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1.
J Bone Miner Metab ; 31(2): 206-11, 2013 Mar.
Article in English | MEDLINE | ID: mdl-23138352

ABSTRACT

This study was performed to investigate the effects of the co-administration of proton pump inhibitor (PPI) on the efficacy of bisphosphonate (BP) treatment for osteoporosis. A total of 180 women with low bone mineral density were randomly divided into four groups, one in which sodium risedronate was administered with sodium rabeprazole and one in which only risedronate was administered (BP + PPI and BP groups, respectively). The biomarkers were measured at the baseline and every 3 months, inlcuding: N-terminal telopeptide of type I collagen corrected for creatinine, bone-specific alkaline phosphatase (BAP), parathyroid hormone, bone mineral density (BMD) of the lumbar spine and physical parameters evaluated according to the SF-36v2™ Health Survey. Statistical comparisons of these parameters were performed after 9 months. Data were available for a total of 137 patients (62 in the BP group and 75 in the BP + PPI group). The Δ % value of increase in BMD and improvement of physical functioning in the BP + PPI group were significantly larger, and its decrease in BAP in the BP + PPI group was significantly smaller than that in the BP group. It is expected that risedronate administration in combination with a PPI may be more effective not only for treating osteoporosis but also improving physical fitness than treatment with risedronate alone.


Subject(s)
Bone Density Conservation Agents/therapeutic use , Etidronic Acid/analogs & derivatives , Osteoporosis/drug therapy , Proton Pump Inhibitors/administration & dosage , Proton Pump Inhibitors/therapeutic use , Bone Density Conservation Agents/administration & dosage , Bone Density Conservation Agents/adverse effects , Drug Therapy, Combination , Etidronic Acid/administration & dosage , Etidronic Acid/adverse effects , Etidronic Acid/therapeutic use , Female , Humans , Middle Aged , Osteoporosis/complications , Osteoporotic Fractures/complications , Osteoporotic Fractures/drug therapy , Proton Pump Inhibitors/adverse effects , Risedronic Acid
2.
Development ; 137(7): 1159-67, 2010 Apr.
Article in English | MEDLINE | ID: mdl-20181744

ABSTRACT

Chondrocyte differentiation is strictly regulated by various transcription factors, including Runx2 and Runx3; however, the physiological role of Runx1 in chondrocyte differentiation remains unknown. To examine the role of Runx1, we generated mesenchymal-cell-specific and chondrocyte-specific Runx1-deficient mice [Prx1 Runx1(f/f) mice and alpha1(II) Runx1(f/f) mice, respectively] to circumvent the embryonic lethality of Runx1-deficient mice. We then mated these mice with Runx2 mutant mice to obtain mesenchymal-cell-specific or chondrocyte-specific Runx1; Runx2 double-mutant mice [Prx1 DKO mice and alpha1(II) DKO mice, respectively]. Prx1 Runx1(f/f) mice displayed a delay in sternal development and Prx1 DKO mice completely lacked a sternum. By contrast, alpha1(II) Runx1(f/f) mice and alpha1(II) DKO mice did not show any abnormal sternal morphogenesis or chondrocyte differentiation. Notably, Runx1, Runx2 and the Prx1-Cre transgene were co-expressed specifically in the sternum, which explains the observation that the abnormalities were limited to the sternum. Histologically, mesenchymal cells condensed normally in the prospective sternum of Prx1 DKO mice; however, commitment to the chondrocyte lineage, which follows mesenchymal condensation, was significantly impaired. In situ hybridization analyses demonstrated that the expression of alpha1(II) collagen (Col2a1 - Mouse Genome Informatics), Sox5 and Sox6 in the prospective sternum of Prx1 DKO mice was severely attenuated, whereas Sox9 expression was unchanged. Molecular analyses revealed that Runx1 and Runx2 induce the expression of Sox5 and Sox6, which leads to the induction of alpha1(II) collagen expression via the direct regulation of promoter activity. Collectively, these results show that Runx1 and Runx2 cooperatively regulate sternal morphogenesis and the commitment of mesenchymal cells to become chondrocytes through the induction of Sox5 and Sox6.


