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Toshitaka Nakamura

Publications and source records attributed to Toshitaka Nakamura.

At least 19 recordsLinked to original sources
PubMed2026

Cysteine excess triggers a mitochondrial iron-dependent cell death.

Thiol-containing metabolites are central to cellular redox homeostasis1. Among these, cysteine functions as a proteogenic amino acid, supports redox balance and iron-sulfur cluster biogenesis, and, when depleted, triggers ferroptosis2. Cells nevertheless maintain cysteine at low levels, reflecting its intrinsic toxicity, but the mechanisms by which excess cysteine causes cell death remain unclear3. Here we performed a genome-wide CRISPR screen and identified mitochondrial iron transporters as essential mediators of cysteine toxicity. Limiting mitochondrial iron availability suppresses cysteine-induced cell death and prevents impairment of iron-sulfur cluster proteins and respiration. Mechanistically, cysteine mobilizes iron from ferritin, expands the cytosolic iron pool and drives mitochondrial iron accumulation. Enhancing glutathione reductase activity specifically within mitochondria restores redox balance downstream of iron accumulation and protects cells by maintaining iron-sulfur cluster integrity. Our findings suggest that maintaining low cysteine levels safeguards mitochondrial iron homeostasis, and that excess cysteine triggers a distinct mitochondrial iron-dependent cell death under conditions of thiol imbalance.

Journal Article↗
PubMed2007

Q89R polymorphism in the LDL receptor-related protein 5 gene is associated with spinal osteoarthritis in postmenopausal Japanese women.

STUDY DESIGN: An association study investigating the genetic etiology for spinal osteoarthritis. OBJECTIVE: To determine the association of single-nucleotide polymorphism (SNP) causing an amino-acid change (Q89R) in the low-density lipoprotein receptor-related protein 5 (LRP5) coding region with spinal osteoarthritis. SUMMARY OF BACKGROUND DATA: Wnt/beta-catenin signaling pathway regulates bone density through a Wnt coreceptor LRP5. This pathway is also involved in cartilage development and homeostasis, suggesting that genetic variation in LRP5 gene may affect the pathogenesis of cartilage-related diseases, such as osteoarthritis. METHODS: We evaluated the presence of osteophytes, endplate sclerosis, and narrowing of disc spaces in 357 Japanese postmenopausal women. Missense coding SNP for Q89R of LRP5 gene was determined using TaqMan polymerase chain reaction (PCR) method. RESULTS: We found that subjects without the R allele (QQ; n = 321) had a significantly lower osteophyte formation score than did subjects bearing at least one R allele (QR + RR; n = 36) (7.80 vs. 10.89, P = 0.0019 by analysis of covariance). CONCLUSIONS: We suggest that a genetic variation at the LRP5 gene locus is associated with spinal osteoarthritis, in line with the involvement of the LRP5 gene in the bone and cartilage metabolism.

Aged↗
PubMed2007

Local application of recombinant human fibroblast growth factor-2 on bone repair: a dose-escalation prospective trial on patients with osteotomy.

Based on preclinical evidence in animal models, the present study examined the clinical efficacy and safety of recombinant human fibroblast growth factor-2 (rhFGF-2) to accelerate bone repair in a dose-escalation prospective trial. One of three dosages (200, 400 or 800 microg) of rhFGF-2 in a biodegradable gelatin hydrogel was injected during surgery into the osteotomy site of 59 knee osteoarthritis patients undergoing high tibial osteotomy, and 57 of them were monitored for 16 weeks. The rhFGF-2 dose dependently increased the percentage of patients with radiographic bone union, and decreased the average time needed for such union. The percentages of patients with an absence of pain and full-weight bearing were also greater in the higher dosage groups than in the low dosage group, especially in the clinically critical periods 6, 8, and 10 weeks. Neither blood chemistries nor clinical adverse events were associated with the rhFGF-2 dosages. We therefore conclude that the rhFGF-2 in gelatin hydrogel dose dependently accelerated radiographic bone union of a surgical osteotomy with a safety profile at least at the dosages used, suggesting the clinical efficacy of this agent for bone repair.

Adult↗
PubMed2007

[Therapeutic agents for disorders of bone and calcium metabolism. Osteoporotic fracture prevention by strontium ranelate].

