclear factor kappa B ligand and is involved in osteoclast adhesion and migration.

Bone remodeling is accompanied by the differentiation of osteoclasts from the monocyte/macrophage lineage of hematopoietic cells. The osteoclast differentiation process requires receptor activator of nuclear factor kappa B (NF-kappa B) ligand (RANKL), which causes complex changes in the expression of various genes. In a cDNA microarray study to identify genes targeted by RANKL, we found that monokine induced by the interferon-gamma (IFN-gamma) (MIG) gene was up-regulated in osteoclast precursor cells. The increase in MIG expression by RANKL was confirmed by reverse transcription-polymerase chain reaction and Western blot analysis. RANKL induction of MIG required the activity of NF-kappa B, whose binding site is present in the MIG promoter. MIG induction by RANKL was also dependent on p38 mitogen-activated protein kinase (MAPK) and signal transducer and activator of transcription 1 (STAT1). RANKL stimulated the phosphorylation of Ser727 of STAT1, which required p38 activity. MIG secreted on RANKL treatment could stimulate the migration and adhesion of osteoclast precursors and osteoclasts that were primed to express CXCR3, the MIG receptor, by macrophage-colony-stimulating factor (M-CSF). Therefore, we provide the first evidence demonstrating that RANKL stimulates the serine phosphorylation of STAT1 through the p38 MAPK pathway, causing MIG gene transcription and secretion, which may have a role in recruiting CXCR3-positive osteoclast precursors and osteoclasts to bone remodeling or inflammatory sites.

Animals↗

PubMed2004

Opposing extracellular signal-regulated kinase and Akt pathways control Schwann cell myelination.

Schwann cells are the myelinating glia of the peripheral nervous system, and their development is regulated by various growth factors, such as neuregulin, platelet-derived growth factor (PDGF), and insulin-like growth factor-I (IGF-I). However, the mechanism of intracellular signaling pathways following these ligand stimuli in Schwann cell differentiation remains elusive. Here, we demonstrate that in cultured Schwann cells, neuregulin and PDGF suppressed the expression of myelin-associated protein markers, whereas IGF-I promoted it. Although these ligands activated common downstream signaling pathways [i.e., extracellular signal-regulated kinase (Erk) and phosphatidylinositol-3-kinase (PI3K)-Akt pathways], the profiles of activation varied among ligands. To elucidate the function of these pathways and the mechanisms underlying Schwann cell differentiation, we used adenoviral vectors to selectively activate or inactivate these pathways. We found that the selective activation of Erk pathways suppressed Schwann cell differentiation, whereas that of PI3K pathways promoted it. Furthermore, lithium chloride, a modulator of glycogen synthase kinase-3beta (GSK-3beta) promoted Schwann cell differentiation, suggesting the involvement of GSK-3beta as a downstream molecule of PI3K-Akt pathways. Selective activation of PI3K pathways in Schwann cells by gene transfer also demonstrated increased myelination in in vitro Schwann cell-DRG neuron cocultures and in vivo allogenic nerve graft experiments. We conclude that signals mediated by PI3K-Akt are crucial for initiation of myelination and that the effects of growth factors are primarily dependent on the balance between Erk and PI3K-Akt activation. Our results also propose the possibility of augmenting Schwann cell functions by modulating intracellular signals in light of future cell therapies.

Animals↗

PubMed2004

Osteoclast differentiation by RANKL requires NF-kappaB-mediated downregulation of cyclin-dependent kinase 6 (Cdk6).

