Primary peritoneal cancer: study of 14 cases and comparison with epithelial ovarian cancer.

PURPOSE OF INVESTIGATION: Primary peritoneal carcinoma (PPC) is histologically similar to ovarian serous carcinoma, but its biochemical features remain obscure. The authors investigated and compared clinical findings, treatments, and outcomes of patients with PPS and those with epithelial ovarian cancer (EOC) patients. MATERIALS AND METHODS: The authors retrospectively reviewed data from 14 patients with PPC and 219 patients with EOC treated at the present hospital from January 2005 to December 2012, including demographic data, pathologic findings, treatments, and outcomes. RESULTS: Patients with PPC were significantly older (62.6 ± 8.4 years) than those with EOC (56.3 ± 11.3 years) (p = 0.045). There was no significant difference in serum CA-125 levels. The five-year survival rates did not differ significantly between patients with PPC (61.1%) and those with EOC (60.3%; p = 0.78); nor between patients with PPC and those with Stage III serous EOC (43.8%; p = 0.40). CONCLUSIONS: Treatment strategies for EOC applied to PPC apparently led to similar survival patterns among the two patient groups. Cytoreductive surgery combined with pre/postoperative platinum-containing chemotherapy may be effective for PPC patients.

In situ electrochemical regeneration of active 1,4-NADH for enzymatic lactic acid formation via concerted functions on Pt-modified TiO2/Ti.

Nicotinamide adenine dinucleotide (NAD+) and its reduced form (NADH) are key cofactors serving as essential hydrogen acceptors and donors to facilitate energy and material conversions under mild conditions. We demonstrate direct electrochemical conversion to achieve highly efficient regeneration of enzymatically active 1,4-NADH using a Pt-modified TiO2 catalyst grown directly on a Ti mesh electrode (Pt-TOT). Spectral analyses revealed that defects formed by the inclusion of Pt species in the lattice of TiO2 play a critical role in the regeneration process. In particular, Pt-TOT containing approximately 3 atom% of Pt exhibited unprecedented efficiency in the electrochemical reduction of NAD+ at the lowest overpotential to date. This exceptional performance led to the production of active 1,4-NADH with a significantly high yield of 86 ± 3% at -0.6 V vs. Ag/AgCl (-0.06 V vs. RHE) and an even higher yield of 99.5 ± 0.4% at a slightly elevated negative potential of -0.8 V vs. Ag/AgCl (-0.2 V vs. RHE). Furthermore, the electrochemically generated NADH was directly applied in the enzymatic conversion of pyruvic acid to lactic acid using lactate dehydrogenase.

Undercarboxylated osteocalcin is positively associated with free testosterone in male patients with type 2 diabetes mellitus.

UNLABELLED: Although a recent study showed that undercarboxylated osteocalcin (ucOC) is important for male fertility and testosterone production by testes, little is known about the relationship between ucOC and testosterone in humans. We found for the first time that ucOC is positively associated with free testosterone in men with type 2 diabetes. INTRODUCTION: The ucOC has been shown to play a key role in energy metabolism as an endocrine hormone. Although a recent animal study demonstrated that ucOC is also important for male fertility and testosterone production by the testes, association between serum osteocalcin and testosterone levels has not been understood in humans. METHODS: Sixty-nine male patients with type 2 diabetes were recruited and chemical bone markers [total osteocalcin (TOC), ucOC, bone-specific alkaline phosphatase (BAP), and urinary N-terminal cross-linked telopeptide of type I collagen (uNTX)], gonadotropic hormones [luteinizing hormone (LH) and follicle-stimulating hormone (FSH)], and free testosterone (FT) were measured. RESULTS: Multiple regression analysis showed that ucOC and ucOC/TOC ratio were associated positively with FT and negatively with LH (for ucOC, ß = 0.30, p = 0.042 and ß = -0.52, p = 0.048; for ucOC/TOC ratio, ß = 0.31, p = 0.031 and ß = -0.54, p = 0.036, respectively) independently of age, duration of diabetes, body mass index, and hemoglobin A1c. ucOC and ucOC/TOC ratio were significantly associated with FT even after adjusting for LH and FSH (ß = 0.24, p = 0.042 and ß = 0.25, p = 0.031, respectively). However, neither TOC, BAP, nor uNTX was associated with the gonadotropic hormones or FT levels. CONCLUSIONS: The present study indicates for the first time that ucOC is associated positively with FT and negatively with LH in type 2 diabetes. These findings support the recent evidence that ucOC is involved in testosterone production in male subjects.

