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Biomedical subjects

Naoshi Ogata

Publications and source records attributed to Naoshi Ogata.

At least 19 recordsLinked to original sources
PubMed2006

Regulation of bone formation by adiponectin through autocrine/paracrine and endocrine pathways.

Since interaction between bone and lipid metabolism has been suggested, this study investigated the regulation of bone metabolism by adiponectin, a representative adipokine, by analyzing deficient and overexpressing transgenic mice. We initially confirmed that adiponectin and its receptors were expressed in osteoblastic and osteoclastic cells, indicating that adiponectin can act on bone not only through an endocrine pathway as a hormone secreted from fat tissue, but also through an autocrine/paracrine pathway. There was no abnormality in bone mass or turnover of adiponectin-deficient (Ad-/-) mice, possibly due to an equivalent balance of the two pathways. In the culture of bone marrow cells from the Ad-/- mice, osteogenesis was decreased compared to the wild-type (WT) cell culture, indicating a positive effect of endogenous adiponectin through the autocrine/paracrine pathway. To examine the endocrine action of adiponectin, we analyzed transgenic mice overexpressing adiponectin in the liver, and found no abnormality in the bone. Addition of recombinant adiponectin in cultured osteoprogenitor cells suppressed osteogenesis, suggesting that the direct action of circulating adiponectin was negative for bone formation. In the presence of insulin, however, this suppression was blunted, and adiponectin enhanced the insulin-induced phosphorylations of the main downstream molecule insulin receptor substrate-1 and Akt. These lines of results suggest three distinct adiponectin actions on bone formation: a positive action through the autocrine/paracrine pathway by locally produced adiponectin, a negative action through the direct pathway by circulating adiponectin, and a positive action through the indirect pathway by circulating adiponectin via enhancement of the insulin signaling.

Adiponectin↗
PubMed2006

Neurologic level diagnosis of cervical stenotic myelopathy.

STUDY DESIGN: A cross-sectional analysis. OBJECTIVE: To elucidate the accuracy of neurologic level diagnosis of cervical stenotic myelopathy. SUMMARY OF BACKGROUND DATA: Neurologic level diagnosis in cervical myelopathy has not been well established. METHODS: A total of 106 patients with cervical stenotic myelopathy, with a single-level intramedullary high-intensity area confirmed on both preoperative and postoperative T2-weighted magnetic resonance imaging (MRI), were included in this study. We performed a level diagnosis on the basis of neurologic signs (the uppermost muscle with weakness, diminished or exaggerated deep tendon reflex, the uppermost level of sensory disturbance of the upper extremities) and compared it with a level diagnosis made by T2-weighted MRI. The sensitivity, specificity, and accuracy of neurologic signs on our index corresponding to each intervertebral level were calculated. RESULTS: The averages of sensitivity, specificity, and accuracy were 42%, 80%, and 70%, respectively, in the uppermost muscle with weakness, 66%, 89%, and 83% in deep tendon reflex, and 74%, 91%, and 87% in the sensory disturbance area. The positive and negative predictive values were 40% and 91%, respectively, in the uppermost muscle with weakness, 66% and 89% in deep tendon reflex, and 74% and 91% in the sensory disturbance area. Accuracy of a diagnosis based on muscle weakness was less high, the reason being that in many patients, the uppermost muscle with weakness was extensor digiti communis or the intrinsic muscles of the hands, and this led to a lower sensitivity. CONCLUSIONS: The average accuracy of neurologic level diagnosis based on the index we proposed was > or =70%. The level diagnosis by a sensory disturbance area showed the highest accuracy (87%).

Adult↗
PubMed2005

Distinct association of gene polymorphisms of estrogen receptor and vitamin D receptor with lumbar spondylosis in post-menopausal women.

Contribution of genetic backgrounds to the etiology of lumbar spondylosis has been suggested by epidemiological studies. This study was designed to determine the association of restriction fragment length polymorphisms (RFLPs) of estrogen receptor (ER), vitamin D receptor (VDR), parathyroid hormone (PTH) and interleukin-1beta (IL-1beta) genes with the radiological severity of lumbar spondylosis at the disk level from L1/2 to L5/S1 in Japanese post-menopausal women. ER and VDR RFLP haplotypes were associated with the severity of spondylosis in the upper levels (L1/2 and L2/3) more than in the lower levels. Association of ER genotype was more pronounced in the group younger than average than in the older group, while that of VDR genotype was more significant in the older group. Neither PTH nor IL1-beta RFLP was associated with the severity at any levels in either stratified group. We thus conclude that ER and VDR genes may contribute to lumbar spondylosis in a distinct manner: estrogen sensitivity influences the severity in the early phase after menopause while vitamin D plays an important role at older ages when the contribution of estrogen loss is weaker.