UNLABELLED: This study investigated the involvement of cell cycle factors in RANKL-induced osteoclast differentiation. Among the G1 cell cycle factors, Cdk6 was found to be a key molecule in determining the differentiation rate of osteoclasts as a downstream effector of the NF-kappaB signaling. INTRODUCTION: A temporal arrest in the G1 phase of the cell cycle is a prerequisite for cell differentiation, making it possible that cell cycle factors regulate not only the proliferation but also the differentiation of cells. This study investigated cell cycle factors that critically influence differentiation of the murine monocytic RAW264.7 cells to osteoclasts induced by RANKL. MATERIALS AND METHODS: Growth-arrested RAW cells were stimulated with serum in the presence or absence of soluble RANKL (100 ng/ml). Expressions of the G1 cell cycle factors cyclin D1, D2, D3, E, cyclin-dependent kinase (Cdk) 2, 4, 6, and Cdk inhibitors (p18 and p27) were determined by Western blot analysis. Involvement of NF-kappaB and c-jun N-terminal kinase (JNK) pathways was examined by overexpressing dominant negative mutants of the IkappaB kinase 2 (IKK(DN)) gene and mitogen-activated protein kinase kinase 7 (MKK7(DN)) gene, respectively, using the adenovirus vectors. To determine the direct effect of Cdk6 on osteoclast differentiation, stable clones of RAW cells transfected with Cdk6 cDNA were established. Osteoclast differentiation was determined by TRACP staining, and cell cycle regulation was determined by BrdU uptake and flow cytometric analysis. RESULTS AND CONCLUSION: Among the cell cycle factors examined, the Cdk6 level was downregulated by RANKL synchronously with the appearance of multinucleated osteoclasts. Inhibition of the NF-kappaB pathway by IKK(DN) overexpression, but not that of the JNK pathway by MKK7(DN) overexpression, caused the decreases in both Cdk6 downregulation and osteoclastogenesis by RANKL. RAW cells overexpressing Cdk6 resist RANKL-induced osteoclastogenesis; however, cell cycle regulation was not affected by the levels of Cdk6 overexpression, suggesting that the inhibitory effect of Cdk6 on osteoclast differentiation was not exerted through cell cycle regulation. These results indicate that Cdk6 is a critical regulator of RANKL-induced osteoclast differentiation and that its NF-kappaB-mediated downregulation is essential for efficient osteoclast differentiation.

Animals↗

PubMed2004

Fcgamma receptor signaling in primary human microglia: differential roles of PI-3K and Ras/ERK MAPK pathways in phagocytosis and chemokine induction.

Cryptococcus neoformans monoclonal antibody immune complex (IC) induces beta-chemokines and phagocytosis in primary human microglia via activation of Fc receptor for immunoglobulin G (FcgammaR). In this report, we investigated microglial FcgammaR signal-transduction pathways by using adenoviral-mediated gene transfer and specific inhibitors of cell-signaling pathways. We found that Src inhibitor PP2 and Syk inhibitor piceatannol inhibited phagocytosis, macrophage-inflammatory protein-1alpha (MIP-1alpha) release, as well as phosphorylation of extracellular-regulated kinase (ERK) and Akt, consistent with Src/Syk involvement early in FcgammaR signaling. Constitutively active mitogen-activated protein kinase kinase (MEK) induced MIP-1alpha, and Ras dominant-negative (DN) inhibited IC-induced ERK phosphorylation and MIP-1alpha production. These results suggest that the Ras/MEK/ERK pathway is necessary and sufficient in IC-induced MIP-1alpha expression. Neither Ras DN nor the MEK inhibitor U0126 inhibited phagocytosis. In contrast, phosphatidylinositol-3 kinase (PI-3K) inhibitors Wortmannin and LY294002 inhibited phagocytosis without affecting ERK phosphorylation or MIP-1alpha production. Conversely, Ras DN or U0126 did not affect Akt phosphorylation. Together, these results demonstrate distinct roles played by the PI-3K and Ras/MEK/ERK pathways in phagocytosis and MIP-1alpha induction, respectively. Our results demonstrating activation of functionally distinct pathways following microglial FcgammaR engagement may have implications for human central nervous system diseases.

Adenoviridae↗

PubMed2004

Src kinase activity is essential for osteoclast function.

Deletion of the c-src gene impairs osteoclast bone resorbing activity, causing osteopetrosis. Although it has been concluded that restoring only the Src adaptor function at least partly rescues the cell attachment and skeletal phenotypes, the contribution of Src kinase activity remains controversial. Src forms a complex with Pyk2 and Cbl after adhesion-induced stimulation of alpha(V)beta(3) integrin. To demonstrate the importance of the Pyk2-Src association in osteoclasts and to distinguish the contributions of the Src adaptor and kinase activities in cytoskeletal organization and osteoclast function, we expressed mutants of Src and Pyk2 in osteoclasts using adenovirus vectors. Eliminating the Src-binding site on Pyk2 (Pyk2(Y402F)) markedly inhibited bone resorption by osteoclast-like cells, whereas kinase-dead Pyk2 had little effect. Kinase-dead Src, unlike kinase-dead Pyk2, markedly inhibited the bone-resorbing activity of wild type osteoclasts and failed to significantly restore bone-resorbing activity to Src(-/-) osteoclast-like cells. Activation of Src kinase by overexpressing kinase-dead Csk failed to reverse the inhibitory effect of Pyk2(Y402F), suggesting that osteoclastic bone resorption requires both c-Src kinase activity and the targeting of Src kinase by Pyk2. Src-catalyzed phosphorylation of Cbl on Tyr-731 is reported to induce the activation and recruitment of phosphatidylinositol 3-kinase to the cell membrane in a signaling pathway that is critical for osteoclast function. Expressing the Cbl(Y731F) mutant in osteoclasts markedly reduced their bone resorbing activity, suggesting that phosphorylation of Cbl(Y731) and the subsequent recruitment and activation of phosphatidylinositol 3-kinase may be critical signaling events downstream of Src in osteoclasts.