The loss of ions from Venus through the plasma wake.

Venus, unlike Earth, is an extremely dry planet although both began with similar masses, distances from the Sun, and presumably water inventories. The high deuterium-to-hydrogen ratio in the venusian atmosphere relative to Earth's also indicates that the atmosphere has undergone significantly different evolution over the age of the Solar System. Present-day thermal escape is low for all atmospheric species. However, hydrogen can escape by means of collisions with hot atoms from ionospheric photochemistry, and although the bulk of O and O2 are gravitationally bound, heavy ions have been observed to escape through interaction with the solar wind. Nevertheless, their relative rates of escape, spatial distribution, and composition could not be determined from these previous measurements. Here we report Venus Express measurements showing that the dominant escaping ions are O+, He+ and H+. The escaping ions leave Venus through the plasma sheet (a central portion of the plasma wake) and in a boundary layer of the induced magnetosphere. The escape rate ratios are Q(H+)/Q(O+) = 1.9; Q(He+)/Q(O+) = 0.07. The first of these implies that the escape of H+ and O+, together with the estimated escape of neutral hydrogen and oxygen, currently takes place near the stoichometric ratio corresponding to water.

Clustered base substitutions in CTP synthetase conferring drug resistance in Chinese hamster ovary cells.

Dominantly acting mutations that eliminate the allosteric regulation of CTP synthetase confer a form of multidrug resistance and a mutator phenotype to cultured Chinese hamster ovary cells. Mutations responsible for this phenotype have been identified in 23 independent strains selected for resistance to arabinosyl cytosine and 5-fluorouracil. All these mutations were due to base substitutions at seven sites within a highly conserved region of the ctps gene. This clustering should make it feasible to assess the role of such mutations in the development of drug resistance encountered in the treatment of malignant disease.

Role of glycosaminoglycans of biglycan in BMP-2 signaling.

Recently we have reported that biglycan (BGN) promotes osteoblast differentiation and that this function is due in part to its ability to positively modulate bone morphogenetic protein (BMP) functions. In this study we investigated the role of glycosaminoglycans (GAGs) of BGN in this function using in vitro and in vivo models. C2C12 myogenic cells were treated or untreated with BMP-2 alone or in combination with glycanated, partially glycanated or de-glycanated BGN, and the effects on BMP signaling and function were assessed by Smad1/5/8 phosphorylation and alkaline phosphatase (ALP) activity. Furthermore, the effect of de-glycanation of BGN on BMP-2 induced osteogenesis was investigated employing a rat mandible defect model. The defects were filled with collagen scaffolds loaded with glycanated or de-glycanated BGN alone or in combination with a sub-optimal dose of BMP-2 (subBMP). In in vitro experiments, BMP signaling and function were the greatest when BMP-2 was combined with de-glycanated BGN among the groups tested. In the rat mandible experiments, µCT analyses revealed that the newly formed bone was significantly increased only when subBMP was combined with de-glycanated BGN. The data indicate that the GAG component of BGN functions as a suppressor for the BGN-assisted BMP function.

Serum undercarboxylated osteocalcin was inversely associated with plasma glucose level and fat mass in type 2 diabetes mellitus.

