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Biomedical subjects

Hiroshi Kaji

Publications and source records attributed to Hiroshi Kaji.

At least 19 recordsLinked to original sources
PubMed2006

Parathyroid hormone increases beta-catenin levels through Smad3 in mouse osteoblastic cells.

PTH, via the PTH/PTH-related protein receptor type 1 that couples to both protein kinase A (PKA) and protein kinase C (PKC) pathways, and the canonical Wnt-beta-catenin signaling pathway play important roles in bone formation. In the present study we have examined the interaction between the PTH and Wnt signaling pathways in mouse osteoblastic MC3T3-E1 cells. PTH dose- and time-dependently increased the concentrations of beta-catenin. The PKA activator, forskolin, and the PKC activator, phorbol 12-myristate-13-acetate, as well as the PTH analog, [Nle(8,18),Tyr(34)]human PTH-(3-34)amide, all increased beta-catenin levels. Both H-89, a specific PKA inhibitor, and PKC inhibitors, staurosporine and calphostin C, antagonized PTH stimulation of beta-catenin levels. TGF-beta as well as transfection of the TGF-beta-signaling molecule, Smad3, enhanced beta-catenin levels, and this was antagonized by transfection of a dominant-negative Smad3. The transcriptional activity of transfected dominant-active beta-catenin was enhanced by PTH, an effect that was antagonized by cotransfection of a dominant-negative Smad3. PTH as well as LiCl(2), which mimics the effects of the Wnt-beta-catenin pathway, rescued the dexamethasone- and etoposide-induced apoptosis of osteoblastic cells. In conclusion, the data demonstrate that PTH stimulates osteoblast beta-catenin levels via Smad3, and that both PKA and PKC pathways are involved. The canonical Wnt-beta-catenin pathway is likely to be involved in the antiapoptotic actions of PTH by acting through Smad3 in osteoblasts.

Animals↗
PubMed2006

The threshold of bone mineral density for vertebral fracture in female patients with glucocorticoid-induced osteoporosis.

Glucocorticoid (GC)-induced osteoporosis (GIO) is a serious problem for patients taking GC therapy. GC increases risk for fracture. However, there are controversies regarding the threshold of bone mineral density (BMD) in patients with GIO. The present study aimed to examine the relationship between the presence or absence of vertebral fracture and various indices including BMD in 136 female Japanese patients treated with oral GC (102 patients with autoimmune diseases). Moreover, we analyzed the cut-off values of BMD for incidence of vertebral fracture in patients with oral GC use and compared these values with those in control subjects. BMD was measured by dual-energy X-ray absorptiometry of the lumbar spine, femoral neck, and distal one third of radius. We compared various indices between patients taking oral GC with and without vertebral fracture. Age, body height, and body weight were significantly greater, shorter, and lower in the group with vertebral fracture, respectively. As for BMD, age-matched BMD seemed lower in the fracture group, although the differences were significant between both groups only at the femoral neck. Duration of GC treatment was longer in the fracture group. Cut-off values of BMD at lumbar spine, femoral neck, and distal radius were higher in patients with GC treatment compared with those of control group [GC vs control (g/cm(2)): 0.807 vs 0.716 at lumbar spine; 0.611 vs 0.581 at femoral; 0.592 vs 0.477 at radius]. The sensitivity and specificity were lower in patients with GC treatment compared with those of control group. The present study demonstrated that the thresholds of BMD for vertebral fracture were higher in Japanese female patients with oral GC treatment at any site compared with postmenopausal subjects. The factors other than BMD were considered to affect bone strength and vertebral fracture risk.

Absorptiometry, Photon↗
PubMed2005

Low-dose parathyroid hormone and estrogen reverse alkaline phosphatase activity suppressed by dexamethasone in mouse osteoblastic cells.