Adenoviridae↗

PubMed2004

Suppression of T cell responses by chondromodulin I, a cartilage-derived angiogenesis inhibitory factor: therapeutic potential in rheumatoid arthritis.

OBJECTIVE: Chondromodulin I (ChM-I), a cartilage matrix protein, promotes the growth and proteoglycan synthesis of chondrocytes. However, it also inhibits angiogenesis. Since ChM-I is expressed not only in cartilage, but also in the thymus, we investigated the modulation of T cell function by ChM-I to assess its therapeutic potential in rheumatoid arthritis (RA). METHODS: The localization of ChM-I expression in mouse thymus tissue was examined by in situ hybridization. The proliferative response of peripheral blood T cells and synovial cells obtained from patients with RA was evaluated by (3)H-thymidine incorporation assay. The effects of ChM-I were examined using recombinant human ChM-I (rHuChM-I). Modulation of the antigen-specific immune response was evaluated by the recall response of splenic T cells and the delayed-type hypersensitivity response induced in the ear of mice primed with ovalbumin (OVA). Antigen-induced arthritis (AIA) was induced in mice by injecting methylated bovine serum albumin into the ankle joints 2 weeks after the priming. RESULTS: ChM-I was expressed in the cortex of the thymus. Recombinant human ChM-I suppressed the proliferative response of mouse splenic T cells and human peripheral blood T cells stimulated with anti-CD3/CD28 antibodies, in a dose-dependent manner. Production of interleukin-2 was decreased in rHuChM-I-treated mouse CD4 T cells. Ten micrograms of rHuChM-I injected intraperitoneally into OVA-primed mice suppressed the induction of the antigen-specific immune response. Finally, rHuChM-I suppressed the development of AIA, and also suppressed the proliferation of synovial cells prepared from the joints of patients with RA. CONCLUSION: These results suggest that ChM-I suppresses T cell responses and synovial cell proliferation, implying that this cartilage matrix protein has a therapeutic potential in RA.

Adjuvants, Immunologic↗

PubMed2004

Traf6 is essential for murine tooth cusp morphogenesis.

Ectodermal appendages such as skin, hair, teeth, and sweat glands are affected in patients with hypohidrotic (anhydrotic) ectodermal dysplasia (HED). It has been established that mutations in the tumor necrosis factor (TNF) superfamily of molecules, i.e., ectodysplasin (EDA), EDA receptor (EDAR), and EDAR-associated death domain (EDARADD; the intracellular adaptor for EDAR), are responsible for several forms of HED in humans and mice. We show here by in situ hybridisation that another TNF family (orphan) receptor, TROY (also known TAJ, TAJ-alpha, TRADE, and TNFRSF19), is strongly coexpressed with Edar in the epithelial enamel knot signalling centres that are believe to regulate cuspal morphogenesis during murine tooth development. Traf6 is known to function as an intracellular adaptor protein for Troy and examination of Traf6 mutant mice revealed abnormalities in molar teeth that are similar but more severe than those produced by mutations in Eda signalling molecules. This finding suggests that, in additional to ectodysplasin, another TNF pathway involving Troy/Traf6 is involved in molar tooth cusp formation and identifies an essential role for a Traf in tooth development. Developmental Dynamics 229:131-135, 2004.

Animals↗

PubMed2004

Activation of ERK or inhibition of JNK ameliorates H(2)O(2) cytotoxicity in mouse renal proximal tubule cells.

