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)

Osteoarthritis is a degenerative joint disease characterized by destruction of the articular cartilage in aging and senescence. The aim of this study was to study the possible treatment of this disease by intraarticular injection of growth factors to osteoarthritic joints of aged animals. 20-month-old female ICR mice were injected with insulin-like growth factor (IGF-1), transforming growth factor-beta (TGF-beta) or TGF-beta+IGF-1 on days 1, 4, and 7. On day 9 the joints were dissected and cultured in the presence of 35S-sulfate and 3H-thymidine. Combined treatment of TGF-beta and IGF-1 resulted in elevated 3H-thymidine incorporation and DNA and protein contents, reduction of 35S-sulfate incorporation and alkaline phosphatase activity, with no significant change in the activity of acid phosphatase. Following injections of TGF-beta, contents of DNA and protein, and incorporations of 3H-thymidine were induced, and 35S-sulfate and alkaline phosphatase activity were reduced. Treatment with IGF-1 resulted in reduced incorporation of 3H-thymidine with no significant changes in the activity of acid phosphatase. Atypically hypertrophic chondrocytes were observed along the articular surface and the endogenous production of TGF-beta and of IGF-1, as revealed by immunohistochemistry, was reduced. It is concluded that although 3H-thymidine incorporation and alkaline phosphatase activity appeared to be induced by TGF-beta and IGF-1, the overall responsiveness of cartilage from aged mice to these growth factors appeared to be inhibitory. Moreover, their effects appeared to be limited to specific cell populations in the cartilage itself.
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PMID:Differential metabolic responses to local administration of TGF-beta and IGF-1 in temporomandibular joint cartilage of aged mice. 1109 Sep 10

We explored to determine if iNOS could be induced by insulin in osteoblast-like UMR-106 cells. Insulin (100 nM) stimulated nitric oxide production by twofold and significantly increased iNOS mRNA and protein levels. Insulin also increased collagen synthesis, but had little effect on alkaline phosphatase activity. In contrast, IGF-1 had little effect on NO production below 10 nM and it stimulated NO production by only 57% at 100 nM. IGF-1 had little effect on collagen levels, whereas it inhibited alkaline phosphatase activities in a dose-dependent manner. When an MEK inhibitor was preincubated, insulin failed to stimulate NO production, whereas insulin dramatically increased NO production in the ERK1 overexpressed cells. Taken together, it is proposed that insulin increases iNOS mRNA, iNOS protein, and NO production, possibly via activation of ERK. These may play an important role in osteoblast functions such as collagen synthesis.
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PMID:Insulin stimulates production of nitric oxide via ERK in osteoblast cells. 1109 73

It was hypothesized that the widespread structural defect of collagen in connective tissue of vitamin B6 deficient-animals and the consequent alteration in bone biomechanical properties cause an additional stress to their inflamed swollen tibiotarsometatarsal joints. The present study showed a 32% elevation (P < 0.02) in mean plasma free cortisol concentration. Vitamin D metabolism was impaired but without changing plasma calcium homeostasis and bone mineral content. Mean plasma calcitriol [1,25(OH)2D] concentration was significantly reduced (P < 0.001). Because plasma calcidiol concentration did not change, we speculated that either renal 25-hydroxycalciferol-1alpha-hydroxylase activity was reduced or 1,25(OH)2D turnover was increased. Plasma osteocalcin, an index of osteoblast function related to bone formation, was significantly decreased (P < 0.05). This adverse effect on osteoblasts was consistent with the reduction of bone specific alkaline phosphatase activity (another index of bone formation) found in a previous study. The excess of cortisol may have impaired these bone cells functions directly and (or) indirectly via the decline in calcitriol synthesis. Plasma hydroxyproline concentrations in B6-deficient animals were found to be significantly reduced (P < 0.001), suggesting that cortisol in excess had also a suppressive effect on another hydroxylase, namely tissue (mainly bone and liver) prolyl hydroxylase. The bone uncoupling (in formation and resorption) associated with vitamin B6 deficiency seems to be due to secondary hypercortisolism and (or) another unknown factors but not related to a change in bone modulators such as IGF-1 and eicosanoids.
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PMID:Perturbations in factors that modulate osteoblast functions in vitamin B6 deficiency. 1110 Sep 39