Glucocorticoid (GC)-induced osteoporosis (GIO) is frequently seen in patients with excessive GC. Numerous questions remain to be clarified about the pathogenesis and treatment of GIO, and the mechanism of GC-inhibited bone formation is not well known. Several studies suggest that parathyroid hormone (PTH) and hormone replacement therapy are effective for GIO. We therefore investigated whether PTH and estrogen would affect cell proliferation and alkaline phosphatase (ALP) activity inhibited by dexamethasone (Dex) in mouse osteoblastic cell-line MC3T3-E1 cells. Low-dose (10(-11) M) PTH as well as 10(-8) M 17-beta-estradiol (17beta-E2) significantly attenuated Dex-inhibited ALP activity, although 10(-8) M PTH did not affect it. ICI 182780 (10(-8) M) antagonized the effects of 17beta-E(2) on Dex-suppressed ALP activity. Neutralizing anti-IGF-I antibody (3 microg/ml) blocked the reverse effects of 17beta-E2 on ALP activity suppressed by Dex. PTH (10(-11) M), but not 17beta-E2, significantly attenuated [3H]thymidine incorporation inhibited by Dex. On the other hand, PTH and estrogen did not affect the level of 11-beta-hydrosteroid dehydrogenase type I mRNA increased by Dex. In conclusion, the present study demonstrated that low-dose PTH and estrogen reversed Dex-inhibited ALP activity in the mouse osteoblastic cell-line.

11-beta-Hydroxysteroid Dehydrogenases↗
PubMed2005

Effects of age, grip strength and smoking on forearm volumetric bone mineral density and bone geometry by peripheral quantitative computed tomography: comparisons between female and male.

Peripheral quantitative computed tomography (pQCT) is useful to measure volumetric bone mineral density (vBMD) distinguishing trabecular from cortical bones as well as quantity of bone geometry. In the present study, we examined the effects of age, grip strength and smoking on vBMD, bone geometry and bone strength index (polar strength strain index (SSIp)), and then compared with the differences between female and male by employing pQCT in Japanese 252 female and 230 male subjects. Age was negatively correlated with vBMD, cortical area (Ct.Ar) and cortical thickness (Ct.Th) as well as SSIp in both sexes, and the correlation coefficients were higher in female, compared with those in male. Although age was correlated with endocortical circumferences (En.Le) in both sexes, periosteal circumferences (Ex.Le) were correlated with age only in male. Volumetric BMD, Ct.Ar, Ct.Th and SSIp were significantly lower in the group with vertebral fractures, although En.Le and Ex.Le were similar between subjects with and without vertebral fractures. Grip strength was positively correlated with vBMD, Ct.Ar, Ct.Th as well as SSIp. The extent of correlation was much higher in female, compared with that in male. Ct.vBMD, Ct.Ar, Ct.Th and SSIp, but not trabecular vBMD, were significantly lower in the group with high Brinkman index (number of cigarettes smoked per day) x (duration of smoking (years)) in female. These parameters were not significantly different between groups with high and low Brinkman index in male. In conclusion, the present study demonstrated that age, grip strength and smoking affected forearm vBMD, bone geometry and bone strength index by pQCT. These effects were greater in female, compared with those in male.

Absorptiometry, Photon↗
PubMed2005

The threshold of bone mineral density for vertebral fractures in female patients with primary hyperparathyroidism.

BACKGROUND AND OBJECTIVE: Primary hyperparathyroidism (pHPT) is one of the causal diseases that induce secondary osteoporosis. Although patients with pHPT have reduced bone mineral density (BMD) especially at the cortical bone, there have been controversies about risk of fracture. Moreover, no reports have been available about the threshold of BMD for fractures in pHPT patients. METHODS: BMD values were measured by dual-energy x-ray absorptiometry at lumbar spine, femoral neck and distal one third of radius. Various indices were compared in 116 female pHPT patients and 716 control subjects. Moreover, we analyzed relationship between the cut-off values of BMD and the prevalence of vertebral fractures in pHPT and control subjects. RESULTS: The prevalence of subjects with vertebral fractures was lower in pHPT patients, compared with that of control subjects. Age and body height were significantly higher and lower in pHPT women with vertebral fractures, respectively. Lumbar spine BMD was significantly lower in pHPT women with vertebral fractures, presumably due to their increased age. There were no differences in femoral neck and radius BMD or in bone metabolic indices between pHPT women with and without vertebral fractures. On the other hand, age-matched BMD was not significantly different between both groups at any measured site. Cut-off values of BMD at lumbar spine and femoral neck were lower in postmenopausal pHPT patients, compared with those of the postmenopausal control group. Moreover, cut-off values of BMD at radius was much lower in postmenopausal pHPT patients, compared with those of the postmenopausal control group (pHPT vs control (g/cm(2)): 0.670 vs 0.706 at lumbar spine; 0.549 vs 0.570 at femoral; 0.394 vs 0.474 at radius). Sensitivity and specificity of vertebral fractures was lower in pHPT patients, compared with those in control group. CONCLUSIONS: The present cross-sectional study demonstrated that thresholds of BMD for vertebral fractures were lower especially at radial bone in female patients with pHPT, compared with those in the control group.