Subject(s)
Core Binding Factor Alpha 1 Subunit/metabolism , Core Binding Factor Alpha 2 Subunit/metabolism , Morphogenesis/physiology , Sternum/embryology , Animals , Bone and Bones/cytology , Bone and Bones/metabolism , Cartilage/cytology , Cartilage/physiology , Cell Differentiation , Cell Lineage , Chondrocytes/cytology , Chondrocytes/metabolism , Core Binding Factor Alpha 1 Subunit/genetics , Core Binding Factor Alpha 2 Subunit/genetics , Gene Expression Regulation, Developmental , HeLa Cells , Homeodomain Proteins/genetics , Homeodomain Proteins/metabolism , Humans , Mesoderm/cytology , Mesoderm/metabolism , Mice , Mice, Knockout , SOXD Transcription Factors/genetics , SOXD Transcription Factors/metabolism , Stem Cells/cytology , Stem Cells/metabolism , Sternum/abnormalities , Sternum/anatomy & histology , Sternum/metabolism , Transgenes
3.
Proc Natl Acad Sci U S A ; 106(49): 20794-9, 2009 Dec 08.
Article in English | MEDLINE | ID: mdl-19933329

ABSTRACT

Growing evidence shows that microRNAs (miRNAs) regulate various developmental and homeostatic events in vertebrates and invertebrates. Osteoblast differentiation is a key step in proper skeletal development and acquisition of bone mass; however, the physiological role of non-coding small RNAs, especially miRNAs, in osteoblast differentiation remains elusive. Here, through comprehensive analysis of miRNAs expression during osteoblast differentiation, we show that miR-206, previously viewed as a muscle-specific miRNA, is a key regulator of this process. miR-206 was expressed in osteoblasts, and its expression decreased over the course of osteoblast differentiation. Overexpression of miR-206 in osteoblasts inhibited their differentiation, and conversely, knockdown of miR-206 expression promoted osteoblast differentiation. In silico analysis and molecular experiments revealed connexin 43 (Cx43), a major gap junction protein in osteoblasts, as a target of miR-206, and restoration of Cx43 expression in miR-206-expressing osteoblasts rescued them from the inhibitory effect of miR-206 on osteoblast differentiation. Finally, transgenic mice expressing miR-206 in osteoblasts developed a low bone mass phenotype due to impaired osteoblast differentiation. Our data show that miRNA is a regulator of osteoblast differentiation.


Subject(s)
Cell Differentiation/genetics , Gene Expression Regulation , MicroRNAs/metabolism , Osteoblasts/cytology , Osteoblasts/metabolism , Animals , Base Sequence , Bone and Bones/metabolism , Bone and Bones/pathology , Cell Line , Connexin 43/genetics , Mice , MicroRNAs/genetics , Molecular Sequence Data , Organ Size , Osteogenesis/genetics
4.
Arthritis Rheum ; 58(9): 2764-75, 2008 Sep.
Article in English | MEDLINE | ID: mdl-18759297