UNLABELLED: Although recent animal studies have shown that undercarboxylated osteocalcin acts as a hormone regulating glucose metabolism and fat mass, little is known about the relationships in humans. We reported here for the first time that undercarboxylated osteocalcin were associated with glucose/fat metabolism in patients with type 2 diabetes. INTRODUCTION: Recent studies have shown that undercarboxylated osteocalcin (ucOC) acts as a hormone regulating glucose metabolism and fat mass. We investigated the relationship between ucOC as well as other bone turnover markers [serum OC, bone-specific alkaline phosphatase (BAP), and urinary N-terminal cross-linked telopeptide of type-I collagen] versus serum levels of glucose, fasting serum C-peptide, and adiponectin as well as the amount of fat mass in type 2 diabetes. METHODS: A total of 180 men and 109 postmenopausal women were consecutively recruited, and radiographic and biochemical characteristics were collected. Fat mass was measured by dual X-ray absorptiometry (DXA) and computed tomography (CT). RESULTS: In men, ucOC negatively correlated with percent trunk fat (%trunk fat; by DXA) and visceral/subcutaneous fat ratio (by CT) as well as fasting plasma glucose and HbA(1c) (at least p < 0.05). Multiple regression analysis showed that these associations were still significant independent of age, duration of diabetes, body stature, and renal function as well as glucose or fat metabolism, whereas BAP, another bone formation marker, did not correlate with any variable. On the other hand, although ucOC also negatively correlated with %fat and %trunk fat as well as HbA(1c) (at least p < 0.05) in postmenopausal women, we found no significant association in multiple regression analysis. CONCLUSIONS: These findings suggest that ucOC is associated with plasma glucose level and fat mass in men with type 2 diabetes.

Discovery of the short gamma-ray burst GRB 050709.

Gamma-ray bursts (GRBs) fall into two classes: short-hard and long-soft bursts. The latter are now known to have X-ray and optical afterglows, to occur at cosmological distances in star-forming galaxies, and to be associated with the explosion of massive stars. In contrast, the distance scale, the energy scale and the progenitors of the short bursts have remained a mystery. Here we report the discovery of a short-hard burst whose accurate localization has led to follow-up observations that have identified the X-ray afterglow and (for the first time) the optical afterglow of a short-hard burst; this in turn led to the identification of the host galaxy of the burst as a late-type galaxy at z = 0.16 (ref. 10). These results show that at least some short-hard bursts occur at cosmological distances in the outskirts of galaxies, and are likely to be caused by the merging of compact binaries.

Increased matrix metalloproteinase-2 and bone sialoprotein response to human coronal caries.

BACKGROUND: It has been suggested that host matrix metalloproteinase-2 (MMP-2) present in dentin may be involved in caries progression, however, its response to caries is not known. Bone sialoprotein (BSP) has been implicated in dentin mineralization and MMP-2 modulation. OBJECTIVE: To identify and compare the distribution of MMP-2 and BSP in healthy human coronal dentin and those with early caries. METHODS: Freshly extracted 3rd molars and premolars with and without early caries were fixed, demineralized and subjected to immunohistochemistry using a monoclonal anti-MMP-2 antibody and monoclonal anti-BSP antibody with an avidin-biotin complex method. Immunoreactivity was visualized with 3,3'-diaminobenzidine substrate and observed under light microscopy. RESULTS: Immunohistochemical analysis revealed that MMP-2 and BSP are not detected in the tubule lumens of healthy dentin. However, intense immunoreactivity for MMP-2 and BSP was detected in association with the full length of the caries-affected dentinal tubules. The MMP-2 and BSP at the dentino-enamel junction appeared unaltered. CONCLUSION: The results indicate that MMP-2 and BSP may be actively secreted by odontoblasts in response to carious insult. MMP-2 and BSP accumulation in the caries-affected dentinal tubules may indicate their potential involvement in the host defense mechanism which results in calcification of regions affected by the carious process.