Female↗
PubMed2005

Involvement of endogenous bone morphogenetic protein (BMP) 2 and BMP6 in bone formation.

Although accumulated evidence has shown the bone anabolic effects of bone morphogenetic proteins (BMPs) that were exogenously applied in vitro and in vivo, the roles of endogenous BMPs during bone formation remain to be clarified. This study initially investigated expression patterns of BMPs in the mouse long bone and found that BMP2 and BMP6 were the main subtypes expressed in hypertrophic chondrocytes that induce endochondral bone formation. We then examined the involvement of the combination of these BMPs in bone formation in vivo by generating the compound-deficient mice (Bmp2+/-;Bmp6-/-). Under physiological conditions, these mice exhibited moderate growth retardation compared with the wild-type (WT) littermates during the observation period up to 52 weeks of age. Both the fetal and adult compound-deficient mice showed a reduction in the trabecular bone volume with suppressed bone formation, but normal bone resorption, whereas the single deficient mice (Bmp2+/- or Bmp6-/-) did not. When a fracture was created at the femoral midshaft and the bone healing was analyzed, the endochondral bone formation, but not intramembranous bone formation, was impaired by the compound deficiency. In the cultures of bone marrow cells, however, there was no difference in osteogenic differentiation between WT and compound-deficient cells in the presence or absence of the exogenous BMP2. We thus concluded that endogenous BMP2 and BMP6 cooperatively play pivotal roles in bone formation under both physiological and pathological conditions.

Animals↗
PubMed2005

The canonical Wnt signaling pathway promotes chondrocyte differentiation in a Sox9-dependent manner.

To better understand the role of the canonical Wnt signaling pathway in cartilage development, we adenovirally expressed a constitutively active (ca) or a dominant negative (dn) form of lymphoid enhancer factor-1 (LEF-1), the main nuclear effector of the pathway, in undifferentiated mesenchymal cells, chondrogenic cells, and primary chondrocytes, and examined the expression of markers for chondrogenic differentiation and hypertrophy. caLEF-1 and LiCl, an activator of the canonical pathway, promoted both chondrogenic differentiation and hypertrophy, whereas dnLEF-1 and the gene silencing of beta-catenin suppressed LiCl-promoted effects. To investigate whether these effects were dependent on Sox9, a master regulator of cartilage development, we stimulated Sox9-deficient ES cells with the pathway. caLEF-1 and LiCl promoted both chondrogenic differentiation and hypertrophy in wild-type, but not in Sox9-deficient, cells. The response of Sox9-deficient cells was restored by the adenoviral expression of Sox9. Thus, the canonical Wnt signaling pathway promotes chondrocyte differentiation in a Sox9-dependent manner.

Animals↗
PubMed2005

Insulin receptor substrate-1 is required for bone anabolic function of parathyroid hormone in mice.

Bone anabolic action of PTH has been suggested to be mediated by induction of IGF-I in osteoblasts; however, little is known about the molecular mechanism by which IGF-I leads to bone formation under the PTH stimulation. This study initially confirmed in mouse osteoblast cultures that PTH treatment increased IGF-I mRNA and protein levels and alkaline phosphatase activity, which were accompanied by phosphorylations of IGF-I receptor, insulin receptor substrate (IRS)-1 and IRS-2, essential adaptor molecules for the IGF-I signaling. To learn the involvement of IRS-1 and IRS-2 in the bone anabolic action of PTH in vivo, IRS-1-/- and IRS-2-/- mice and their respective wild-type littermates were given daily injections of PTH (80 mug/kg) or vehicle for 4 wk. In the wild-type mice, the PTH injection increased bone mineral densities of the femur, tibia, and vertebrae by 10-20% without altering the serum IGF-I level. These stimulations were similarly seen in IRS-2-/- mice; however, they were markedly suppressed in IRS-1-/- mice. Although the PTH anabolic effects were stronger on trabecular bones than on cortical bones, the stimulations on both bones were blocked in IRS-1-/- mice but not in IRS-2-/- mice. Histomorphometric and biochemical analyses showed an increased bone turnover by PTH, which was also blunted by the IRS-1 deficiency, though not by the IRS-2 deficiency. These results indicate that the PTH bone anabolic action is mediated by the activation of IRS-1, but not IRS-2, as a downstream signaling of IGF-I that acts locally as an autocrine/paracrine factor.