In the present study, we test the hypothesis that the stimulation of osteoprogenitor differentiation by the glucocorticoid dexamethasone (Dex) is mediated, at least in part, through components of the insulin-like growth factor (IGF) system. Because it has been suggested that osteoprogenitors and adipocyte progenitors originate from the same precursor cells, and that their differentiation in many systems is reciprocally regulated, the effects of Dex and IGF on adipocyte formation were also evaluated in the same cultures. In view of the presence of IGFs and their binding proteins in serum, we also evaluated to what degree the effects of IGF-1 and IGF-2 on differentiation of osteoblasts and adipocytes were affected by the serum concentration of the culture media. Bone cell populations were isolated from vertebrae of 3-month-old female Wistar rats using an explant culture technique. Osteoprogenitor differentiation was evaluated by a colony assay: Bone-forming osteoblastic colonies (bone nodules) derived from single osteoprogenitors were identified by alkaline phosphatase (ALP) staining and/or staining for mineralized matrix according to the von Kossa technique. Unmineralized nodules and osteoblastic colonies were subsequently identified by their distinctive color and morphology after methylene blue counterstaining. Differentiated adipocytes were identified by Sudan IV staining. IGF-1 and IGF-2 stimulated both osteoprogenitor and adipocyte progenitor differentiation in a dose-dependent pattern. The stimulation of osteoprogenitor differentiation by IGF was not dependent on Dex, but differentiation of adipocytes was. The stimulatory effects of IGF-1 and IGF-2 on osteoprogenitor differentiation were greater in media containing 2.5% fetal bovine serum (FBS) than in media containing 5% or 10% FBS, whereas stimulation of adipocyte formation was greater in media containing 10% FBS. Neutralizing antibody against the type 1 IGF receptor (IGF-1R) partially blocked IGF- and Dex-induced osteoprogenitor differentiation, but did not affect IGF-induced adipocyte formation. This suggests that IGF-stimulated osteoprogenitor differentiation is mediated through IGF-1R, that the stimulation of adipocyte formation by IGF is not, that the stimulatory effects of Dex on osteoprogenitor differentiation are partially mediated through IGF-1R, and that the effects on adipocyte differentiation appear to be mediated through signaling pathways other than the IGF-1R.
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PMID:Insulin-like growth factor-1 and -2 stimulate osteoprogenitor proliferation and differentiation and adipocyte formation in cell populations derived from adult rat bone. 1111 89

Renal osteodystrophy is a metabolic bone disease occurring in patients with end-stage renal failure. The aim of the study was to compare serum concentrations of some bone markers in hemodialysed (HD) patients and in patients undergoing continuous ambulatory peritoneal dialysis (CADO). We studied two groups of patients with end-stage renal failure: 52 hemodialysed individuals aged 24-74 years and 19 peritoneally dialysed patients aged 20-70 years. Serum calcium and phosphate concentration, cholesterol, triglycerides, total protein, albumin, alkaline phosphatase, urea before and after HD, urea in CADO patients were determined by standard laboratory methods. Serum PTH, osteocalcin, 1,25(OH)2D3 and insulin-like growth factor (IGF-1) concentrations were measured by commercially available radioimmunoassay. Serum tumor necrosis factor (TNF-alpha) and interleukin-1 (IL-1) concentrations were measured by ELISA. There were no differences between serum concentrations of the studied bone markers in hemodialysed patients and CAPD patients. All dialysed patients presented high concentrations of serum PTH, osteocalcin, alkaline phosphatase activity, lower serum IGF-1 concentration and normal serum calcitriol concentration. High serum PTH and osteocalcin concentrations may indicate intensification of bone synthesis, what is typical for osteitis fibrosa.
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PMID:[Selected parameters of bone metabolism in hemodialyzed and peritoneally dialyzed patients]. 1139 92