Bicarbonate in Arteries Measured Preoperatively for Cadaveric Single-lung Transplantation is Related to Intraoperative Extra-Corporeal Membrane Oxygenation Use: A Retrospective Preliminary Study.

Background: There are no known predictors of extracorporeal membrane oxygenation (ECMO) induction for single lung transplantation. Objective: The purpose of the present study was to clarify the relationship between variables and ECMO requirements in single lung transplantation. Methods: This study included adult patients who underwent cadaveric single lung transplantation between 2010 and 2019. After general anesthesia, the transplanted lungs were ventilated in all cases. The analysis included 38 patients in the ECMO required (RQ) group and 12 patients in the ECMO non-required (FR) group. Comparisons were made between the two groups for data affecting ECMO implementation, and data that were significantly different were subjected to multivariate analysis. Results: Prior to anesthesia, the bicarbonate (HCO3-) value of the FR group was lower than that of the RQ group (24.6±2.7 vs. 29.7±5.3 mmol/L, p=0.005). Multivariate analysis showed that the cut-off bicarbonate value was 29.6. The area under the receiver operating characteristic curve (AUROC) of the model was 0.869 (R2: 0.331), with a sensitivity of 79% and a specificity of 88%. The odds ratio was 1.63 for every unit increase in the bicarbonate value (95%CI: 1.11-2.39, p<0.001). Further, the FR group had higher arterial blood pressure (mean: 79.0±11.5 vs. 68.9±8.3 mmHg, p=0.030), less blood loss (432±385 vs. 1,623±1,997 g, p<0.001), shorter operation time (417±44 vs. 543±111 min, p<0.001), and shorter ICU stay (11±9 vs. 25±38 days, p=0.039). Conclusion: Preoperative evaluation of bicarbonate could predict the need for ECMO for single lung transplantation.

Urinary deoxypyridinoline is a BMD-independent marker for prevalent vertebral fractures in postmenopausal women treated with glucocorticoid.

SUMMARY: Urinary deoxypyridinoline (DPD) level was associated with prevalent vertebral fractures in glucocorticoid (GC)-treated postmenopausal women independently of lumbar spine bone mineral density (BMD). INTRODUCTION: Bone metabolic indices are the potential predictors of bone fragility. However, their diagnostic efficiency for identifying the risk of GC-induced vertebral fractures is still unclear. We therefore evaluated whether bone metabolic indices would assess the risk of vertebral fractures in GC-treated women. METHODS: One hundred seventy-five women treated with GC for more than 6 months were enrolled in this study. RESULTS: Both premenopausal and postmenopausal women with vertebral fractures had significantly higher urinary DPD levels than those without vertebral fractures. When multivariable logistic regression analysis was performed with the presence of vertebral fractures as a dependent variable and each of DPD or osteocalcin level adjusted for age, weight, height, current and maximum doses of GC, duration of GC treatment, as well as lumbar spine BMD as an independent variable, DPD level was identified as a factor associated with the presence of vertebral fractures in postmenopausal women but not in premenopausal women. CONCLUSION: Urinary DPD level was significantly associated with prevalent vertebral fractures in GC-treated postmenopausal women independently of lumbar spine BMD.

Baseline atherosclerosis parameter could assess the risk of bone loss during pioglitazone treatment in type 2 diabetes mellitus.