Bone loss results in osteoporosis and increased susceptibility to bone fractures. Importantly, osteoporosis is a major cause of morbidity and mortality in the elderly population. With a constantly increasing aging population worldwide, early prevention of bone loss is essential for adequate control of this condition. Strontium ranelate, an oral treatment for postmenopausal osteoporosis, is unique in its mode of action as it is the sole anti-osteoporotic agent that both decreases bone resorption and increases bone formation. Its efficacy to reduce vertebral and non-vertebral fractures including those of the hip, in addition to its safety profile has been demonstrated in the Spinal Osteoporosis Therapeutic Intervention (SOTI) and Treatment of Peripheral Osteoporosis (TROPOS) clinical studies over 3 years and recently confirmed over the long-term. Furthermore, a pre-planned analysis of a sub-group of patients aged 80 years and over demonstrated that, currently, strontium ranelate is the only anti-osteoporotic agent to reduce vertebral and non-vertebral fractures in this age group.

Administration, Oral↗
PubMed2006

A functional single nucleotide polymorphism in the vitamin-K-dependent gamma-glutamyl carboxylase gene (Arg325Gln) is associated with bone mineral density in elderly Japanese women.

The vitamin-K-dependent gamma-glutamyl carboxylase (GGCX) carboxylates vitamin-K-dependent proteins including bone Gla protein (osteocalcin) and matrix Gla protein, which play important roles in bone metabolism. Therefore, GGCX polymorphism might explain in part individual susceptibility to osteoporosis. In the present study, polymorphisms in the exons of this gene were screened in Japanese elderly women and a non-synonymous single nucleotide polymorphisms (SNP) were found; c.8762 G>A; (Arg325Gln). When the kinetic parameters of GGCX325-Gln and GGCX325-Arg were compared in vitro, Vmax/Km was significantly higher for GGCX325-Gln (944.4+/-9.21 pmol/30 min/mg/mM FLEEL) than for GGCX325-Arg (671.9+10.79 pmol/30 min/mg/mM FLEEL) (p=0.018). Then, association study of this polymorphism with forearm bone mineral density (BMD) of Japanese postmenopausal women (n=500, age 73.6+/-5.74) was conducted. As a result, the body mass index (BMI)-adjusted Z score in the subpopulation older than 75 years (n=207) was higher in those with 325-Gln (0.650+/-0.883, mean+/-SD) than those with 325-Arg/Gln or 325-Arg (0.133+/-0.650) (p=0.0383). This is the first report to demonstrate the different activities of GGCX between the common genotypes and their association with BMD.

Aged↗
PubMed2006

The short chain sugar acid, 2-buten-4-olide, activates oxytocin-secreting neurons but not arginine vasopressin-secreting neurons in the hypothalamus of rats.

The effects of intraperitoneal (i.p.) administration of 2-buten-4-olide (2-B4O), an endogenous sugar acid, on the hypothalamo-neurohypophyseal system were examined in rats. Plasma oxytocin (OXT) levels were significantly increased 15-60 min after i.p. administration of 2-B4O (100 mg/kg), whereas plasma arginine vasopressin (AVP) did not change. Dual immunostaining revealed that Fos-like immunoreactivity (LI) was predominantly observed in OXT-secreting neurons in the paraventricular (PVN) and the supraoptic nuclei (SON) 120 min after i.p. administration of 2-B4O. In addition, many Fos-LI neurons were observed in the nucleus of the tractus solitarius (NTS) after i.p. administration of 2-B4O. These results suggest that a peripherally administered high dose of 2-B4O activates OXT-secreting neurons in the hypothalamus through activation of NTS neurons, possibly as a result of a stress response.

4-Butyrolactone↗
PubMed2006

Cyclooxygenase-2 selective inhibition suppresses restoration of tibial trabecular bone formation in association with restriction of osteoblast maturation in skeletal reloading after hindlimb elevation of mice.

