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)

Estrogen therapy, using either oral or transdermal routes, decreases bone turnover and prevents postmenopausal bone loss. It has been suggested that oral and transdermal 17beta-estradiol (E2) may have different effects on serum insulin-like growth factor I (IGF-I), a potent bone-forming growth factor. In this study we investigated the effects of a new route of administration, the intranasal E2 spray (S21400), on bone turnover and circulating IGF-I and IGF-binding protein-3 (IGFBP-3). Four hundred and twenty early postmenopausal women (<5 yr since menopause; mean age, 52 yr) were enrolled in a 3-month, double blind, placebo-controlled study of four doses of intranasal E2 (100, 200, 300, and 400 microg/day), two doses of oral E2 valerate (1 or 2 mg/day), and placebo. One hundred and twelve women were further treated for 12 months with intranasal E2 (300 microg/day, i.e. the dose that has been shown to be adequate for the majority of postmenopausal women). Markers of bone resorption (urinary type I collagen C telopeptides) and formation [serum osteocalcin, serum type I collagen N-terminal extension propeptide (PINP), and serum bone alkaline phosphatase (BAP)] were measured at baseline, 1 month, 3 months, and 15 months. Serum IGF-I and IGFBP-3 were measured at baseline, 1 month, and 3 months. Urinary type I collagen C telopeptides decreased significantly in all active treatment groups as soon as 1 month (P<0.001 vs. placebo) and continued to decrease at 3 months with a dose effect for intranasal E2. Serum osteocalcin and PINP did not change at 1 month for oral E2 (1 and 2 mg), but decreased significantly at 3 months. In contrast, formation markers increased significantly at 1 month for the two highest doses of intranasal E2 (P<0.01 vs. placebo for osteocalcin and BAP) and did not decrease at 3 months. Oral E2 induced a marked decrease in circulating IGF-I as early as 1 month, which was amplified at 3 months (-29% and -32% for 1 and 2 mg, respectively), whereas no significant change from placebo was observed for intranasal E2 during the 3-month period. Changes in circulating IGF-I correlated significantly (P<0.01) with changes in osteocalcin, PINP, and BAP at 3 months. Oral and intranasal E2 did not induce any significant change from placebo in serum IGFBP-3 at both 1 and 3 months. After 1 yr of treatment with intranasal E2 (300 microg/day), both resorption and formation markers decreased, reaching the levels in premenopausal women, regardless of the type of treatment during the first 3 months. We conclude that E2 administered by this new nasal route normalizes bone turnover to premenopausal levels. The delayed decrease in bone formation observed with intranasal E2 compared to oral E2 may be related to different effects on serum IGF-I levels.
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PMID:Effects of intranasal 17beta-estradiol on bone turnover and serum insulin-like growth factor I in postmenopausal women. 1040 9

Changes in bone modeling and remodeling in the tibia of growing rats within 30 days of ovariectomy (ovx) were evaluated by histomorphometric, mechanical; and biochemical means. Three days after ovx, suppressed bone formation was seen. This was shown by reduced osteoid volume, osteoblast surface, and bone formation rate in the secondary spongiosa, and a reduced longitudinal growth rate in the growth plate. In addition, the alkaline phosphatase and tartrate-resistant acid phosphatase activity in bone marrow supernatants was suppressed in conjunction with elevated serum sialic acid levels, indicating inflammation. Although estrogen deprivation itself may provoke the inflammatory process, the serum sialic acid level in the ovx group returned to the baseline level within 5 days after surgery, while that of estradiol in the ovx group remained consistently lower. This suggests that surgical stress, not estrogen deprivation, is the primary cause of the inflammatory response shortly after ovx. A significant difference (p < 0.01) between the ovx and sham rats was seen in the osteoclast surface, which peaked on day 7 in the ovx rats. On day 14 postovariectomy, the bone formation rate peaked and remained constant until day 30. In the ovx rats, there was a sustained reduction in the serum albumin level until day 30. Estrogen deprivation may be the primary cause of these changes, because both surgical ovx and medical oophorectomy with gonadotropin-releasing hormone agonist (G(nRHa) reduce the serum albumin level. In numerous studies dealing with changes after ovx in rats, we have observed: 1) a transient reduction in bone formation in relation to inflammatory changes evoked by ovx surgery, and 2) a sustained reduction in the serum albumin level for at least 30 days after ovx that is possibly due to estrogen deprivation.
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PMID:Reduction in bone formation and elevated bone resorption in ovariectomized rats with special reference to acute inflammation. 1061 56