BACKGROUND: Our previous studies suggest that the balance between the activation of extracellular signal-regulated kinase (ERK) and the c-Jun N-terminal/stress-activated protein kinase (JNK) might determine cell fate following oxidant injury in vivo. METHODS: The mouse proximal tubule cell line (TKPTS) was used to study hydrogen peroxide (H(2)O(2))-induced death and survival. The role of ERK and JNK in this process was studied by using adenoviruses that contain either a constitutively active mitogen-activated protein kinase kinase 1 (MEK1) or a dominant-negative JNK. Acridine orange plus ethidium bromide staining was applied to distinguish between viable, apoptotic, and necrotic cells following H(2)O(2) treatment. We analyzed cell cycle events by fluorescence-activated cell sorter (FACS) analysis and the phosphorylation status of ERK and JNK by Western blotting. RESULTS: TKPTS cells survived a moderate level of oxidative stress (0.5 mM/L H(2)O(2)) via temporary growth arrest, while high dose of H(2)O(2) (1 mM/L) caused extensive necrosis. Survival was associated with activation of both ERK and JNK, while death was associated with JNK activation only. Prior adenovirus-mediated up-regulation of ERK or inhibition of JNK function increased the survival (8- or 7-fold, respectively) of TKPTS cells after 1 mmol/L H(2)O(2) treatment. Interestingly, ERK activation and, thus, survival was associated with growth arrest not proliferation. CONCLUSION: We demonstrate that oxidant injury-induced necrosis could be ameliorated by either up-regulation of endogenous ERK or by inhibition of JNK-related pathways. These results directly demonstrate that the intracellular balance between prosurvival and prodeath mitogen-activated protein kinases (MAPKs) determine proximal tubule cell survival from oxidant injury and reveal possible mediators of survival.

Adenoviridae↗

PubMed2004

Critical roles of c-Jun signaling in regulation of NFAT family and RANKL-regulated osteoclast differentiation.

Receptor activator of NF-kappaB ligand (RANKL) plays an essential role in osteoclast formation and bone resorption. Although genetic and biochemical studies indicate that RANKL regulates osteoclast differentiation by activating receptor activator of NF-kappaB and associated signaling molecules, the molecular mechanisms of RANKL-regulated osteoclast differentiation have not yet been fully established. We investigated the role of the transcription factor c-Jun, which is activated by RANKL, in osteoclastogenesis using transgenic mice expressing dominant-negative c-Jun specifically in the osteoclast lineage. We found that the transgenic mice manifested severe osteopetrosis due to impaired osteoclastogenesis. Blockade of c-Jun signaling also markedly inhibited soluble RANKL-induced osteoclast differentiation in vitro. Overexpression of nuclear factor of activated T cells 1 (NFAT1) (NFATc2/NFATp) or NFAT2 (NFATc1/NFATc) promoted differentiation of osteoclast precursor cells into tartrate-resistant acid phosphatase-positive (TRAP-positive) multinucleated osteoclast-like cells even in the absence of RANKL. Overexpression of NFAT1 also markedly transactivated the TRAP gene promoter. These osteoclastogenic activities of NFAT were abrogated by overexpression of dominant-negative c-Jun. Importantly, osteoclast differentiation and induction of NFAT2 expression by NFAT1 overexpression or soluble RANKL treatment were profoundly diminished in spleen cells of the transgenic mice. Collectively, these results indicate that c-Jun signaling in cooperation with NFAT is crucial for RANKL-regulated osteoclast differentiation.

Adenoviridae↗

PubMed2004

Distinct roles of Smad pathways and p38 pathways in cartilage-specific gene expression in synovial fibroblasts.

The role of TGF-beta/bone morphogenetic protein signaling in the chondrogenic differentiation of human synovial fibroblasts (SFs) was examined with the adenovirus vector-mediated gene transduction system. Expression of constitutively active activin receptor-like kinase 3 (ALK3CA) induced chondrocyte-specific gene expression in SFs cultured in pellets or in SF pellets transplanted into nude mice, in which both the Smad and p38 pathways are essential. To analyze downstream cascades of ALK3 signaling, we utilized adenovirus vectors carrying either Smad1 to stimulate Smad pathways or constitutively active MKK6 (MKK6CA) to activate p38 pathways. Smad1 expression had a synergistic effect on ALK3CA, while activation of p38 MAP kinase pathways alone by transduction of MKK6CA accelerated terminal chondrocytic differentiation, leading to type X collagen expression and enhanced mineralization. Overexpression of Smad1 prevented MKK6CA-induced type X collagen expression and maintained type II collagen expression. In a mouse model of osteoarthritis, activated p38 expression as well as type X collagen staining was detected in osteochondrophytes and marginal synovial cells. These results suggest that SFs can be differentiated into chondrocytes via ALK3 activation and that stimulating Smad pathways and controlling p38 activation at the proper level can be a good therapeutic strategy for maintaining the healthy joint homeostasis and treating degenerative joint disorders.

Activin Receptors↗

PubMed2004

[TNF-alpha].

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Animals↗