SUMMARY: We found that serum osteocalcin, femoral bone mineral density (F-BMD), and 1/3R-BMD were decreased during pioglitazone treatment in patients with type 2 diabetes. Moreover, baseline atherosclerosis parameter, serum insulin-like growth factor-I (IGF-I), and urinary N-terminal cross-linked telopeptide of type I collagen (uNTX) values were associated with changes in bone mineral density (BMD). Therefore, these parameters could assess the risk of BMD reduction in patients treated with pioglitazone. INTRODUCTION: The aim of this study was to investigate the effects of pioglitazone or metformin on bone mass and atherosclerosis in patients with type 2 diabetes. METHODS: A total of 55 Japanese patients were enrolled in this 1-year open-label study and randomized to either pioglitazone (n = 22, 15-30 mg/day) or metformin (n = 23, 500-750 mg/day) groups. BMD at the lumbar spine, femoral neck (F), and one third of the radius (1/3R), bone markers, and atherosclerosis parameters were measured. RESULTS: In the pioglitazone group, serum osteocalcin significantly decreased at 6 months (p < 0.05), although it almost recovered to baseline level at 12 months. F-BMD significantly decreased at 6 months (p < 0.05), and 1/3R-BMD significantly decreased at 6 and 12 months (p < 0.05), while bone markers or BMD at any site were not changed in the metformin group. Although atherosclerosis parameters were not changed in the pioglitazone group, intima-media thickness (IMT)-mean significantly increased at 6 months (p < 0.05) and plaque score significantly increased at 6 and 12 months (p < 0.01) in the metformin group. In the pioglitazone group, %changes in F-BMD were significantly and negatively correlated with baseline IMT-Max, IMT-mean, and plaque scores (r = -0.61, p < 0.01; r = -0.71, p < 0.01; and r = -0.68, p < 0.01, respectively), and %changes in 1/3R-BMD were significantly and negatively correlated with baseline uNTX and IMT-Max (r = -0.57, p < 0.01 and r = -0.48, p < 0.05, respectively) and positively with IGF-I (r = 0.45, p < 0.05). CONCLUSIONS: Baseline IMT, uNTX, and IGF-I could assess the risk of BMD reduction in diabetic patients treated with pioglitazone.

The Calcium-sensing Receptor (CaR) is involved in strontium ranelate-induced osteoblast differentiation and mineralization.

Strontium ranelate is known to reduce fracture risk in osteoporotic patients by stimulating bone formation and suppressing bone resorption. However, the mechanism by which strontium exerts this beneficial effect on bone is unclear. We examined whether or not the calcium-sensing receptor (CaR), which is activated by divalent cations including Sr (2+), is involved in this mechanism. Both strontium ranelate and strontium chloride dose-dependently stimulated phosphorylation of extracellular signal-regulated kinase (ERK) in Human Embryonic Kidney 293 cells transiently transfected with the human CaR. Strontium ranelate also dose- and time-dependently stimulated phosphorylation of ERK in mouse osteoblastic MC3T3-E1 cells expressing the CaR endogenously. Strontium ranelate increased mRNA expression of osteocalcin and bone morphogenetic protein-2 in MC3T3-E1 cells as well as mineralization and proliferation of the cells. Pretreatments of NPS2390, a CaR inhibitor, almost totally antagonized strontium ranelate-induced mineralization and proliferation of MC3T3-E1 cells. These findings indicate that strontium ranelate induces not only osteoblast proliferation but also its differentiation and mineralization by activating the CaR, and confirm that the therapeutic efficacy of strontium ranelate for osteoporosis may be partly mediated by the CaR.

Effect of cyclic mechanical loading on osteoclast recruitment in periodontal tissue.

BACKGROUND AND OBJECTIVE: It is well accepted that cyclic mechanical loading induces osteoclastogenesis in periodontal tissue, but its molecular mechanisms are not well understood, in part because of a lack of appropriate models. In this study, we investigated a novel device that allows cyclic mechanical loading to be performed in a well-controlled manner. Furthermore, by employing this model, the effect of cyclic loading on osteoclast recruitment in the periodontal tissue was described. MATERIAL AND METHODS: By using a newly developed device, the cyclic loading of 20 n (reference loading corresponding to the fracture hardness of dietary pellets) and two excessive loadings (i.e. 30 and 40 n) were applied to maxillary right molars in rats for up to 7 d, and osteoclast recruitment in the periodontal tissue was evaluated by analyzing relevant marker proteins using immunohistochemistry. RESULTS: Osteoclastogenesis was induced by day 3 within alveolar bone subjected to a compression force of 30 n. With both 30 and 40 n loadings, cells that were positive to for tartrate-resistant acid phosphate, receptor activator of nuclear factor-kappaB ligand and osteoprotegerin were significantly increased in the alveolar bone/periodontal ligament in a time-dependent manner. CONCLUSION: A new device was developed that allows various levels of cyclic mechanical loading to be exerted. By using this device in rats, early events of osteoclast recruitment in the periodontal tissues were observed with excessive loadings in a time-dependent manner, indicating the usefulness of this model.

