Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.1.3.1 (alkaline phosphatase)
47,916 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

PTH is a potent systemic regulator of cellular differentiation and function in bone. It acts upon cells of the osteoblastic lineage via the G protein-coupled type-1 PTH/PTH-related peptide receptor (PTH1R). Carboxyl fragments of intact PTH(1-84) (C-PTH fragments) are cosecreted with it by the parathyroid glands in a calcium-dependent manner and also are generated via proteolysis of the hormone in peripheral tissues. Receptors that recognize C-PTH fragments (CPTHRs) have been described previously in osteoblastic and chondrocytic cells. To directly study CPTHRs in bone cells, we isolated clonal, conditionally transformed cell lines from fetal calvarial bone of mice that are homozygous for targeted ablation of the PTH1R gene and transgenically express a temperature-sensitive mutant SV40 T antigen. Cells with the highest specific binding of the CPTHR radioligand (125)I-[Tyr(34)]hPTH(19-84) exhibited a stellate, dendritic appearance suggestive of an osteocytic phenotype and expressed 6- to 10-fold more CPTHR sites/cell than did osteoblastic cells previously isolated from the same bones. In these osteocytic (OC) cells, expression of mRNAs for CD44, connexin 43, and osteocalcin was high, whereas that for alkaline phosphatase and cbfa-1/osf-2 was negligible. The CPTHR radioligand was displaced completely by hPTH(1-84), hPTH(19-84) and hPTH(24-84) (IC(50)s = 20-50 nM) and by hPTH(39-84) (IC(50) = 500 nM) but only minimally (24%) by 10,000 nM hPTH(1-34). CPTHR binding was down-regulated dose dependently by hPTH(1-84), an effect mimicked by ionomycin and active phorbol ester. Human PTH(1-84) and hPTH(39-84) altered connexin 43 expression and increased apoptosis in OC cells. Apoptosis induced by PTH(1-84) was blocked by the caspase inhibitor DEVD. We conclude that osteocytes, the most abundant cells in bone, may be principal target cells for unique actions of intact PTH(1-84) and circulating PTH C-fragments that are mediated by CPTHRs.
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PMID:Receptors for the carboxyl-terminal region of pth(1-84) are highly expressed in osteocytic cells. 1115 65

The periodontal ligament (PDL) is a connective tissue located between the cementum of teeth and the alveolar bone of the mandibula. It plays an integral role in the maintenance and regeneration of periodontal tissue. The cells responsible for maintaining this tissue are thought to be fibroblasts, which can be either multipotent or composed of heterogenous cell populations. However, as no established cell lines from the PDL are available, it is difficult to assess what type of cell promotes all of these functions. As a first step to circumvent this problem, we have cloned and characterized cell lines from the PDL from mice harboring a temperature-sensitive SV 40 large T-antigen gene. RT-PCR and in situ hybridization studies demonstrated that a cell line, designated PDL-L2, mimics the gene expression of the PDL in vivo: it expresses genes such as alkaline phosphatase, type I collagen, periostin, runt-related transcription factor-2 (Runx2) and EGF receptor, but does not express genes such as bone sialoprotein and osteocalcin. Unlike osteoblastic cells and a mixed cell population from the PDL, PDL-L2 cells do not produce mineralized nodules in the mineralization medium. When PDL-L2 cells were incubated in the presence of recombinant human bone morphogenetic protein-2 alkaline phosphatase activity increased and mineralized nodules were eventually produced, although the extent of mineralization is much less than that in osteoblastic MC3T3-E1 cells. Furthermore, PDL-L2 cells appeared to have a regulatory mechanism by which the function of Runx2 is normally suppressed.
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PMID:A cell line with characteristics of the periodontal ligament fibroblasts is negatively regulated for mineralization and Runx2/Cbfa1/Osf2 activity, part of which can be overcome by bone morphogenetic protein-2. 1235 21