Animals↗
PubMed2005

Inhibition of Cdk6 expression through p38 MAP kinase is involved in differentiation of mouse prechondrocyte ATDC5.

Because a temporal arrest in the G1-phase of the cell cycle is a prerequisite for cell differentiation, this study investigated the involvement of cell cycle factors in the differentiation of cultured mouse prechondrocyte cell line ATDC5. Among the G1 cell cycle factors examined, both protein and mRNA levels of cyclin-dependent kinase (Cdk6) were downregulated during the culture in a differentiation medium. The protein degradation of Cdk6 was not involved in this downregulation because proteasome inhibitors did not reverse the protein level. When inhibitors of p38 MAPK, ERK-1/2, and PI3K/Akt were added to the culture, only a p38 MAPK inhibitor SB203580 blocked the decrease in the Cdk6 protein level by the differentiation medium, indicating that the Cdk6 inhibition was mediated by p38 MAPK pathway. In fact, p38 MAPK was confirmed to be phosphorylated during differentiation of ATDC5 cells. Enforced expression of Cdk6 in ATDC5 cells blocked the chondrocyte differentiation and inhibited Sox5 and Sox6 expressions. However, the Cdk6 overexpression did not affect the proliferation or the cell cycle progression, suggesting that the inhibitory effect of Cdk6 on the differentiation was exerted by a mechanism largely independent of its cell cycle regulation. These results indicate that Cdk6 may be a regulator of chondrocyte differentiation and that its p38-mediated downregulation is involved in the efficient differentiation.

Animals↗
PubMed2004

Stimulatory G protein directly regulates hypertrophic differentiation of growth plate cartilage in vivo.

Stimulatory heterotrimeric G protein (Gs) transduces signals from various cell-surface receptors to adenylyl cyclases, which generate cAMP. The alpha subunit of Gs (Gsalpha) is encoded by GNAS (Gnas in mice), and heterozygous Gsalpha inactivating mutations lead to Albright hereditary osteodystrophy. The in vivo role of Gsalpha in skeletogenesis is largely unknown, because of early embryonic lethality of mice with disruption of Gnas exon 2 (Gnas(E2-/E2-)) and the absence of easily detectable phenotypes in growth plate chondrocytes of heterozygous mutant mice (Gnas(+/E2-)). We generated chimeric mice containing wild-type cells and either Gnas(E2-/E2-) or Gnas(+/E2-) cells. Gnas(E2-/E2-) chondrocytes phenocopied PTH/PTHrP receptor (PPR)(-/-) cells by prematurely undergoing hypertrophy. Introduction of a transgene expressing Gsalpha, one of several gene products that include Gnas exon 2, into Gnas(E2-/E2-) cells prevented premature hypertrophy. Gsalpha mRNA expression detected by real-time RT-PCR analysis was reduced to approximately half that of the wild-type in both paternal and maternal Gnas(+/E2-) growth plate chondrocytes, indicating biallelic expression of Gsalpha in these cells. Hypertrophy of Gnas(+/E2-) chondrocytes was modestly but significantly premature in chimeric growth plates of mice containing wild-type and Gnas(+/E2-) cells. These data suggest that Gsalpha is the primary mediator of the actions of PPR in growth plate chondrocytes and that there is haploinsufficiency of Gsalpha signaling in Gnas(+/E2-) chondrocytes.

Animals↗
PubMed2004

Deficiency of insulin receptor substrate-1 impairs skeletal growth through early closure of epiphyseal cartilage.

