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1.  BMP-2 Induced Expression of Alx3 That Is a Positive Regulator of Osteoblast Differentiation 
PLoS ONE  2013;8(6):e68774.
Bone morphogenetic proteins (BMPs) regulate many aspects of skeletal development, including osteoblast and chondrocyte differentiation, cartilage and bone formation, and cranial and limb development. Among them, BMP-2, one of the most potent osteogenic signaling molecules, stimulates osteoblast differentiation, while it inhibits myogenic differentiation in C2C12 cells. To evaluate genes involved in BMP-2-induced osteoblast differentiation, we performed cDNA microarray analyses to compare BMP-2-treated and -untreated C2C12 cells. We focused on Alx3 (aristaless-like homeobox 3) which was clearly induced during osteoblast differentiation. Alx3, a homeobox gene related to the Drosophilaaristaless gene, has been linked to developmental functions in craniofacial structures and limb development. However, little is known about its direct relationship with bone formation. In the present study, we focused on the mechanisms of Alx3 gene expression and function during osteoblast differentiation induced by BMP-2. In C2C12 cells, BMP-2 induced increase of Alx3 gene expression in both time- and dose-dependent manners through the BMP receptors-mediated SMAD signaling pathway. In addition, silencing of Alx3 by siRNA inhibited osteoblast differentiation induced by BMP-2, as showed by the expressions of alkaline phosphatase (Alp), Osteocalcin, and Osterix, while over-expression of Alx3 enhanced osteoblast differentiation induced by BMP-2. These results indicate that Alx3 expression is enhanced by BMP-2 via the BMP receptors mediated-Smad signaling and that Alx3 is a positive regulator of osteoblast differentiation induced by BMP-2.
doi:10.1371/journal.pone.0068774
PMCID: PMC3689002  PMID: 23825702
2.  R848, a toll-like receptor 7 agonist, inhibits osteoclast differentiation but not survival or bone-resorbing function of mature osteoclasts 
Cytotechnology  2012;64(3):331-339.
R848, also known as resiquimod, acts as a ligand for toll-like receptor 7 (TLR7) and activates immune cells. In this study, we examined the effects of R848 on differentiation, survival, and bone-resorbing function of osteoclasts. R848 inhibited osteoclast differentiation of mouse bone marrow-derived macrophages (BMMs) and human peripheral blood-derived monocytes induced by receptor activator of NF-κB ligand in a dose-dependent manner. In addition, it inhibited mouse osteoclast differentiation induced in cocultures of bone marrow cells and osteoblasts in the presence of dihydroxyvitamin D3 [1,25(OH)2D3]. However, R848 did not affect the survival or bone-resorbing activity of mouse mature osteoclasts. R848 also upregulated the mRNA expression levels of interleukin (IL)-6, IL-12, interferon (IFN)-γ, and inducible nitric oxide synthase in mouse BMMs expressing TLR7. IFN-β was consistently expressed in the BMMs and addition of neutralizing antibodies against IFN-β to the cultures partially recovered osteoclast differentiation inhibited by R848. These results suggest that R848 targets osteoclast precursors and inhibits their differentiation into osteoclasts via TLR7.
doi:10.1007/s10616-012-9442-5
PMCID: PMC3386391  PMID: 22358541
R848; Resiquimod; Osteoclasts; Toll-like receptor; Cellular differentiation; Bone
3.  Downregulation of Carbonic Anhydrase IX Promotes Col10a1 Expression in Chondrocytes 
PLoS ONE  2013;8(2):e56984.
Carbonic anhydrase (CA) IX is a transmembrane isozyme of CAs that catalyzes reversible hydration of CO2. While it is known that CA IX is distributed in human embryonic chondrocytes, its role in chondrocyte differentiation has not been reported. In the present study, we found that Car9 mRNA and CA IX were expressed in proliferating but not hypertrophic chondrocytes. Next, we examined the role of CA IX in the expression of marker genes of chondrocyte differentiation in vitro. Introduction of Car9 siRNA to mouse primary chondrocytes obtained from costal cartilage induced the mRNA expressions of Col10a1, the gene for type X collagen α-1 chain, and Epas1, the gene for hypoxia-responsible factor-2α (HIF-2α), both of which are known to be characteristically expressed in hypertrophic chondrocytes. On the other hand, forced expression of CA IX had no effect of the proliferation of chondrocytes or the transcription of Col10a1 and Epas1, while the transcription of Col2a1 and Acan were up-regulated. Although HIF-2α has been reported to be a potent activator of Col10a1 transcription, Epas1 siRNA did not suppress Car9 siRNA-induced increment in Col10a1 expression, indicating that down-regulation of CA IX induces the expression of Col10a1 in chondrocytes in a HIF-2α-independent manner. On the other hand, cellular cAMP content was lowered by Car9 siRNA. Furthermore, the expression of Col10a1 mRNA after Car9 silencing was augmented by an inhibitor of protein kinase A, and suppressed by an inhibitor for phosphodiesterase as well as a brominated analog of cAMP. While these results suggest a possible involvement of cAMP-dependent pathway, at least in part, in induction of Col10a1 expression by down-regulation of Car9, more detailed study is required to clarify the role of CA IX in regulation of Col10a1 expression in chondrocytes.
doi:10.1371/journal.pone.0056984
PMCID: PMC3575511  PMID: 23441228
4.  Oral health in the Japan self-defense forces - a representative survey 
BMC Oral Health  2011;11:14.