Influence of BMI, Age and duration of diabetes mellitus on glycaemic control with twice-daily injections of biphasic insulin aspart 30 versus multiple daily injections of insulin aspart (JDDM 18): retrospective reanalysis of a 6-month, randomized, open-label, multicentre trial in Japan.

BACKGROUND AND OBJECTIVE: Good glycaemic control in patients with diabetes mellitus often requires insulin supplementation therapy. Recent developments of analogue insulin and premixed formulations have increased the therapeutic options for patients who need such therapy. This study aimed to retrospectively clarify appropriate treatment regimens according to age, body mass index (BMI) and duration of diabetes in Japanese patients with type 2 diabetes previously entered in an open-label, randomized trial that compared convenience-oriented biphasic insulin aspart 30 versus multiple injections of insulin aspart with or without NPH insulin. METHODS: Japanese insulin-naïve patients were randomized to receive either biphasic insulin aspart 30 twice daily or insulin aspart three times daily with or without multiple injections of NPH insulin for a treatment period lasting 6 months. RESULTS: Reduction of glycosylated haemoglobin (HbA(1c)) at the end of 6 months was not different in the two treatment groups irrespective of BMI, age and duration of diabetes. However, the achievement rate of HbA(1c) <7.0% was significantly higher in patients with a BMI <25 kg/m2 in the multiple-injection group and tended to be higher in patients with a diabetes duration <10 years in the twice-daily injection group. CONCLUSION: Twice-daily injections of biphasic insulin aspart 30 may be more suitable for obese patients whereas multiple injections of insulin aspart with or without NPH insulin may be preferable for those with a longer duration of diabetes.

DEVELOPMENT OF A JAPANESE INFANT HEAD-CHEST PHANTOM AND INVESTIGATION OF THE CURRENT STATUS OF INFANT HEAD CT EXAMINATIONS IN JAPAN.

The aim of this study was to develop a head-chest phantom that could mimic the physique of a Japanese 0.5-year-old child and to investigate the current status of exposure dose in infant head computed tomography examinations in Japan. The phantom was produced by machine processing, and radiophotoluminescence glass dosemeters were installed in the phantom for dose measurement. Organ doses were measured for seven different head scan protocols routinely used in three hospitals. In this study, the average dose of the brain and lens within the scan region was equivalent to that measured using infant phantoms in previous studies. In contrast, the doses of both salivary glands and thyroid glands adjacent to the scan region were 1.4-1.8 times higher than those in previous studies. Expansion of the scan area accompanied by a transition of the scan mode from non-helical to helical may have resulted in the differences in organ doses.

Bone fragility in male glucocorticoid-induced osteoporosis is not defined by bone mineral density.