Insulin-like growth factor (IGF) system components appear to be the most important regulators of bone cell function. On the other hand, IGF-1 is shown to be an important regulator for erythropoiesis. The aim of the study was to examine the relationships between IGF system, requirements of erythropoietin, endogenous erythropoietin levels, bone metabolism assessed by biochemical markers, markers of nutrition such as cholesterol and albumin in recombinant human erythropoietin (rHuEPO)-treated patients maintained on chronic hemodialyses or peritoneal dialyses as well as in kidney transplant recipients. The studies were performed on 79 chronically hemodialyzed patients; 28 of them did not receive rHuEPO, 51 subjects received rHuEPO, 34 patients on continuous ambulatory peritoneal dialysis (CAPD), 16 of them did not receive rHuEPO, 18 were given rHuEPO and 46 kidney allograft recipients. Endogenous erythropoietin concentration, bone-specific alkaline phosphatase and serum CrossLaps were assayed by ELISA. Intact PTH, osteocalcin, 1,25-(OH)(2) D(3), 25-OH D(3), IGF-1, procollagen type I carboxy-terminal extension peptide (PICP) and procollagen type I cross-linked carboxy-terminal telopeptide (ICTP) were studied by RIA, whereas IGFBP-1 and IGFBP-3 concentrations were assayed by IRMA. We found a significantly higher IGF-1 and IGFBP-3 in rHuEPO-treated HD patients when compared to CAPD subjects given rHuEPO as well as to hemodialysis (HD) patients not treated with rHuEPO. IGF-1 was significantly higher in kidney transplant recipients when compared to dialyzed patients without rHuEPO therapy. IGFBP-1 was similar in all groups of patients (including kidney transplant recipients) studied. In CAPD patients not given rHuEPO concentrations of ICTP and PICP were significantly lower when compared to rHuEPO-treated CAPD subjects and HD patients not receiving rHuEPO therapy. Serum CrossLaps in CAPD patients treated with rHuEPO were significantly higher when compared to CAPD subjects without rHuEPO treatment and to kidney transplant recipients. In rHuEPO-treated CAPD subjects IGF-1 and IGFBP-1 correlated positively with serum CrossLaps (r = 0.61, p < 0.05 and r = 0.64, p < 0.05, respectively), whereas in hemodialyzed patients without rHuEPO a significant negative correlation between IGFBP-3 and serum CrossLaps was found (r = --0.69, p < 0.001) as well as between IGFBP-3 and aluminium (r = 0.51, p < 0.05), IGF-1 and ICTP (r = --0.43, p < 0.05). In conclusion, our data indicate a probable functional relationship between IGF system components, erythropoietin treatment in dialyzed patients and bone metabolism in renal replacement therapy in a form of hemodialyses, peritoneal dialyses and kidney transplantation. Dialyzed patients exhibit more pronounced renal osteodystrophy than kidney allograft recipients. IGF system components are influenced by erythropoietin therapy, but are not related to serum erythropoietin levels and rHuEPO requirements.
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PMID:Insulin-like growth factor system components in relation to erythropoietin therapy and bone metabolism in dialyzed patients and kidney transplant recipients. 1186 49