To clarify the role of cyclooxygenase-2 (COX-2) in acute recovery of trabecular bone in reloaded hindlimbs of tail-suspended mice, we administered a COX-2 selective inhibitor in the mice during the reloading period after unloading. Experiments were conducted on 140 male C57BL/6J mice (8 weeks old). They were divided into ground control (GC) and unloading by tail suspension (UL) groups. On day 7, Group GC was divided into Groups GC+Vehicle (Veh) and GC+Celecoxib (Cel), while Group UL mice were fed on the ground [reloading (RL)] after 7-day unloading and were then divided into Groups RL+Veh and RL+Cel. Bone histomorphometry, osteogenic cell development, and mRNA expression of osteogenic molecules were assessed. At 5 days after reloading, the increase of bone formation rate and the ratio of osteocalcin mRNA expression per CFU-f colony in Group RL+Cel were significantly decreased compared with those in Group RL+Veh, while alkaline phosphatase-positive (ALP+) CFU-f formation and the ratios of cbfa-1, osterix, and type 1 collagen mRNA expression per CFU-f colony increased to the same levels in both RL groups. At 14 days after reloading, decreased bone volume by unloading in RL+Veh recovered to the same level as that of GC+Veh, but that in RL+Cel did not recover completely. The increase of c-fos mRNA expression in bone marrow cells at 1, 24, and 48 h after reloading, osteocalcin mRNA at 6 h, and osterix mRNA at 24 h were suppressed by COX-2 inhibitor. These data indicate that the COX-2 selective inhibitor celecoxib suppresses the restoration of tibial trabecular bone formation and the acute recovery of trabecular bone. These actions are closely related to restriction of c-fos and osteocalcin mRNA expressions and osteoblast differentiation in bone marrow cells.

Animals↗
PubMed2006

The sample size required for intervention studies on fracture prevention can be decreased by using a bone resorption marker in the inclusion criteria: prospective study of a subset of the Nagano Cohort, on behalf of the Adequate Treatment of Osteoporosis (A-TOP) Research Group.

In drug developments for osteoporosis, large-scale and longterm fracture prevention studies have been required. We investigated whether or not it was possible to reduce the sample size and observation period under new selection criteria for an osteoporotic fracture-prevention study. A Poisson regression model was used to identify independent risks for incident vertebral fracture in 515 postmenopausal women who had had no intervention for osteoporosis; this group was a subset of Nagano Cohort participants. The total observation period for this group was 2,577 person-years, and a total of 146 new vertebral fractures were observed. Risk assessment for incident vertebral fracture among numerical covariates revealed that the following items showed significant independent risks for incident fractures; namely, baseline age (hazard ratio [HR]; 1.84; 95% confidence interval (CI), 1.44-2.35; P < 0.001), number of preexisting vertebral fractures (HR, 1.28; 95% CI, 1.17-1.40; P < 0.001), baseline lumbar bone mineral density (LBMD) (HR, 0.79; 95% CI, 0.71-0.88; P < 0.001), and urinary excretion of deoxypyridinoline (DPD) (HR, 1.18; 95% CI, 1.03-1.35; P = 0.016). Because the initial urinary excretion of DPD was found to be a risk for incident vertebral fracture, in addition to the conventional risks, we assessed whether or not the sample size or observation period could be reduced by the incorporation of the urinary excretion of DPD into the selection criteria of a fracture-prevention study. The assessment of sample size was calculated, using the log rank test, at a two-tailed significance level of 5% and with a power of 80%. When osteoporotic patients with preexisting fracture were selected (conventional criteria), the 3-year probability of vertebral fracture was estimated as 14.3% in the present population. On the other hand, the new vertebral fracture rate during 3 years in the osteoporotic patients with preexisting fracture plus high urinary DPD (HR, above 1.0); (new selection criteria) was estimated as 23.2%. When the HR between test drug and placebo was changed from 0.4 to 0.8, the required sample size for any level of HR showed a 40% reduction for the new selection criteria compared to the conventional criteria. Therefore, the addition of urinary DPD level to the selection criteria is useful to reduce sample size in an osteoporosis fracture-prevention study.

Aged↗
PubMed2006

Prevalence and involvement patterns of radiographic hand osteoarthritis in Japanese women: the Hizen-Oshima Study.