Absorptiometry, Photon↗
PubMed2005

Dexamethasone suppresses Smad3 pathway in osteoblastic cells.

Central in the pathogenesis of glucocorticoid (GC)-induced osteoporosis is the effects of GC on bone formation. However, the mechanism of GC-inhibited bone formation is not well known. Transforming growth factor (TGF)-beta is most abundant in bone matrix compared with other tissues, and we have recently proposed that Smad3, a TGF-beta signaling molecule, is important for promoting bone formation. However, no reports have been available about the effects of GC on Smad3 in osteoblasts. In the present study, we investigated whether dexamethasone (Dex), an active GC analog, would affect the expression and activity of Smad3 in mouse osteoblastic MC3T3-E1 and rat osteoblastic UMR-106 cells. Dex significantly suppressed Smad3-stimulated alkaline phosphatase (ALP) activity, although it did not affect TGF-beta-inhibited ALP activity in MC3T3-E1 cells. Moreover, pretreatment with Dex suppressed TGF-beta-enhanced expression of type I collagen in MC3T3-E1 and UMR-106 cells. In the luciferase assay using p3TP-Lux with a Smad3-specific response element, Dex significantly suppressed the transcriptional activity induced by TGF-beta as well as Smad3. However, Dex did not affect the expression of Smad3 in these cells at both mRNA and protein levels. In conclusion, the present study indicates that Dex inhibits ALP activity and type I collagen expression, presumably by suppressing Smad3-induced transcriptional activity but not by modulating Smad3 expression in osteoblastic cells.

Alkaline Phosphatase↗
PubMed2005

[Treatment of osteoporosis with parathyroid hormone: evidence and perspective].

Parathyroid hormone (PTH) is a promising bone formation-stimulating agent, and the recent large-scale randomized controlled trial (RCT) revealed that parathyroid hormone increases and reduces lumbar bone mineral density and fracture risk, respectively, more potently than bisphosphonates. Moreover, PTH is also effective for male or glucocorticoid-induced osteoporosis. However, the recent studies showed that the co administration of PTH and bisphosphonate is not good. The further accumulation of evidence about the combined or subsequent therapy is expected.

Bone Density↗
PubMed2005

[The genes related to the effects of vitamin D on muscle and bone].

Vitamin D is most frequently used as a drug for osteoporosis in Japan, and its effects on the maintenance of bone mineral density and inhibition of fracture risk have been shown. Recently, the actions of vitamin D on muscle have been elaborated, and its prevention of falls is noted. Active vitamin D modulates several genes in muscle and bones. The studies using vitamin D receptor deletion mice revealed that active vitamin D modulates the genes related to muscle differentiation and bone resorption.

Animals↗
PubMed2005

[The mechanism of parathyroid hormone action].

PTH is one of the promising bone forming agents. However, its mechanism for bone formation remains unknown. The putative accumulating hypothesis about the mechanism is the following;the involvement of local bone forming growth factors, such as insulin-like growth factor-I, anti-apoptotic actions through Runx2 and Smad3 etc, the transcriptional regulators, such as AP-1 and CREB. The research for the action of PTH would bring the development of effective PTH treatment and the investment of agents, which are more effective to increase bone formation.

Humans↗
PubMed2005

[Clinical analysis of home oxygen therapy in patients with pneumoconiosis at Iwamizawa Rosai Hospital].

Although home oxygen therapy (HOT) has become one of the standard therapies in the management of chronic respiratory failure, especially for patient with hypoxia, there are very few studies about HOT in patients with pneumoconiosis. Therefore, we clinically investigated the characteristics of 97 patients with pneumoconiosis and 30 patients with COPD on home oxygen therapy (HOT) followed at Iwamizawa Rosai Hospital during the period from 1990 to 2003. The mean survival time in patients with pneumoconiosis (42 months) by the Kaplan-Meier method was shorter than in patents with COPD (75 months). Among the patients with pneumoconiosis divided by chest radiography classification of pneumoconiosis, there was no significant difference in mean survival time. The survival time in pneumoconiosis patients with dyspnea grade IV was shorter than in patients with dyspnea grade III.