Insulin receptor substrates (IRS) 1 and 2 are phosphorylated on serine/threonine (Ser/Thr) residues in quiescent cells (basal phosphorylation), and phosphorylation on both Ser/Thr and tyrosine residues is increased upon insulin stimulation. To determine whether basal Ser/Thr phosphorylation of IRS proteins influences insulin receptor catalyzed tyrosine phosphorylation, recombinant FLAG epitope-tagged IRS-1 (F-IRS-1) and IRS-2 (F-IRS-2) were expressed, purified, and subjected to both dephosphorylation and hyperphosphorylation prior to phosphorylation by the insulin receptor kinase. As expected, hyperphosphorylation of F-IRS-1 and F-IRS-2 by GSK3beta decreased their subsequent phosphorylation on tyrosine residues by the insulin receptor. Surprisingly, however, dephosphorylation of the basal Ser/Thr phosphorylation sites impaired subsequent phosphorylation on tyrosine, suggesting that basal Ser/Thr phosphorylation of F-IRS-1 and F-IRS-2 plays a positive role in phosphorylation by the insulin receptor tyrosine kinase. Dephosphorylation of basal Ser/Thr sites on F-IRS-1 also significantly reduced tyrosine phosphorylation by the IGF-1 receptor. However, dephosphorylation of F-IRS-2 significantly increased phosphorylation by the IGF-1 receptor, suggesting that basal phosphorylation of IRS-2 has divergent effects on its interaction with the insulin and IGF-1 receptors. Phosphorylation of endogenous IRS-1 and IRS-2 from 3T3-L1 adipocytes was modulated in a similar manner. IRS-1 and IRS-2 from serum-fed cells were hyperphosphorylated, and dephosphorylation induced either by serum deprivation or by alkaline phosphatase treatment after immunoprecipitation led to an increase in tyrosine phosphorylation by the insulin receptor. Dephosphorylation of IRS-1 and IRS-2 immunoprecipitated from serum-deprived cells, however, resulted in inhibition of tyrosine phosphorylation by the insulin receptor. These data suggest that Ser/Thr phosphorylation can have both a positive and a negative regulatory role on tyrosine phosphorylation of IRS-1 and IRS-2 by insulin and IGF-1 receptors.
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PMID:Positive and negative regulatory role of insulin receptor substrate 1 and 2 (IRS-1 and IRS-2) serine/threonine phosphorylation. 1203 42

Bone marrow (BM) contains numerous adipocytes. These share a common precursor with osteoblasts and chondrocytes, but their function is unknown. It is unclear what regulates the differentiation of these three different cell types, though their subsequent metabolic activity is under hormonal regulation. GH and estrogen stimulate bone growth and mineralization, by direct effects on chondrocytes and osteoblasts. GH also stimulates lipolysis in subcutaneous and visceral adipocytes. However, adipocytes in BM have largely been ignored as potential targets for GH or estrogen action. We have addressed this by measuring BM adipocyte number, perimeter and area as well as bone area and osteoblast activity in GH-deficient dwarf (dw/dw), normal, or ovariectomized (Ovx) rats, with or without GH, IGF-1, PTH, or estrogen treatment or high fat feeding. Marrow adipocyte numbers were increased 5-fold (P < 0.001) in dw/dw rats, and cell size was also increased by 20%. These values returned toward normal in dw/dw rats given GH but not when given IGF-1. Cancellous bone area and osteoblast number were significantly (P < 0.005) lower in dw/dw rats, though alkaline phosphatase (ALP) activity in individual osteoblasts was unchanged. GH treatment increased % osteoblast covered bone surface without affecting individual cell ALP activity. Ovariectomy in normal or dw/dw rats had no affect on marrow adipocyte number nor size, although estrogen treatment in ovariectomized (Ovx) normal rats did increase adipocyte number. Ovx decreased tibial cancellous bone area in normal rats (64%; P < 0.05) and decreased osteoblast ALP-activity (P < 0.01) but did not affect the percentage of osteoblast-covered bone surface. Estrogen replacement reversed these changes. While treatment with PTH by continuous sc infusion decreased cancellous bone (P < 0.05) and high fat feeding increased the size of BM adipocytes (P < 0.01), they did not affect BM adipocyte number. These results suggest that GH has a specific action on BM adipocytes that is not simply due to altered bone or fat metabolism. We conclude that the marrow adipocyte lineage is an important and specific target for GH action. The inverse relationship between adipocyte number and osteoblast covered bone surface, together with the well-known effects of GH on epiphysial chondrocytes leads us to propose that GH plays two important roles on cells of all three lineages. During differentiation, it regulates the numbers of each cell type that are maintained from the common precursor lineage. Subsequently it has cell-specific effects on the metabolic activities of the differentiated cells. In the case of marrow adipocytes, GH-dependent lipolysis could provide an important hormonally regulated local high energy source in bone.
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PMID:Bone marrow adipocytes: a neglected target tissue for growth hormone. 1223 18