ABSTRACT

OBJECTIVE: Runx2 is a transcription factor that regulates chondrocyte differentiation. This study was undertaken to address the role of the different Runx proteins (Runx1, Runx2, or Runx3) in chondrocyte differentiation using chondrocyte-specific Runx-transgenic mice, and to study the importance of the QA domain of Runx2, which is involved in its transcriptional activation. METHODS: Runx expression was analyzed in the mouse embryo by in situ hybridization. Overexpression of Runx1, Runx2 (lacking the QA domain [DeltaQA]), or Runx3 was induced in chondrocytes in vivo, to produce alpha(1)II-Runx1, alpha(1)II-Runx2DeltaQA, and alpha(1)II-Runx3 mice, respectively, for histologic and molecular analyses. Runx expression was also examined in an experimental mouse model of mechanical stress-induced intervertebral disc (IVD) degeneration and in human patients with IVD degeneration. RESULTS: Runx1 expression was transiently observed in condensations of mesenchymal cells, whereas Runx2 and Runx3 were robustly expressed in prehypertrophic chondrocytes. Similar to alpha(1)II-Runx2 mice, alpha(1)II-Runx2DeltaQA and alpha(1)II-Runx3 mice developed ectopic mineralization of cartilage, but this was less severe in the alpha(1)II-Runx2DeltaQA mice. In contrast, alpha(1)II-Runx1 mice displayed no signs of ectopic mineralization. Surprisingly, alpha(1)II-Runx1 and alpha(1)II-Runx2 mice developed scoliosis due to IVD degeneration, characterized by an accumulation of extracellular matrix and ectopic chondrocyte hypertrophy. During mouse embryogenesis, Runx2, but not Runx1 or Runx3, was expressed in the IVDs. Moreover, both in the mouse model of IVD degeneration and in human patients with IVD degeneration, there was significant up-regulation of Runx2 expression. CONCLUSION: Each Runx protein has a distinct, yet overlapping, role during chondrocyte differentiation. Runx2 contributes to the pathogenesis of IVD degeneration.


Subject(s)
Cell Differentiation/genetics , Chondrocytes/metabolism , Core Binding Factor alpha Subunits/metabolism , Intervertebral Disc Degeneration/metabolism , Intervertebral Disc/metabolism , Animals , Autoradiography , Bone Diseases/genetics , Bone Diseases/metabolism , Bone Diseases/pathology , Bone and Bones/metabolism , Bone and Bones/pathology , Bone and Bones/physiology , Calcinosis/metabolism , Calcinosis/pathology , Cartilage/metabolism , Cartilage/pathology , Chondrocytes/pathology , Chondrogenesis/genetics , Core Binding Factor alpha Subunits/genetics , Gene Expression Regulation, Developmental , Humans , Immunohistochemistry , In Situ Hybridization , Intervertebral Disc Degeneration/genetics , Mice , Mice, Transgenic , RNA, Messenger/genetics , RNA, Messenger/metabolism , Reverse Transcriptase Polymerase Chain Reaction , Time Factors , Weight-Bearing/physiology
5.
Nat Med ; 13(10): 1234-40, 2007 Oct.
Article in English | MEDLINE | ID: mdl-17873881

ABSTRACT

Bone remodeling, the function affected in osteoporosis, the most common of bone diseases, comprises two phases: bone formation by matrix-producing osteoblasts and bone resorption by osteoclasts. The demonstration that the anorexigenic hormone leptin inhibits bone formation through a hypothalamic relay suggests that other molecules that affect energy metabolism in the hypothalamus could also modulate bone mass. Neuromedin U (NMU) is an anorexigenic neuropeptide that acts independently of leptin through poorly defined mechanisms. Here we show that Nmu-deficient (Nmu-/-) mice have high bone mass owing to an increase in bone formation; this is more prominent in male mice than female mice. Physiological and cell-based assays indicate that NMU acts in the central nervous system, rather than directly on bone cells, to regulate bone remodeling. Notably, leptin- or sympathetic nervous system-mediated inhibition of bone formation was abolished in Nmu-/- mice, which show an altered bone expression of molecular clock genes (mediators of the inhibition of bone formation by leptin). Moreover, treatment of wild-type mice with a natural agonist for the NMU receptor decreased bone mass. Collectively, these results suggest that NMU may be the first central mediator of leptin-dependent regulation of bone mass identified to date. Given the existence of inhibitors and activators of NMU action, our results may influence the treatment of diseases involving low bone mass, such as osteoporosis.