The prevalence and pattern of joint involvement in radiographic hand osteoarthritis (OA) have been reported in Western populations, but similar data are lacking for Japanese. We examined this issue in 551 Japanese women aged > or = 40 years. Radiographs were obtained of both hands and graded according to the Kellgren-Lawrence (K-L) criteria. OA was defined as K-L grade 2 or higher. The prevalence of radiographic OA in the IP, MCP, and CMC joints was distributed similarly in both hands. The most frequent locations of radiographic OA were the distal IP joints of the index finger, the IP joint of the thumb, and the distal IP joints of the middle finger, in this order. The prevalence of radiographic OA in each joint group increased significantly with age, and that in Japanese women was lower in the thumb CMC joint and higher in the thumb IP joint compared to those in Caucasian women reported previously. The strongest predictor for the presence of radiographic OA in a particular joint was the disease status in the same joint of the opposite hand (OR = 18.5; 95% CI; 15.2-22.7), followed by the joints in the same row of the same hand (OR = 15.5; 95% CI, 11.9-20.1), and then by the joints in the same ray of the same hand (OR = 1.3; 95% CI, 1.0-1.6). Although the prevalence of hand OA is likely to show site-specific differences between Japanese and Caucasian women, our results indicate that both groups show similar involvement pattern symmetrically and in the same row of the same hand.

Aged↗
PubMed2006

Effect of raloxifene on clinical fractures in Asian women with postmenopausal osteoporosis.

Osteoporosis is becoming a major public health problem in Asian countries, with a rapid increase in osteoporotic fractures projected as urbanization increases, particularly in China. The purpose of this post hoc analysis was to assess the effects of 12 months of treatment with raloxifene on the incidence of clinical fractures in postmenopausal Asian women, compared to a placebo, by combining two independently designed studies (one Japanese study and one Chinese study). A total of 488 women, 284 in Japan and 204 in China were included in the analysis. Baseline characteristics (mean +/- SD) for the Japanese and Chinese women were: age, 64.8 +/- 6.3 years and 65.3 +/- 6.0 years; body mass index, 21.8 +/- 2.8 kg/m(2) and 23.0 +/- 2.9 kg/m(2); and prevalent vertebral fractures, 26.4% and 13.7%, respectively. In both studies, the clinical vertebral and nonvertebral fractures were confirmed by radiographs or clinical reports at a central research facility. From the two combined studies, the incidence of new clinical vertebral fractures was significantly lower in the raloxifene 60 mg/day (RLX60) group (0 out of 194, P = 0.01) and in the pooled raloxifene group (those taking 60 mg/day and those taking 120 mg/day) (0 out of 289, P = 0.002), compared with the placebo group (7 out of 199, 3.5%). The pooled raloxifene group, as well as the RLX60 group, also had a significantly lower incidence of any new clinical fracture (P = 0.001 and P = 0.01, respectively) compared to the placebo group. In conclusion, raloxifene treatment at 60 mg/day for 1 year resulted in a significant reduction in the risk of new clinical vertebral fractures and any new clinical fracture in postmenopausal Asian women with osteoporosis.

Aged↗
PubMed2006

Efficacy and tolerability of once-weekly administration of 17.5 mg risedronate in Japanese patients with involutional osteoporosis: a comparison with 2.5-mg once-daily dosage regimen.

In this multicenter, randomized, double-blind controlled trial, the efficacy and safety of once-weekly dosing with 17.5 mg risedronate was compared with once-daily dosing with 2.5 mg risedronate in Japanese patients with involutional osteoporosis. A total of 496 patients were randomized to receive either once-weekly (n = 249) or once-daily (n = 247) treatment. All patients were supplemented with 200 mg/day calcium. Following 48 weeks of treatment, the mean (+/-SD) percent changes, from baseline, in the bone mineral density of the lumbar spine (L2-L4 BMD) in the once-weekly and once-daily treatment groups were 5.36 +/- 4.27% and 5.87 +/- 4.47%, respectively. The difference between the groups was -0.5% (95% confidence interval: -1.35% to 0.35%), demonstrating that the effect on BMD of once-weekly treatment was not inferior to that of once-daily treatment. The time-course reductions in biochemical markers of bone resorption (urinary N- and C-telopeptide of type I collagen) and bone formation (bone-specific alkaline phosphatase) were similar for the two dosing regimens. There were no differences in the incidence of new vertebral fractures or the worsening of existing fractures between the once-weekly (2.2%) and once-daily (2.7%) dosing regimens. No significant differences were observed between the two dosing regimens in the incidence or the type of adverse events. However, 10.1% of the patients in the once-daily group withdrew due to adverse events as compared to 5.2% in the once-weekly group. Moreover, drug-related adverse events, including upper gastrointestinal disorders and abnormal changes in laboratory parameters, tended to be less in the once-weekly dosing regimen than in the once-daily dosing regimen. In conclusion, once-weekly oral dosing with 17.5 mg risedronate was well tolerated in Japanese osteoporotic patients, and showed equivalent efficacy to once-daily oral dosing with 2.5 mg risedronate. This once-weekly regimen is expected to provide a more convenient therapeutic option as an alternative to daily dosing and to enhance patient compliance in long-term therapy for osteoporosis.