UNLABELLED: Eighty-seven male Japanese subjects taking prednisolone > or = 5 mg for more than 6 months and 132 age- and body mass index (BMI)-matched control subjects were examined. Multiple regression analysis adjusted for age and BMI showed that spinal bone mineral density (BMD) in the prednisolone group was not associated with prevalent vertebral fractures (VFs). INTRODUCTION: Glucocorticoid (GC) treatment is known to increase the risk for bone fractures. However, the association between VFs and BMD in GC-treated male patients remains unclear. METHODS: Eighty-seven male subjects taking prednisolone > or = 5 mg for more than 6 months and 132 age- and BMI-matched control subjects were examined using lateral thoracic and lumbar spine radiographs and spine dual energy X-ray absorptiometry. RESULTS: The presence of GC use was an independent risk factor for VFs adjusted for age and BMI (odds ratio 10.93, P < 0.001). By receiver operating characteristic analysis, the absolute BMD values for detecting VFs were higher and the sensitivity and specificity were lower in the GC group than in the control group (0.936 vs 0.825 g/cm(2) and 53.5% vs 74.0%, respectively). Multiple regression analysis adjusted for age and BMI showed that spinal BMD in the GC group was not associated with prevalent VFs, even after adding current and past maximum GC doses as independent variables. CONCLUSIONS: These results show that lumbar BMD values are not associated with prevalent VFs in GC-treated male patients, suggesting that bone fragility in male GC users is affected by bone quality rather than by BMD.

Inhibition of the mevalonate pathway rescues the dexamethasone-induced suppression of the mineralization in osteoblasts via enhancing bone morphogenetic protein-2 signal.

We used dexamethasone (DEX)-treated osteoblastic MC3T3-E1 cells, and investigated the effects of an AMP-activated protein kinase activator, 5-aminoimidazole-4-carboxamide-1-beta- D-ribonucleoside (AICAR), a Rho-associated protein kinase inhibitor, fasudil hydrochrolide, as well as HMG-CoA reductase inhibitors, simvastatin and pitavastatin, all of which inhibit the mevalonate pathway. DEX (10(-8) M) significantly enhanced mRNA expression of bone morphogenetic protein (BMP)-2 antagonists, follistatin and Dan, and addition of each of 10 (-4) M AICAR, 10 (-5) M fasudil, 10(-6) M simvastatin, and 10(-6) M pitavastatin significantly reversed the enhancement in mRNA expression of follistatin and Dan and stimulated that of BMP-2 in the cells (p<0.05). DEX (10(-8) M) also significantly suppressed mineralization in the cells, and addition of each of these agents significantly reversed the suppression of mineralization (p<0.05). These findings suggest that the mevalonate pathway was involved in glucocorticoid-induced osteoblast dysfunction, and that its inhibition might promote bone formation through BMP-2 and alleviate glucocorticoid-induced osteoporosis.

Parathyroid hormone upregulates BMP-2 mRNA expression through mevalonate kinase and Rho kinase inhibition in osteoblastic MC3T3-E1 cells.

It is well known that parathyroid hormone (PTH) possesses an anabolic effect on bone. However, the mechanisms are not fully elucidated. So far, it is unclear whether or not PTH could stimulate the expression of bone morphogenetic protein-2 (BMP-2), a strong mediator for bone formation. Growing evidence suggests that BMP-2 expression is regulated by the mevalonate pathway and Rho-associated protein kinase (ROK) activity. This study was performed to examine if PTH affects BMP-2 expression and to clarify its involvement of the mevalonate pathway. Osteoblastic MC3T3-E1 cells were treated with human PTH-(1-34) to determine BMP-2 mRNA expression levels by real-time PCR and to measure the ROK activity by the kinase assay. Incubation with 10 (-9)-10 (-8) M of hPTH-(1-34) for 6 h induced significant upregulation of BMP-2 mRNA levels in MC3T3-E1 cells. Short-term treatment of hPTH-(1-34) suppressed Rho kinase activity and mevalonate kinase mRNA levels. PTH-induced BMP-2 mRNA upregulation was selectively reversed by geranylgeranyl pyrophosphate (GGPP) pretreatment, but not by mevalonate pretreatment. These findings suggest that BMP-2 mRNA expression was upregulated by PTH in MC3T3-E1 cells mediated by mevalonate pathway suppression followed by ROK inhibition. We have now demonstrated for the first time that PTH stimulated BMP-2 mRNA expression via the mevalonate pathway and ROK in osteoblastic MC3T3-E1 cells.