Subject(s)
Bone Remodeling/drug effects , Neuropeptides/metabolism , Neuropeptides/pharmacology , Absorptiometry, Photon , Animals , Bone Density/drug effects , Cell Proliferation , Cells, Cultured , Dose-Response Relationship, Drug , Female , Immunohistochemistry , Leptin/metabolism , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Mice, Mutant Strains , Models, Biological , Neuropeptides/analysis , Neuropeptides/genetics , Osteoblasts/drug effects , Osteoblasts/physiology , Sex Factors , Sympathetic Nervous System/metabolism , Tomography, X-Ray Computed
6.
Eur J Neurosci ; 22(6): 1277-86, 2005 Sep.
Article in English | MEDLINE | ID: mdl-16190883

ABSTRACT

Mutations of PQBP-1 (polyglutamine binding protein-1) have been shown recently to cause human mental retardation accompanied by microcephaly at a high frequency. As a first step towards understanding the molecular basis of this developmental anomaly, we analysed developmental expression of PQBP-1 by in situ hybridization, immunohistochemistry and Western blot analysis. Although it had been shown by Northern blot analysis that PQBP-1 mRNA is expressed in multiple organs in adult mice, our present results revealed that PQBP-1 mRNA and protein are dominantly expressed in the central nervous system (CNS) in embryos and in newborn mice. The mean expression level of PQBP-1 reaches a peak around birth and is down-regulated in adulthood. Furthermore, the expression pattern in the CNS changes remarkably following birth. PQBP-1 mRNA in the cerebral cortex is high in embryos but it rapidly decreases after birth. PQBP-1 mRNA increases in external and internal granular cell layers of the cerebellum from postnatal day 1 (P1) to P5. In addition, expression in the subventricular zone, where neurogenesis occurs, was high from P5 to adulthood. Collectively, these findings suggest that PQBP-1 might be involved in neuronal proliferation and/or maturation. These ideas may be relevant to the insufficient growth of brain structure reported in PQBP-1-linked human mental retardation.


Subject(s)
Carrier Proteins/genetics , Central Nervous System/growth & development , Central Nervous System/metabolism , Nuclear Proteins/genetics , Animals , Animals, Newborn/physiology , Blotting, Western , Brain/growth & development , Brain Chemistry/genetics , Carrier Proteins/biosynthesis , Cerebral Cortex/metabolism , DNA-Binding Proteins , Embryo, Mammalian/metabolism , Female , Glyceraldehyde-3-Phosphate Dehydrogenases/metabolism , Immunohistochemistry , In Situ Hybridization , Mice , Mice, Inbred C57BL , Nuclear Proteins/biosynthesis , Oligonucleotides, Antisense/metabolism , Pregnancy , RNA, Messenger/biosynthesis , RNA, Messenger/genetics
8.
Microbiol Immunol ; 47(1): 109-16, 2003.
Article in English | MEDLINE | ID: mdl-12636261

ABSTRACT

Mesenchymal cells from various sources are pluripotent and are attractive sources for cell transplantation. In this study, we analyzed recombinant adeno-associated virus (rAAV)-mediated gene expression in human placenta-derived mesenchymal cells (hPDMCs), which reside in placental villi. After transduction of AV-CAG-EGFP, a rAAV expressing enhanced green fluorescence protein (EGFP), hPDMCs showed much higher level of EGFP expression than human umbilical vein endothelial cells or rat aortic smooth muscle cells. The number of EGFP-positive hPDMCs infected by AV-CAG-EGFP alone did not increase significantly by coinfection of adenovirus, which enhanced expression level of the rAAV vector. Moreover, flow cytometric analysis showed discrete positive fraction of EGFP-expressing hPDMCs, which is about 15-20% of the cells infected with AV-CAG-EGFP. Therefore, some cell population in hPDMCs might be highly susceptible to rAAV-mediated gene transduction. In addition, stable EGFP expressions were observed in about 1% of hPDMCs infected with AV-CAG-EGFP at 4 weeks post-infection. Collectively, hPDMCs have characters favorable for rAAV-mediated gene expression.