Estrogen receptors are extensively expressed in the gastrointestinal tract, however their physiological role is not clear yet. Estrogen and 1,25-dihydroxyvitamin D [1,25(OH)2D3] apparently share common activities in the intestine such as growth-suppressing effects on the colonic mucosa and positively influence intestinal calcium absorption. In view of our previous studies showing up-regulation of vitamin D receptors (VDR) in the duodenal mucosa and in osteoblasts, the present study was designed to address a possible interaction between estrogen and the vitamin D endocrine system in the colonic mucosa. Three groups of female rats were studied: sham operated ('Sham'), ovariectomized ('OVX'), and ovariectomized estrogen-treated ('OVX+E'). VDR gene expression was assessed by Northern blot analysis, VDR protein expression was assessed by ligand-binding assays, and Western-blotting. Endogenous 1,25(OH)2D3 bioactivity in colonic mucosal extracts was assessed by alkaline phosphatase activity and calbindin-9kD mRNA expression. Northern blots revealed marked increase in band intensity corresponding with the VDR mRNA product in 'Sham' or 'OVX+E' vs. 'OVX'. In ligand-binding experiments, 1,25(OH)2D3 was shown to bind specifically to a single class of receptors in extracts obtained from each of the groups (Kd--0.03 nM). The maximal VDR binding capacity of colonic mucosal extracts was 203 +/- 23 fmol/mg protein in 'Sham', 362 +/- 41 in 'OVX+E' and 102 +/- 15 in 'OVX' ('Sham' or 'OVX+E' vs. 'OVX', p < 0.001). Western-blot analysis also revealed higher VDR protein expression in the estrogen-exposed animals. Alkaline phosphatase activity and calbindin-9kD mRNA expression were significantly higher in colonic mucosal extracts from estrogen-exposed rats. Estrogen increases VDR gene transcript level, protein expression and endogenous 1,25(OH)2D3 bioactivity in colonic mucosa, which may suggest that some of the estrogen activities in the colonic mucosa, such as its growth-suppressing effect, could be mediated, at least in part, by an increase in colonic mucosa responsiveness to endogenous 1,25(OH)2D3.
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PMID:Estrogen controls expression and bioresponse of 1,25-dihydroxyvitamin D receptors in the rat colon. 1072 36

Recently, we showed that supplementation with nitric oxide (NO) via donor nitroglycerin (NG) alleviated the ovariectomy and corticosteroid-induced bone loss in rats. In humans, high doses or frequent applications of NG (i.e., for angina) lead to rapid loss of its efficacy in relieving angina. To examine whether there is a similar effect on the loss of efficacy of NG on bone, we examined the frequency-dependent effects of NG on bone mineral density (BMD), bone mass, trabecular bone volumes (BV/TV), and blood pressure in rats. Thirty 7-month-old female Brown Norway rats underwent ovariectomy, and an additional six rats were sham-operated. The ovariectomized rats were treated either with vehicle (ovariectomized control), 17beta-estradiol (E2; positive control), or 0.2 mg NG (via dermal application) once, twice, or three times a day. Before and at the end of the 10-week treatment period, BMD of the lumbar spine was measured by dual-energy X-ray absorptiometric (DXA) scanning and expressed as a percentage change. BMD in ovariectomized rats was significantly lower (-2.5 +/- 2.0%) compared with the sham-operated rats (+6.3 +/- 5.3%; p < 0.01). Estrogen therapy completely abolished the ovariectomy-induced potential bone loss (+5.9 +/- 3.4%). Application of NG once daily also completely prevented (+6.2 +/- 2.8%; p < 0.01) the ovariectomy-induced bone loss (i.e., it was as effective as estrogen). However, the beneficial effects of NG on BMD were significantly reduced with increased frequency of application of NG (+1.9 +/- 2.1%, twice a day and -0.2 +/- 3.3% three times a day). Estrogen or once daily administration of NG preserved femur weights, BV/TV, and decreased urinary deoxypyridinoline levels as expected. However, a higher level of serum osteocalcin and bone-specific alkaline phosphatase levels were maintained only with once daily administration of NG. There were no adverse effects of these doses of NG on blood pressure, but a tendency to lower blood pressure was noticed with increased frequency of NG. These results confirmed our previous findings that NO donors counteract the bone loss associated with estrogen deficiency. However, these beneficial effects of maintaining BMD are lost with increased frequency of NG application.
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PMID:Frequency-dependent effect of nitric oxide donor nitroglycerin on bone. 1084 Nov 80