Aged↗
PubMed2004

Menin suppresses osteoblast differentiation by antagonizing the AP-1 factor, JunD.

Mice null for menin, the product of the multiple endocrine neoplasia type 1 (MEN1) gene, exhibit cranial and facial hypoplasia suggesting a role for menin in bone formation. We have shown previously that menin is required for the commitment of multipotential mesenchymal stem cells into the osteoblast lineage in part by interacting with the bone morphogenetic protein (BMP)-2 signaling molecules Smad1/5, and the key osteoblast transcriptional regulator, Runx2 (Sowa H., Kaji, H., Hendy, G. N., Canaff, L., Komori, T., Sugimoto, T., and Chihara, K. (2004) J. Biol. Chem. 279, 40267-40275). However, menin inhibits the later differentiation of committed osteoblasts. The activator protein-1 (AP-1) transcription factor, JunD, is expressed in osteoblasts and has been shown to interact with menin in other cell types. Here, we examined the consequences of menin-JunD interaction on osteoblast differentiation in mouse osteoblastic MC3T3-E1 cells. JunD expression, assessed by immunoblot, gradually increased during osteoblast differentiation. Stable expression of JunD enhanced expression of the differentiation markers, Runx2, type 1 collagen (COL1), and osteocalcin (OCN) and alkaline phosphatase (ALP) activity and mineralization. Hence, JunD promotes osteoblast differentiation. In MC3T3-E1 cells in which menin expression was reduced by stable menin antisense DNA transfection, JunD levels were increased. When JunD and menin were co-transfected in MC3T3-E1 cells, they co-immunoprecipitated. JunD overexpression increased the transcriptional activity of an AP-1 luciferase reporter construct, and this activity was reduced by co-transfection of menin. Therefore, JunD and menin interact both physically and functionally in osteoblasts. Furthermore, menin overexpression inhibited the ALP activity induced by JunD. In conclusion, the data suggest that menin suppresses osteoblast maturation, in part, by inhibiting the differentiation actions of JunD.

Alkaline Phosphatase↗
PubMed2004

Involvement of calcium-sensing receptor in osteoblastic differentiation of mouse MC3T3-E1 cells.

We have previously shown that the extracellular calcium-sensing receptor (CaR) is expressed in various bone marrow-derived cell lines and plays an important role in stimulating their proliferation and chemotaxis. It has also been reported that the CaR modulates matrix production and mineralization in chondrogenic cells. However, it remains unclear whether the CaR plays any role in regulating osteoblast differentiation. In this study, we found that mineralization of the mouse osteoblastic MC3T3-E1 cells was increased when the cells were exposed to high calcium (2.8 and 3.8 mM) or a specific CaR activator, NPS-R467 (1 and 3 microM). Next, we stably transfected MC3T3-E1 cells with either a CaR antisense vector (AS clone) or a vector containing the inactivating R185Q variant of the CaR (DN clone) that has previously been shown to exert a dominant negative action. Alkaline phosphatase activities were decreased compared with controls in both the AS and DN clones. However, the levels of type I procollagen and osteopontin mRNA in the AS clone, as detected by Northern blotting, were almost the same as in the controls. On the other hand, the expression of osteocalcin, which is expressed at a later stage of osteoblastic differentiation, was significantly reduced in both the AS and DN clones. Mineralization was also decreased in both clones. In conclusion, this study showed that the abolition of CaR function results in diminishing alkaline phosphatase activity, osteocalcin expression, and mineralization in mouse osteoblastic cells. This suggests that the CaR may be involved in osteoblastic differentiation.

3T3 Cells↗
PubMed2004

Menin is required for bone morphogenetic protein 2- and transforming growth factor beta-regulated osteoblastic differentiation through interaction with Smads and Runx2.