UNLABELLED: Morphological analyses in and around the epiphyseal cartilage of mice deficient in insulin receptor substrate-1 (IRS-1) showed IRS-1 signaling to be important for skeletal growth by preventing early closure of the epiphyseal cartilage and maintaining the subsequent bone turnover at the primary spongiosa. INTRODUCTION: IRS-1 is an essential molecule for intracellular signaling by IGF-I and insulin, both of which are potent anabolic regulators of cartilage and bone metabolism. To clarify the role of IRS-1 signaling in the skeletal growth, morphological analyses were performed in and around the epiphyseal cartilage of mice deficient in IRS-1 (IRS-1(-/-)), whose limbs and trunk were 20-30% shorter than wildtype (WT) mice. MATERIALS AND METHODS: The epiphyseal cartilage and the primary spongiosa at proximal tibias of homozygous IRS-1(-/-) and WT male littermates were compared using histological, immunohistochemical, enzyme cytohistochemical, ultrastructural, and bone histomorphometrical analyses. RESULTS: In and around the WT epiphyseal cartilage, IRS-1 and insulin-like growth factor (IGF)-1 receptors were widely expressed, whereas IRS-2 was weakly localized in bone cells. Chronological observation revealed that height of the proliferative zone and the size of hypertrophic chondrocytes were decreased in WT mice as a function of age, and these decreases were accelerated in the IRS-1 (-/-) cartilage, whose findings at 12 weeks were similar to those of WT at 24 weeks. In the IRS-1(-/-) cartilage, proliferating chondrocytes with positive proliferating cell nuclear antigen (PCNA) or parathyroid hormone (PTH)/PTH-related peptide (PTHrP) receptor immunostaining had almost disappeared by 12 weeks. Contrarily, TUNEL+ apoptotic cells were increased in the hypertrophic zone, at the bottom of which most of the chondrocytes were surrounded by the calcified matrix, suggesting the closure of the cartilage. In the primary spongiosa, bone volume, alkaline phosphatase (ALP)+ osteoblasts, TRACP+ osteoclasts, and the osteopontin-positive cement line were markedly decreased. Bone histomorphometrical parameters for both bone formation and resorption were significantly lower in IRS-1(-/-) mice, indicating the suppression of bone turnover. CONCLUSION: The IRS-1(-/-) epiphyseal cartilage exhibited insufficient proliferation of chondrocytes, calcification of hypertrophic chondrocytes, acceleration of apoptosis, and early closure of the growth plate. Thus, the data strongly suggest that IRS-1 signaling is important for the skeletal growth by preventing early closure of the epiphyseal cartilage and by maintaining the subsequent bone turnover at the primary spongiosa.

Animals↗
PubMed2004

[Recent topics on bone remodeling].

The Wnt signaling pathway has recently been demonstrated to play an important role in regulation of bone formation. LRP5 is thought to signal through the canonical Wnt pathway. In humans, LRP5 loss-of-function mutations lead to low bone mass with fractures, while LRP5 gain-of-function mutations lead to high bone mass, thus identifying LRP5 as an important regulator of bone mass. Patients with sclerosteosis have a severe skeletal disorder with progressive bone overgrowth due to a loss of function of the SOST gene, which implicates its role as a suppressor of bone formation. Recent study revealed that SOST is a BMP antagonist with unique ligand specificity, negatively regulating bone formation by repressing BMP-induced osteoblast differentiation or function or both.

Adaptor Proteins, Signal Transducing↗
PubMed2004

[Ossitication of the posterior longitudinal ligament of spine (OPLL)].

Ossification of the posterior longitudinal ligament of spine (OPLL) is a disease that causes ectopic ossification of the ligament to develop in the spinal canal. Although OPLL causes severe neurologic symptoms caused by spinal cord compression, the mechanisms of OPLL initiation and promotion have not yet been identified. It is a common disease with an incidence of 2-4% in the middle age and older populations of Asian countries, whereas lower incidence has been reported in non-Asian countries. The disorder is believed to be a collective result of heterogeneous etiopathologic factors affecting the spinal ligament.

Animals↗
PubMed2003

Mouse Snail family transcription repressors regulate chondrocyte, extracellular matrix, type II collagen, and aggrecan.

Snail family genes are conserved among species during evolution and encode transcription factors expressed at different stages of development in different tissues. These genes are involved in a broad spectrum of biological functions: cell differentiation, cell motility, cell cycle regulation, and apoptosis. However, little is known about the target genes involved in these functions. Here we show that mouse Snail family members, Snail (Sna) and Slug (Slugh), are involved in chondrocyte differentiation by controlling the expression of type II collagen (Col2a1) and aggrecan. In situ hybridization analysis of developing mouse limb demonstrated that Snail and Slug mRNAs were highly expressed in hypertrophic chondrocytes. Inversely, the expression of collagen type II mRNA disappeared during hypertrophic differentiation. Snail and Slug mRNA expression was down-regulated during differentiation of the mouse chondrogenic cell line ATDC5 and overexpression of exogenous Snail or Slug in ATDC5 cells inhibited expression of collagen type II and aggrecan mRNA. Reporter analysis revealed Snail and Slug suppressed the promoter activity of Col2a1, and the E-boxes in the promoter region were the responsible element. Gel shift assay demonstrated the binding of Snail to the E-box. Because type II collagen and aggrecan are major functional components of extracellular matrix in cartilage, these results suggest an important role for Snail-related transcription repressors during chondrocyte differentiation.

Aggrecans↗
PubMed2002

Insulin receptor substrate-2 maintains predominance of anabolic function over catabolic function of osteoblasts.