Evidence for the role of estrogen in male bone metabolism has been confirmed by studies on a man with a genetic defect in the estrogen receptor as well as men with aromatase defects. All exhibited tall stature, delayed epiphysial closure, decreased bone density and increased bone turnover. Estrogen is likely to affect bone turnover in men throughout life; therefore, we hypothesized that older men would show decreased bone resorption in response to estrogen therapy. To test our hypothesis, fourteen community-dwelling men with osteopenia of the femoral neck were treated for 9 weeks with micronized estradiol, 1 mg/d, a dose which is effective in postmenopausal women. Each subject served as his own control. Markers of bone resorption, N-terminal collagen crosslinks (NTX) and C-terminal collagen crosslinks (CTX) and markers of bone formation, osteocalcin (OC) and bone specific alkaline phosphatase (BSAP) were measured every 3 weeks during a 9-week treatment period and 9 weeks post-treatment. Sex hormones, gonadotrophins and calciotropic hormones were measured at baseline, 9 weeks on treatment and 9 weeks post- treatment. After 9 weeks of treatment, estradiol and estrone levels increased significantly by greater than 6-fold and 15-fold, respectively. SHBG levels increased significantly by 17%. Testosterone and free testosterone levels decreased significantly by 27% and 34%, respectively. Markers of bone resorption showed wide variation at baseline and while on treatment. There was no correlation between changes in bone markers and changes in estrogen levels. During treatment, 11 patients showed a decrease of NTX or CTX, but three showed an increase. These three and one other subject had high initial levels of FSH and LH, suggesting some degree of primary gonadal failure, which decreased during estrogen therapy. Thus, the change in NTX (and CTX) after 9 weeks of E2 treatment was correlated with initial FSH (r= -.66, p= .01) and LH (r= -.73, p= .003) values. In addition, the largest decrease in free testosterone at 9 weeks was correlated with the higher values for NTX, CTX and BAP (r=-0.66, -0.68, -0.70 respectively; p< or =.01 for each of the markers). Treatment was generally well tolerated. Side effects of treatment were minimal, and included breast tenderness and decreased libido which reversed after treatment. We conclude that it is feasible to give low dose estrogen to healthy older men, but that the effects on bone turnover are not consistent. Changes in central feedback and in endogenous sex hormone production may alter the response of bone turnover to exogenous estrogen in this population.
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PMID:The effect of short-term treatment with micronized estradiol on bone turnover and gonadotrophins in older men. 1101 3

High-dose estrogen both stimulates new medullary bone formation and suppresses hematopoiesis in mouse long bones. To determine whether the latter response is a direct consequence of the former, we compared the time course of estrogen's effects on osteogenesis and hematopoietic bone marrow. Flow cytometry was employed to measure hematopoietic subpopulations in bone marrow from femurs of female mice killed at different times after commencing 0.5 mg estradiol/wk to each animal. Estrogen markedly reduced the number of leucocytes (CD11a positive), which had already diminished by 75% after 4 days and had virtually disappeared by 18 days. Specific populations showed a similar pattern of decline after estrogen, including B lymphocytes, monocytes, and endothelial cells. In contrast, the osteogenic precursor population showed a marked increase after estrogen treatment, as assessed by assaying alkaline phosphatase-positive colony-forming units (fibroblastic) ex vivo. However, this rise did not reach significance until 8 days after estrogen administration, suggesting that it follows rather than precedes estrogen's effects on hematopoiesis. We conclude that estrogen does not suppress hematopoiesis in mouse long bones as a direct consequence of its effects on osteogenesis.
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PMID:Effects of high-dose estrogen on murine hematopoietic bone marrow precede those on osteogenesis. 1105 72

Osteoblast differentiation under in vitro conditions is associated with increased expression of non-collagenous bone proteins including osteocalcin, osteopontin, and osteonectin, the exact function of which remain poorly understood. To determine whether these proteins play an important role in the formation of mineralised bone matrix by osteoblasts in vivo, we analysed the time-course of their expression during estrogen-induced osteogenesis in female mice, and compared this with the formation of new cancellous bone. Female mice were sacrificed prior to or following treatment with 17beta-estradiol for up to 32 days (500 microg/animal/week). Total RNA was extracted from femurs, and changes in expression of genes for a range of osteoblast-derived proteins assessed by Northern blot analysis. In parallel experiments, the time course of cancellous bone formation was determined by measuring bone mineral density (BMD) of the distal femur. Estrogen led to a rapid increase in BMD, which reached significance by Day 16. This was preceded by three-fold increases in expression of alkaline phosphatase (ALP) and type I collagen (COL I) at Days 8 and 12 respectively. In contrast, osteocalcin, osteopontin, and osteonectin expression showed no change during this initial period, although modest increases were observed at later times (i.e., Days 20 and 24). Our results suggest that osteocalcin, osteopontin, and osteonectin are not involved in the initial phase of the osteogenic response to estrogen, suggesting that these non-collagenous bone proteins do not play a direct role in the formation of mineralised bone matrix by osteoblasts in vivo.
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PMID:Characterisation of the temporal sequence of osteoblast gene expression during estrogen-induced osteogenesis in female mice. 1150 Sep 46