Menin, the product of the multiple endocrine neoplasia type 1 (MEN1) gene, is required for commitment of multipotential mesenchymal stem cells to the osteoblast lineage, however, it inhibits their later differentiation (Sowa, H., Kaji, H., Canaff, L., Hendy, G.N., Tsukamoto, T., Yamaguchi, T., Miyazono, K., Sugimoto, T., and Chihara, K. (2003) J. Biol. Chem. 278, 21058-21069). Here, we have examined the mechanism of action of menin in regulating osteoblast differentiation using the mouse bone marrow stromal ST2 and osteoblast MC3T3-E1 cell lines. In ST2 cells, reduced menin expression achieved by transfection of menin antisense DNA (AS) antagonized bone morphogenetic protein (BMP)-2-induced alkaline phosphatase activity and osteocalcin and Runx2 mRNA expression. Menin was co-immunoprecipitated with Smad1/5 in ST2 and MC3T3-E1 cells, and inactivation of menin antagonized BMP-2-induced transcriptional activity of Smad1/5 in ST2 cells, but not MC3T3-E1 cells. Menin was co-immunoprecipitated with the key osteoblast regulator, Runx2, and AS antagonized Runx2 transcriptional activity and the ability of Runx2 to stimulate alkaline phosphatase activity only in ST2 cells but not in MC3T3-E1 cells. In the osteoblast MC3T3-E1 cells, transforming growth factor-beta and its signaling molecule, Smad3, negatively regulated Runx2 transcriptional activity. Menin and Smad3 were co-immunoprecipitated, and combined menin and Smad3 overexpression antagonized, whereas menin and the dominant-negative Smad3DeltaC together enhanced BMP-2-induced transcriptional activity of Smad1/5 and Runx2. Smad3 alone had no effect. Therefore, menin interacts physically and functionally with Runx2 in uncommitted mesenchymal stem cells, but not in well differentiated osteoblasts. In osteoblasts the interaction of menin and the transforming growth factor-beta/Smad3 pathway negatively regulates the BMP-2/Smad1/5- and Runx2-induced transcriptional activities leading to inhibition of late-stage differentiation.

3T3 Cells↗
PubMed2004

Menin inactivation leads to loss of transforming growth factor beta inhibition of parathyroid cell proliferation and parathyroid hormone secretion.

Primary hyperparathyroidism is a common endocrine disorder caused by parathyroid gland enlargement and excessive parathyroid hormone (PTH) secretion. However, the precise mechanisms of tumorigenesis of the parathyroids are unknown. Here we have investigated the roles of transforming growth factor (TGF)-beta and menin, the product of the multiple endocrine neoplasia type 1 (Men1) gene, in the proliferation and PTH production of parathyroid cells from either patients with secondary hyperparathyroidism or Men1. TGF-beta was expressed in the parathyroid endocrine cells. Addition of TGF-beta to parathyroid cells from patients with secondary hyperparathyroidism inhibited their proliferation and PTH secretion. These responses to TGF-beta were lost when menin was specifically inactivated by antisense oligonucleotides. Moreover, TGF-beta did not affect the proliferation and PTH production of parathyroid cells from a Men1 patient. These results indicate that menin is required for TGF-beta action in the parathyroid. We conclude that TGF-beta is an important autocrine/paracrine negative regulator of parathyroid cell proliferation and PTH secretion and that loss of TGF-beta signaling due to menin inactivation contributes to parathyroid tumorigenesis.

Cell Division↗
PubMed2004

[A case of chronic pulmonary paracoccidioidomycosis].

In a 43-year-old Japanese Brazilian who came to Japan in 2001, since subjective symptoms such as cough, sputum, and dyspnea on exertion had become severe, he was referred to our hospital because of suspicion of pulmonary tuberculosis in chest radiography and CT findings. A chest radiograph of initial examination showed interstitial shadows in both lungs with nodular, infiltrative or cavitary changes. No Mycobacterium tuberculosis was found. The mycetocyte with multipolar budding resembling the steerage of a ship, which was characteristic of Paracoccidioides was observed in sputum and transbronchial lung biopsy specimens. We cultured a fungus to show dimorphism of temperature dependency, and a diagnosis of chronic lung paracoccidioidomycosis was arrived at. By administration of ITCZ 200 mg/day, the chest radiography findings and clinical manifestations were improved. This case seems to be worthy of reporting in Japan since the affected site or organ was limited to the two lungs with multiple cavitary lesions and fibrotic changes on radiographic examination, and final diagnosis was made by cytology of sputum and pathology of TBLB specimens.

Antifungal Agents↗