Subject(s)
Dependovirus/genetics , Placenta/virology , Transduction, Genetic/methods , DNA, Viral/chemistry , DNA, Viral/genetics , Female , Flow Cytometry , Gene Expression Regulation, Viral , Genetic Therapy , Green Fluorescent Proteins , HeLa Cells , Humans , Luminescent Proteins/biosynthesis , Luminescent Proteins/chemistry , Luminescent Proteins/genetics , Mesoderm , Myocytes, Smooth Muscle/immunology , Myocytes, Smooth Muscle/virology , Nucleic Acid Hybridization , Placenta/immunology , Placenta/metabolism , Pregnancy , Recombinant Proteins/chemistry , Recombinant Proteins/genetics
9.
Ann N Y Acad Sci ; 973: 75-8, 2002 Nov.
Article in English | MEDLINE | ID: mdl-12485837

ABSTRACT

The primary culture of rat osteoblasts was treated with 1alpha,25 dihydroxyvitamin D(3) and fixed with guanidine isothiocyanate solution during a space shuttle flight. The mRNA levels were analyzed by quantitative reverse transcription-polymerase chain reaction. Microgravity decreased the mRNA levels of insulin-like growth factor-I (IGF-I) and increased reciprocally the IGF-I receptor mRNA levels, as compared to the ground (1 x g) control. Microgravity completely suppressed the mRNA expression of the insulin receptor substrate-1, the postreceptor signaling molecule of IGF-I. Microgravity might deteriorate the action and signaling of IGF-I in rat osteoblasts.


Subject(s)
Gene Expression Regulation/physiology , Insulin-Like Growth Factor I/genetics , Osteoblasts/physiology , Signal Transduction/physiology , Space Flight , Weightlessness , Animals , Calcitriol/pharmacology , Cells, Cultured , Osteoblasts/drug effects , RNA, Messenger/genetics , Rats , Reference Values , Reverse Transcriptase Polymerase Chain Reaction
10.
J Orthop Sci ; 7(4): 433-8, 2002.
Article in English | MEDLINE | ID: mdl-12181655

ABSTRACT

This study evaluated the internal rotation limit prior to bony impingement of the proximal femur on the pelvis after total hip arthroplasty (THA). Reconstructed computed tomography (CT) images of 90 degrees hip flexion were used to simulate the internal rotation limit against safety limits measured intraoperatively. Ninety joints in 86 subjects (12 men and 74 women) underwent THA for the treatment of secondary coxarthrosis. The correlation between the internal rotation limit prior to the bony impingement intraoperatively and the simulated internal rotation angle on the reconstructed CT image was statistically significant. We provide a new method to simulate the internal rotation limit prior to bony impingement based on postoperative CT.


Subject(s)
Arthroplasty, Replacement, Hip/adverse effects , Hip Dislocation/diagnostic imaging , Hip Dislocation/etiology , Hip Joint/diagnostic imaging , Hip Prosthesis , Range of Motion, Articular/physiology , Tomography, X-Ray Computed/methods , Acetabulum/physiopathology , Adult , Aged , Aged, 80 and over , Arthroplasty, Replacement, Hip/methods , Evaluation Studies as Topic , Female , Femur Head/physiopathology , Humans , Male , Middle Aged , Patient Simulation , Prosthesis Design , Prosthesis Failure , Sensitivity and Specificity
11.
J Gravit Physiol ; 9(1): P263-4, 2002 Jul.
Article in English | MEDLINE | ID: mdl-15002572

ABSTRACT

The mechanism of space flight-induced bone mass loss is unknown. We conducted experiments aboard the Space Shuttle using primary cultured osteoblasts. During flight, quadruplicate cultures were treated with 1 nM of 1alpha,25 dihydroxyvitamin D3 for one day, then fixed with guanidine isothiocyanate solution on board. After return to the Earth, the mRNA levels were analyzed by quantitative RT-PCR. Microgravity increased the mRNA levels of JNK, c-Jun N-terminal kinase or stress-activated protein kinase, in rat osteoblasts, as compared to the 1G ground control. Microgravity decreased the mRNA levels of the principal heat shock protein, Hsp 70. JNK is known to play a key role particularly in the stress-activated cell apoptosis. Data suggested apoptotic and anti-apoptotic effects of microgravity on rat osteoblast.

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