The process of osteoblast differentiation and matrix mineralization requires a rise in alkaline phosphatase enzymatic activity resulting in the generation of free phosphate. The ability of inorganic phosphate to regulate gene transcription and cellular function represents a potentially novel extracellular signaling mechanism. Using microarray analysis we have identified a discrete set of genes that are either positively or negatively regulated by increased phosphate in MC3T3-E1 cells. The genes downregulated by phosphate encode for osteoblast-related extracellular factors such as collagens, periostin, and decorin. The genes increased by phosphate encode a novel group of transcription factors that may be important in the later stages of osteoblast development in which the environment is high in phosphate. The transcription factor Nrf2 is one such gene. Elevated phosphate levels stimulate an increase in Nrf2 RNA that is not blocked by the translation inhibitor cycloheximide, suggesting that Nrf2 is an immediate response gene. Cloning of the murine nrf2 promoter reveals that elevated phosphate produces an increase in promoter activity that is both time and dose dependent. This analysis reveals multiple genes regulated by the increase in phosphate associated with osteoblast differentiation, adding to our understanding of the intricate communication between osteoblasts and their extracellular environment.
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PMID:Inorganic phosphate regulates multiple genes during osteoblast differentiation, including Nrf2. 1291 20

A cell line of murine osteogenic progenitor cells, Kusa, was established from femoral bone marrow stromal cells with other types of mesenchymal progenitor cells. We characterized two sublines of Kusa (Kusa-A1 and Kusa-O) from several aspects, including the use of an expression profiling system, a cDNA microarray. The original Kusa subline (Kusa-A1) had high alkaline phosphatase activity and high accumulation of calcium deposits in a condition inducing mineralization, with ascorbic acid and beta-glycerophosphate. Kusa-O, a low osteogenic subline of Kusa, had high alkaline phosphatase activity but slow accumulation of calcium deposits even in the inducing condition. These two Kusa sublines differed in the expression of the osteogenic marker genes, osteocalcin and osteopontin, during mineralization. A type of cDNA microarray revealed marked downregulation of gene expression in the inducing condition in both Kusa-A1 and Kusa-O. Another type of high-throughput microarray was performed to examine the difference in gene expression patterns between Kusa-A1 and Kusa-O. By this analysis, periostin, which would be involved in a stage of osteogenesis, was low in Kusa-A1. On the contrary, Myocyte enhancer factor 2C (MEF2C), a myogenic transcriptional factor, was high in Kusa-A1, although no expression of any other myogenic genes was shown.
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PMID:Molecular and cell biological properties of mouse osteogenic mesenchymal progenitor cells, Kusa. 1575 Jun 90

Tissue ossification in Peyronie disease (commonly known as Peyronie's disease [PD]), a localized fibrotic lesion within the tunica albuginea (TA) of the penis, may result from osteogenic differentiation of fibroblasts, myofibroblasts, and/or adult stem cells in the TA, and may be triggered by chronic inflammation, oxidative stress, and profibrotic factors like transforming growth factor beta 1 (TGFB1). In this study, we have investigated whether cultures of cells from normal TA and PD plaques undergo osteogenesis, express markers for stem cells, and originate other cell lineages via processes modulated by TGFB1. We found that TA and PD cells in osteogenic medium (OM) expressed osteogenic markers, alkaline phosphatase, and osteopontin and underwent calcification. PD cells, but not TA cells, formed foci in soft agar that were positive for alkaline phosphatase and calcification and expressed the mRNAs for osteoblast-specific factors pleiotrophin and periostin and bone morphogenic protein 2. Both cultures expressed stem cell marker CD34 antigen but not protein tyrosine phosphatase, receptor type c. TA and PD cells expressed smooth-muscle cell markers smoothelin and transgelin. None of the cultures underwent adipogenesis in adipogenic medium. Incubation with TGFB1 increased osteogenesis and myofibroblast differentiation and reduced CD34 antigen expression in both cultures. TA and PD cells modulated the differentiation of the multipotent C3H 10T(1/2) cells in dual cultures, into osteoblasts and myofibroblasts. In conclusion, both TA and PD cultures contain cells, presumably stem cells, that undergo osteogenic and myofibroblast differentiation, and may induce these processes by paracrine interactions. This may explain progression of fibrosis in the PD plaque and its eventual calcification.
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PMID:Evidence that osteogenic progenitor cells in the human tunica albuginea may originate from stem cells: implications for peyronie disease. 1609 62