Estrogen therapy decreases bone remodeling, but the association between endogenous estradiol (E2), estrone (E1), testosterone (T), and bone turnover in older women is not clear. To test the association of serum E2, E1, free T, and sex hormone-binding globulin (SHBG) with bone turnover, we analyzed cross-sectional relationships among E2, E1, T, SHBG, and biochemical markers of bone turnover serum osteocalcin [OC], serum bone-specific alkaline phosphatase [bAP], and serum breakdown products of C telopeptide of type I collagen [CTx] in 704 women enrolled in the Study of Osteoporotic Fractures. Women with lower estradiol levels tended to have higher levels of bone turnover, but the association was weak (R(2) = 0.01 for the association E2-OC, p = 0.03; and R(2) = 0.024 for E2-CTx, p = 0.001). Relationships between SHBG and turnover were also weak (R(2) for the association SHBG-OC was 0.07, p < 0.001, and 0.03 for SHBG-sCTx, p = 0.03), or not significant (R(2) < 0.01 for the association SHBG-bAP). Associations of E1 and T with these markers were of the same magnitude. These results were not modified after adjustment for age, weight, and smoking status. We conclude that older women with low endogenous hormones have somewhat higher bone turnover, but these associations are weak. Bone turnover is determined mainly by factors other than endogenous concentrations of sex hormones.
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PMID:Association between endogenous hormones and sex hormone-binding globulin and bone turnover in older women: study of osteoporotic fractures. 1159 22

Estrogen has been reported to regulate the growth and differentiation of cultured murine osteoprogenitor cells in bone marrow stroma. This study tested the ability of 17beta-estradiol (E2) to regulate growth and expression of alkaline phosphatase (ALP), an osteoblastic differentiation marker, in strains of normal human bone marrow stromal cells derived from different donors. In eight strains examined, E2 at 1 and 10 nM produced at most modest effectxs on growth and ALP activity. Growth inhibition, seen in 4 of the 8 strains, was more common than stimulation (2 of the 8 strains); the greatest observed E2 effect was an inhibition of ca. 50%. E2 altered ALP activity less dramatically than cell growth. Differences from control in total ALP per culture were seen in only two strains: one was a reduction, one an increase. Colony forming assays were used to determine if E2 changed the proportion of ALP-expressing cells in marrow stromal cell cultures. In contrast to growth experiments, ALP expression under colony forming conditions (200 cells per 35 mm-diameter well) was dependent on the type of serum supplementation used. Under permissive conditions using medium supplemented with 10% charcoal-treated fetal bovine serum, 10 nM E2 increased the number of ALP-positive colonies (cfu-ap) but not the total number of colonies formed (cfu-f). When cells cultured in the presence or absence of 10 nM E2 were replated at colony forming densities, significantly higher proportions of cfu-ap were found in 2 of 6 strains examined, while pretreatment with E2 affected the number of cfu-f in only 1 of the 6 strains. Similar results were obtained when colony formation was carried out in the presence of dexamethasone and ascorbate, although these agents themselves increased the formation of both cfu-f and cfu-ap. These results show that the direct effects of E2 on human marrow stromal cells are small and vary depending on the cell strain and on the experimental conditions; however, the E2 actions observed in this study were consistent with reports that E2 exerts direct actions on osteoblasts and osteoblast progenitor cells that favor rather than suppress their phenotypic expression.
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PMID:Estrogen regulation of growth and alkaline phosphatase expression by cultured human bone marrow stromal cells. 1191 7

Estrogen is known to act on osteoblasts according to their stage of differentiation and estrogen receptor (ER) isoform expression. The aim of this study was to determine when type I collagen (COL1) synthesis by cultured low-passage, human bone-derived osteoblasts (hOBs) is upregulated in response to estrogen. Cell lines from female donors aged 1 and 66 years were cultured for 11 days on collagen in growth medium supplemented with human serum, hydrocortisone, and beta-glycerophosphate. Young-donor hOBs grew more quickly than old-donor hOBs and did not mineralize. Old-donor hOBs formed mineralized nodules 5 days after reaching confluence. Changes in mRNA levels with time for ERs, type I collagen, and alkaline phosphatase reflected the faster differentiation of the old-donor cells. The ERbeta/ERalpha ratio fell threefold in young-donor hOBs but rose 300-fold in old-donor hOBs. Increased ERbeta/ERalpha ratios prevented ligand-dependent downregulation of ERalpha transcription, resulting in reduced proliferation in old-donor hOBs. Upregulation of COL1 mRNA expression in response to estrogen was confined to intermediate stages of differentiation, resulting in significant increases in COL1 mRNA by estradiol only in young-donor cells. Since the young and old-donor hOBs were cultured under identical conditions, our results indicate that the response of hOBs to estrogen is largely dependent on intracellular mechanisms that control the timing of cellular differentiation.
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PMID:Effects of estrogen on collagen synthesis by cultured human osteoblasts depend on the rate of cellular differentiation. 1211 94


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