Insulin receptor substrates (IRS-1 and IRS-2) are essential for intracellular signaling by insulin and insulin-like growth factor-I (IGF-I), anabolic regulators of bone metabolism. Although mice lacking the IRS-2 gene (IRS-2-/- mice) developed normally, they exhibited osteopenia with decreased bone formation and increased bone resorption. Cultured IRS-2-/- osteoblasts showed reduced differentiation and matrix synthesis compared with wild-type osteoblasts. However, they showed increased receptor activator of nuclear factor kappaB ligand (RANKL) expression and osteoclastogenesis in the coculture with bone marrow cells, which were restored by reintroduction of IRS-2 using an adenovirus vector. Although IRS-2 was expressed and phosphorylated by insulin and IGF-I in both osteoblasts and osteoclastic cells, cultures in the absence of osteoblasts revealed that intrinsic IRS-2 signaling in osteoclastic cells was not important for their differentiation, function, or survival. It is concluded that IRS-2 deficiency in osteoblasts causes osteopenia through impaired anabolic function and enhanced supporting ability of osteoclastogenesis. We propose that IRS-2 is needed to maintain the predominance of bone formation over bone resorption, whereas IRS-1 maintains bone turnover, as we previously reported; the integration of these two signalings causes a potent bone anabolic action by insulin and IGF-I.

Animals↗
PubMed2002

Association of bone metabolism regulatory factor gene polymorphisms with susceptibility to ossification of the posterior longitudinal ligament of the spine and its severity.

STUDY DESIGN: A case-control association study and a stratified study investigating the genetic etiology for ossification of the posterior longitudinal ligament of the spine. OBJECTIVE: To determine the association of restriction fragment length polymorphisms of estrogen receptor, vitamin D receptor, parathyroid hormone, and interleukin-1alpha and -1beta with susceptibility to ossification of the posterior longitudinal ligament of the spine and its severity. SUMMARY OF BACKGROUND DATA: Contribution of genetic backgrounds to the etiology for ossification of the posterior longitudinal ligament of the spine has been suggested by epidemiologic studies. METHODS: Genomic deoxyribonucleic acid samples obtained from 120 patients (77 men and 43 women) with ossification of the posterior longitudinal ligament of the spine and 306 control subjects without the disorder (166 men and 140 women) were amplified by polymerase chain reaction, and polymorphism genotypes were determined by restriction endonuclease digestion. The distribution of genotypes was compared between patients with the disorder and control subjects. In addition, the severity of ossification was determined by the number of ossified vertebrae in patients with the disorder, and associations of the severity with age, gender, and genotypes were examined. RESULTS: Estrogen receptor (P = 0.007) and interleukin-1beta (P = 0.001) polymorphisms exhibited different distributions between patients with ossification of the posterior longitudinal ligament of the spine and control subjects in women, but not in men. In patients with the disorder, the severity of ossification was negatively correlated with age in women (P = 0.013), but not in men. Estrogen receptor polymorphism was associated with the severity only in women (P = 0.001). CONCLUSIONS: The contribution of genetic backgrounds is likely to be stronger in women than in men with ossification of the posterior longitudinal ligament of the spine. Estrogen receptor polymorphism was associated with both initiation and promotion of the disorder, but interleukin-1beta polymorphism was associated only with its initiation in women.

Adult↗
PubMed2002

Nucleotide pyrophosphatase gene polymorphism associated with ossification of the posterior longitudinal ligament of the spine.

Ossification of the posterior longitudinal ligament (OPLL) of the spine is a disease that causes paralysis by compressing the spinal cord. Based on the fact that the nucleotide pyrophosphatase (Npps) gene is responsible for ectopic ossification in ttw, an OPLL model mouse, the possibility was explored whether the human NPPS gene is associated with susceptibility to and severity of OPLL. First, we screened for single-nucleotide polymorphisms (SNPs) in the human NPPS locus using selected 25 OPLL patients with young onset (< 35 years old) or severe ossification (> 10 ossified vertebrae), and identified three novel SNPs in the locus. A case-control association study between 180 OPLL patients and 265 non-OPLL controls showed that one of these SNPs, IVS15-14T --> C substitution, was more frequently observed in OPLL patients (p = 0.022), especially in those with severe ossification (p < 0.0001) and young onset (p = 0.002), than in controls. A stratified study with the number of ossified vertebrae in OPLL patients revealed that IVS15-14T --> C substitution (p = 0.013) as well as young onset (p = 0.046) and female sex (p = 0.006) were associated with severe ossification. We conclude that the IVS15-14T --> C substitution in the human NPPS gene is associated not only with susceptibility to, but also with severity of OPLL.

Adult↗