The periodontal ligament (PDL) is a highly specialized tissue connecting the cementum with the tooth socket bone and affects the life span of the tooth. However, little is known about the precise characteristics and regenerative mechanism of PDL cells because of the absence of specific markers and cell lines. Therefore, we aimed to establish three immortalized human PDL fibroblast cell lines by using simian virus40 T-antigen (SV40T-Ag) and human telomerase reverse transcriptase (hTERT) transfection, expecting these cells to have the characteristics of primary cells. The transfected cells were named STPLF. The expression of SV40T-Ag and hTERT in all STPLF lines was verified by using the semi-quantitative reverse transcription-polymerase chain reaction (RT-PCR) method, stretch PCR analysis, or Western blotting analysis. All STPLF showed stable proliferation at more than 120 population doublings (PD), whereas primary human PDL fibroblasts (HPLF) stopped at 10-20 PD. Characterization by RT-PCR analysis revealed that all STPLF genes mimicked the expression of their respective original HPLF genes. STPLF expressed runt-related transcription factor-2, osterix, alkaline phosphatase, osteopontin, osteocalcin, periostin, receptor activator of NF-kappa B ligand, osteoprotegerin, epidermal growth factor receptor, alpha-smooth muscle actin, and type XII collagen. STPLF stimulated with 50 micro g/ml ascorbic acid and 2 mM beta-glycerophosphate for 4 weeks produced more calcified deposits than did HPLF cultured with the same reagents. These results suggest that each STPLF line retained the characteristics of the respective original HPLF, that STPLF gained increased calcification activity, and that STPLF are helpful tools for studying the biology and regenerative mechanisms of human PDL.
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PMID:Establishing and characterizing human periodontal ligament fibroblasts immortalized by SV40T-antigen and hTERT gene transfer. 1640

Osteoblasts and osteocytes derive from the same precursors, and osteocytes are terminally differentiated osteoblasts. These two cell types are distinguishable by their morphology, localization and levels of expression of various bone cell-specific markers. In the present study on the chicken femur we investigated the properties of the mesenchymal cells within cartilage canals on their course into the secondary ossification centre (SOC). We examined several developmental stages after hatching by means of light microscopy, electron microscopy, immunohistochemistry and in situ hybridization. Cartilage canals appeared as extensions of the perichondrium into the developing distal epiphysis and they were arranged in a complex network. Within the epiphysis an SOC was formed and cartilage canals penetrated into it. In addition, they were successively incorporated into the SOC during its growth in the radial direction. Thus, the canals provided this centre with mesenchymal cells and vessels. It should be emphasized that regression of cartilage canals could never be observed in the growing bone. Outside the SOC the mesenchymal cells of the canals expressed type I collagen and periostin and thus these cells had the characteristics of preosteoblasts. Periostin was also expressed by numerous chondrocytes. Within the SOC the synthesis of periostin was down-regulated and the majority of osteoblasts were periostin negative. Furthermore, osteocytes did not secret this protein. Tissue-non-specific alkaline phosphatase (TNAP) staining was only detectable where matrix vesicles were present. These vesicles were found around the blind end of cartilage canals within the SOC where newly formed osteoid started to mineralize. The vesicles originated from osteoblasts as well as from late osteoblasts/preosteocytes and thus TNAP was only expressed by these cells. Our results provide evidence that the mesenchymal cells of cartilage canals express various bone cell-specific markers depending on their position. We suggest that these cells differentiate from preosteoblasts into osteocytes on their course into the SOC and consider that cartilage canals are essential for normal bone development within the epiphysis. Furthermore, we propose that the expression of periostin by preosteoblasts and several chondrocytes is required for adhesion of these cells to the extracellular matrix.
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PMID:Identification and location of bone-forming cells within cartilage canals on their course into the secondary ossification centre. 1676 72