The effects of melatonin on osteoclastic and osteoblastic cells were examined using a culture system of the goldfish scale. Tartrate-resistant acid phosphatase (TRACP) and alkaline phosphatase (ALP) were used as markers of osteoclastic and osteoblastic cells, respectively. In Earle's minimum essential medium containing melatonin (10(-9) to 10(-5) m), activities of both enzymes in scales were significantly suppressed at 6 hr after incubation (TRACP: 10(-8), 10(-6), 10(-5) m; ALP: 10(-7) to 10(-5) m), but at 18 hr only ALP activity was significantly lowered (10(-8), 10(-7) m). Estradiol-17beta (E(2)) enhanced both activities, which were significantly inhibited and brought down to the level of the controls when co-incubated with E(2) and melatonin (TRACP at 6 hr: 10(-9) to 10(-5) m; ALP at 6 hr: 10(-7) m; ALP at 18 hr: 10(-8) m). Moreover, using reverse-transcription polymerase chain reaction, the mRNA expression of the estrogen receptor (ER) and insulin-like growth factor (IGF)-1, which are related to osteoblastic growth and differentiation, was decreased in the melatonin-treated scales. These results suggest that melatonin acts directly on the scale osteoclastic and osteoblastic cells where it suppresses the ALP activity via down-regulation of ER and IGF-1 mRNAs expression. This is the first report on the function of melatonin in osteoclasts and on the suppressive effect of melatonin in osteoblasts among vertebrates.
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PMID:Melatonin suppresses osteoclastic and osteoblastic activities in the scales of goldfish. 1239 May 9

Postmenopausal hormone-sensitive breast cancer is currently treated with either antioestrogens or aromatase inhibitors (AIs), due to the clinical efficacy and safety of these drugs. Today's challenge is the sequential use of AIs with different structure and no cross-resistance to improve the therapeutic outcome. The present study describes the biological action of the steroidal structure (SS)-AI exemestane (EXE), in patients progressing on aminoglutethimide (AG) or other non-steroidal structure (NSS)-AIs (letrozole or anastrozole). Thirteen patients were evaluated for serum insulin-like growth factor (IGF) components [total IGF-1, IGF-2 and IGF binding protein (IGFBP)-3], interleukin (IL)-6 system [IL-6 and soluble IL-6 receptor (sIL-6-R)] and bone metabolism markers [bone gla protein/osteocalcin (BGP), bone-specific isoform of alkaline phosphatase (BAP) and carboxy-telopeptide of type I procollagen (ICTP)]. IGF system components show a trend to increase both in patients progressing on AG and in patients progressing on other NSS-AIs. Such an increase depends on the wash-out length from the previous treatment and is strictly linked to the circulating oestrogen levels. Serum IL-6 and sIL-6-R are mainly related to the patients' clinical outcome. Bone formation (BGP and BAP) and bone resorption (ICTP) markers seem to be at equilibrium with oestrogen levels when starting EXE and do not appear to be uncoupled over treatment. The observed variations seem to be mainly linked to the circulating oestrogen levels rather than directly to the way of action of the AI employed.
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PMID:Could exemestane affect insulin-like growth factors, interleukin 6 and bone metabolism in postmenopausal advanced breast cancer patients after failure on aminoglutethimide, anastrozole or letrozole? 1268 75


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