Background
The oral health of military populations is usually not very well characterized compared to civilian populations. The aim of this study was to investigate two physical oral health characteristics and one perceived oral health measure and their correlation in the Japan self-defense forces (JSDF).
Methods
Number of missing teeth, denture status, and OHRQoL as evaluated by the Japanese 14-item version of the Oral Health Impact Profile (OHIP-J14) as well as the correlation between these oral health measures was investigated in 911 personnel in the JSDF.
Results
Subjects did not have a substantial number of missing teeth and only 4% used removable dentures. The mean OHIP-J14 score was 4.6 ± 6.7 units. The magnitude of the correlation between the number of missing teeth with OHIP-J14 scores was small (r = 0.22, p < 0.001). Mean OHIP-J14 scores differed between subjects with and without dentures (8.6 and 4.4, p < 0.001).
Conclusions
Compared to Japanese civilian populations, personnel of the JSDF demonstrated good oral health. Two physical oral health characteristics were associated with perceived oral health.
doi:10.1186/1472-6831-11-14
PMCID: PMC3100240  PMID: 21501526
5.  Association between perceived chewing ability and oral health-related quality of life in partially dentate patients 
Background
One of the most immediate and important functional consequences of many oral disorders is a reduction in chewing ability. The ability to chew is not only an important dimension of oral health, but is increasingly recognized as being associated with general health status. Whether perceived chewing ability and oral health-related quality of life (OHRQoL) are correlated to a similar degree in patient populations has been less investigated. The aim of this study was to examine whether perceived chewing ability was related to OHRQoL in partially dentate patients.
Methods
Consecutive partially dentate patients (N = 489) without signs or symptoms of acute oral disease at Tokyo Medical and Dental University's Prosthodontic Clinic participated in the study (mean age 63.0 ± 11.5, 71.2% female). A 20-item chewing function questionnaire (score range 0 to 20) was used to assess perceived chewing ability, with higher scores indicating better chewing ability. The 14-item Oral Health Impact Profile-Japanese version (OHIP-J14, score range 0 to 56) was used to measure OHRQoL, with higher scores indicating poorer OHRQoL. A Pearson correlation coefficient was calculated to assess the correlation between the two questionnaire summary scores. A linear regression analysis was used to describe how perceived chewing ability scores were related to OHRQoL scores.
Results
The mean chewing function score was 12.1 ± 4.8 units. The mean OHIP-J14 summary score was 13.0 ± 9.1 units. Perceived chewing ability and OHRQoL were significantly correlated (Pearson correlation coefficient: -0.46, 95% confidence interval [CI]: -0.52 to -0.38), indicating that higher chewing ability was correlated with lower OHIP-J14 summary scores (p < 0.001), which indicate better OHRQoL. A 1.0-unit increase in chewing function scores was related to a decrease of 0.87 OHIP-J14 units (95% CI: -1.0 to -0.72, p < 0.001). The correlation between perceived chewing ability and OHRQoL was not substantially influenced by age and number of teeth, but by gender, years of schooling, treatment demand and denture status.
Conclusion
Patients' perception of their chewing ability was substantially related to their OHRQoL.
doi:10.1186/1477-7525-8-118
PMCID: PMC2974665  PMID: 20955614
6.  Validating an alternate version of the chewing function questionnaire in partially dentate patients 
BMC Oral Health  2009;9:9.
Background
The aim of this study was to investigate the dimensionality, reliability, and validity of an alternate version of the chewing function questionnaire in partially dentate patients in Japan.
Methods
Subjects were partially dentate patients who attended the prosthodontic clinic at Tokyo Medical and Dental University (N = 491, 71% women, mean age (± SD): 63.0 ± 11.5 years). The questionnaire asked each subject to rate his or her ability to chew 20 common Japanese foods. For each individual, responses were combined to yield a chewing function summary score, with higher scores indicating better self-reported chewing ability. We used exploratory factor analysis to investigate the scores' dimensionality. For validity assessment, we computed the correlations between the chewing function score and oral health-related quality of life (OHRQoL, as measured by the Japanese 14-item Oral Health Impact Profile (OHIP-14)) Internal consistency of scores and test-retest reliability were investigated by asking a subset of subjects (N = 62) to complete the questionnaire twice, 2 weeks apart.
Results
Exploratory factor analysis provided some evidence that self-reported chewing ability can be characterized by a summary score as the original authors suggest. Support for the validity of chewing function scores using the alternate version of the questionnaire was derived from correlations with OHIP-14 scores (r = -0.46, 95% confidence interval (CI): -0.53 to -0.39); thus, better chewing ability was associated with less impaired OHRQoL. Internal consistency was 'satisfactory,' with a Cronbach's alpha of 0.90 (lower limit of 95% CI: 0.89). The test-retest reliability was 'good,' with an intraclass correlation coefficient of 0.69 (95% CI: 0.56 to 0.82).
Conclusion
The alternate version of the chewing function questionnaire can be used as a stand-alone instrument because of the demonstrated reliability and validity of scores obtained using the questionnaire in partially dentate patients.
doi:10.1186/1472-6831-9-9
PMCID: PMC2667387  PMID: 19291293

Results 1-6 (6)