Aged↗
PubMed2006

Report on the Japanese Orthopaedic Association's 3-year project observing hip fractures at fixed-point hospitals.

BACKGROUND: The aim of this study was to assess the disability and mortality of hip fractures 1 year after initial visit (postoperatively) at fixed-point hospitals selected by the Japanese Orthopaedic Association Committee on Osteoporosis. METHOD: A total of 158 core orthopedic hospitals were selected for participation in this research. Subjects were all aged 65 years and older with hip fractures at the selected hospitals between January 1, 1999 and December 31, 2001. A prognostic survey of activities of daily living (ADL), assessed by the long-term care insurance criteria established by the Ministry of Health, Labour, and Welfare of Japan was performed 1 year after the initial visit. RESULTS: A total of 1992 hip fractures in patients aged 65 to 111 years were treated over the 3 years from 1999 to 2001. Among the 1992 patients, 4537 had femoral neck fractures and 6217 had trochanteric fractures. Surgical treatment was chosen for 85.6% of the femoral neck fractures and 88.2% of the trochanteric fractures. The mean duration from fracture to admission was 3.1 days, and the mean duration from admission to surgery was 11.2 days. The mean duration from surgery to discharge over the 3-year period was 49.8 days. Before hip fracture, the ratio of patients with J1 ("able to go out freely utilizing public transportation") or J2 ("able to visit immediate neighbors independently") on the long-term care insurance criteria was 50.9%. At 1 year after the initial visit, that result represented a decrease of 24.1 percentage points before hip fracture. A total of 70 patients died before undergoing surgery. In the present study, the 1-year mortality rate for the entire patient population over the 3-year period was 10.1%. CONCLUSIONS: Hip fracture patients show a decrease in the ADL score 1 year after the initial visit. Compared to other countries, the duration of hospitalization is longer in Japan, but the mortality rate is lower.

Age Distribution↗
PubMed2006

Effects of unipedal standing balance exercise on the prevention of falls and hip fracture among clinically defined high-risk elderly individuals: a randomized controlled trial.

BACKGROUND: The aim of this study was to assess the effectiveness of the unipedal standing balance exercise for 1 min to prevent falls and hip fractures in high-risk elderly individuals with a randomized controlled trial. This control study was designed as a 6-month intervention trial. SUBJECTS: Subjects included 553 clinically defined high-risk adults who were living in residences or in the community. They were randomized to an exercise group and a control group. METHODS: Randomization to the subjects was performed by a table of random numbers. A unipedal standing balance exercise with open eyes was performed by standing on each leg for 1 min three times per day. As a rule, subjects of the exercise group stood on one leg without holding onto any support, but unstable subjects were permitted to hold onto a bar during the exercise time. Falls and hip fractures were reported by nurses, physical therapists, or facility staff with a survey sheet every month. This survey sheet was required every month for both groups. RESULTS: Registered subjects were 553 persons ranging in age from 37 to 102 years (average, 81.6 years of age). Twenty-six subjects dropped out. The number of falls and hip fractures for the 6-month period after the trial for 527 of the 553 subjects for whom related data were available were assessed. The exercise group comprised 315 subjects and the control group included 212 subjects. The cumulative number of falls of the exercise group, with 1 multiple faller omitted, was 118, and the control group recorded 121 falls. A significant intergroup difference was observed. However, the cumulative number of hip fractures was only 1 case in both groups. This difference was not statistically significant. CONCLUSIONS: The unipedal standing balance exercise is effective to prevent falls but was not shown to be statistically significant in the prevention of hip fracture in this study.