The dental follicle contains mesenchymal cells that differentiate into osteoblasts, cementoblasts, and fibroblasts. However, the characteristics of these mesenchymal cells are still unknown. alpha-Smooth muscle actin (alpha-SMA) is known to localize in stem cells and precursor cells of various tissues. In the present study, to characterize the undifferentiated cells in the dental follicle, immunohistochemical localization of alpha-SMA was examined during rat molar tooth development. Rat mandibles were collected at embryonic days (E) 15-20 and postnatal days (P) 7-28. Immunohistochemical stainings for alpha-SMA, periostin, Runt-related transcription factor-2 (Runx2), tissue nonspecific alkaline phosphatase (TNAP), and bone sialoprotein (BSP) were carried out using paraffin-embedded sections. alpha-SMA localization was hardly detected in the bud and cap stages. At the early bell stage, alpha-SMA-positive cells were visible in the dental follicle around the cervical loop. At the late bell to early root formation stage (P14), these cells were detected throughout the dental follicle, but they were confined to the apical root area at P28. Double immunostaining for alpha-SMA and periostin demonstrated that alpha-SMA-positive cells localized to the outer side of periostin-positive area. Runx2-positive cells were visible in the alpha-SMA-positive region. TNAP-positive cells in the dental follicle localized nearer to alveolar bone than Runx2-positive cells. BSP was detected in osteoblasts as well as in alveolar bone matrix. These results demonstrate that alpha-SMA-positive cells localize on the alveolar bone side of the dental follicle and may play a role in alveolar bone formation.
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PMID:Immunohistochemical localization of alpha-Smooth muscle actin during rat molar tooth development. 1692 23

Periodontal regeneration requires the coordinated movement and differentiation of several cell types in order to re-establish the cementum, periodontal ligament (PDL), and alveolar bone. Cells in culture are often used as model systems for mature tissues, although they may represent expanded progenitor cell populations. Comparison of transcript expression between fresh PDL tissue and PDL cell isolates by MicroArray analysis has revealed numerous molecular differences. Several transcripts (including alkaline phosphatase, bone sialoprotein, periostin, and fibromodulin) are expressed at higher levels in fresh PDL than in cultured PDL cells. In contrast, PDL cells in culture selectively express a variety of growth factors. Several of these growth factors alter PDL fibroblast behavior. Two members of the transforming growth factor beta family of growth factors, namely, bone morphogenic protein-7 (BMP7) and growth differentiation factor-5 (GDF5), reduce cell proliferation and Stro-1 expression (a bone marrow stromal stem cell marker), whereas only BMP7 induces alkaline phosphatase activity. In contrast, fibroblast growth factor-5 induces enhanced cell proliferation and Stro-1 expression, while repressing alkaline phosphatase activity. The stimulation of PDL cells to differentiate (either by BMP7 or GDF5) inhibits cell motility. Thus, PDL cells in culture are regulated by several factors that differentially stimulate a mineralized (cementoblast-like) fate, a non-mineralized fate (mature fibroblasts), or the propagation of a more naive phenotype (potential progenitors).
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PMID:Use of microarrays to find novel regulators of periodontal ligament fibroblast differentiation. 1702 20

We aimed to histologically elucidate whether bioresorbable plates (DeltaSystem) can induce cortical bone formation, which is essential for long-lasting bone augmentation. Standardized bone defects in rat calvariae were covered with a convexly-shaped DeltaSystem plate, and then processed for histological observations. At 1 week, alkaline phosphatase-positive osteoblasts were seen in the newly-formed bone extending from the cavity's bottom, indicating accelerated osteogenesis. A thick layer of soft connective tissue positive for periostin, a hallmark of periosteum, covered this new bone. At 2 weeks, a spongy bone had filled the cavity up to half its height. The inner layer of the soft tissue facing the spongy bone revealed abundant periostin and osteopontin, and had many tartrate-resistant acid phosphatase-positive osteoclasts. At 4 weeks, this layer had given rise to thin new bony matrices without relation to the spongy bone arising from the cavity. These bone matrices had been thickened by 8 weeks, and turned into a thick cortical bone outlining the regenerated bone at 12 weeks. Thus, our study has provided histological evidences of cortical osteogenesis when DeltaSystem plates are used for bone augmentation procedures.
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PMID:Histochemical examinations on cortical bone regeneration induced by thermoplastic bioresorbable plates applied to bone defects of rat calvariae. 1787 2


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