Accidental Falls↗
PubMed2006

Enhanced intraarticular free radical reactions in adjuvant arthritis rats.

One of the reasons of rheumatoid arthritis (RA) development is widely recognized the relation of free radical reactions in tissue injuries. The aim of this study was to evaluate the location where in vivo free radical reactions was enhanced in adjuvant arthritis (AA) model rats using in vivo electron spin resonance (ESR)/nitroxyl spin probe technique. The signal decay after intravenous injection of spin probe was enhanced in AA than that in control and suppressed by the pre-treatment of dexamethasone (DXT). Interestingly, the decay in joint cavity occurred prior to paw swelling of AA and suppressed by a simultaneous injection of free radical scavengers, indicating that the enhancement of free radical reactions in joint cavity of AA rats. This technique would be useful tool to determine the location of the enhanced free radical reactions and evaluate the activity of antioxidant medicine with non-invasive real-time measurement.

Adjuvants, Immunologic↗
PubMed2006

Enlargement of cervical spinal cord correlates with improvement of motor function in upper extremities after laminoplasty for cervical myelopathy.

OBJECTIVE: The correlation between postoperative spinal cord enlargement at the most compressive disc level and clinical outcome is controversial. The relationship between spinal cord enlargement at neurologically symptomatic disc level and clinical recovery has not been explored. The purpose of this study was to clarify the relationship between postoperative spinal cord enlargement at neurologically symptomatic disc level and neurologic outcome. METHODS: We studied 55 consecutive patients between 1995 and 2002. All patients underwent preoperative neurologic examination to determine the neurologically symptomatic disc level of the spinal cord and computed tomographic myelography twice before and 4 weeks after laminoplasty. The cross-sectional areas of both spinal cord and dural sac from C3/4 to C7/T1 disc levels were measured on computed tomographic myelography images. The Japanese Orthopedic Association scoring system was used for clinical evaluation before and 1 year after surgery. RESULTS: Total score improved significantly from 10.2+/-2.8 (SD) to 13.0+/-3.0 after operation. Motor and sensory function scores of upper and lower extremities also improved significantly. The enlargement of spinal cord area at the neurologically symptomatic disc level correlated significantly with improvement in motor function scores of upper extremities (rs=0.421 P=0.0052). However, there were no significant relationships between the enlargement of the spinal cord at the most compressive disc level or that at the dural sac and any categories of Japanese Orthopedic Association scoring system. CONCLUSION: Postsurgical enlargement of the cervical spinal cord at the neurologically symptomatic disc level at 4 weeks postoperatively correlated with recovery of motor function of the upper extremities at 1 year.

Cervical Vertebrae↗
PubMed2006

Centrally administered neuropeptide W-30 activates magnocellular neurosecretory cells in the supraoptic and paraventricular nuclei with neurosecretion in rats.

We examined the effects of i.c.v. administration of neuro-peptide W-30 (NPW30) on plasma arginine vasopressin (AVP) and plasma oxytocin (OXT) using RIA. The induction of c-fos mRNA, AVP heteronuclear (hn)RNA, and c-Fos protein (Fos) in the supraoptic nucleus (SON) and paraventricular nucleus (PVN) of rats were also investigated using in situ hybridization histochemistry for c-fos mRNA and AVP hnRNA, and immunohistochemistry for Fos. Both plasma AVP and OXT were significantly increased at 5 and 15 min after i.c.v. administration of NPW30 (2.8 nmol/rat). In situ hybridization histochemistry revealed that the induction of c-fos mRNA and AVP hnRNA in the SON and PVN were significantly increased 15, 30, and 60 min after i.c.v. administration of NPW30 (1.4 nmol/rat). Dual immunostaining for Fos/AVP and Fos/OXT revealed that both AVP-like immunoreactive (LI) cells and OXT-LI cells exhibited nuclear Fos-LI in the SON and PVN, 90 min after i.c.v. administration of NPW30 (2.8 nmol/rat). These results suggest that central NPW30 may be involved in the regulation of secretion of AVP and OXT in the magnocellular neurosecretory cells in the SON and PVN.

Animals↗