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)

Peroxisome proliferator-activated receptor gamma (PPARgamma), a ligand-activated transcription factor, is considered as an anti-osteoblastic factor associated with adiposity and the elderly osteoporosis due to a defect in osteoblastogenesis. We have found that oral administration of PPARgamma activator rosiglitazone decreased tibia BMD and serum ALP but left serum calcium and osteoclast marker C-terminal telopeptide unaffected. In addition, we examined the inhibitory mechanisms of PPARgamma on the bone formation by using PPARgamma activators ciglitazone and 15-deoxy-Delta(12,14)-prostaglandin-J2 (15d-PGJ2). Our data indicated that PPARgamma ligands decreased both mineralized bone nodules and alkaline phosphatase (ALP) activities in cultured primary osteoblasts. Reverse transcription polymerase chain reaction (RT-PCR) showed that the expression of bone morphogenetic protein-2 (BMP-2) and osteocalcin (OCN) was inhibited by ciglitizone and 15d-PGJ2. Furthermore, PPARgamma ligands inhibited NF-kappaB associated downstream COX-2 and iNOS osteogenic signaling. The ultrasound (US)-induced elevation of COX-2 and iNOS expression and nitric oxide (NO) production were attenuated in the presence of PPARgamma ligands. Furthermore, local administration of PPARgamma ligands into the metaphysis of rat tibia decreased the bone volume in secondary spongiosa. These results suggest that the activation of PPARgamma inhibits osteoblastic differentiation and the expression of several anabolic mediators involved in bone formation. These data may reflect osteoporosis and less bone formation in the aging people and patients treated with thiazolidinediones.
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PMID:PPARgamma inhibits osteogenesis via the down-regulation of the expression of COX-2 and iNOS in rats. 1766 5

Hypophosphatasia is a rare inherited disorder characterized by defective bone and tooth mineralization, and deficiency of serum and bone alkaline phosphatase activity. The frequency of the disease has been estimated to be one in 100 000 for severe forms, but mild forms of hypophosphatasia may be more common. The symptoms are highly variable in their clinical expression, which ranges from stillbirth without mineralized bone to early tooth loss without bone symptoms. The transmission of severe forms is autosomal recessive, while milder forms may be transmitted as dominant or recessive autosomal traits. The diagnosis is based on serum alkaline phosphatase assay and molecular analysis of the liver/bone/kidney alkaline phosphatase gene (ALPL). Currently, there is no treatment for the disease. Over the past 10 years, great progress has been made in understanding the structure of tissue non-specific alkaline phosphatase, its function in bone mineralization, and the effect of ALPL mutations responsible for hypophosphatasia.
Best Pract Res Clin Rheumatol 2008 Mar
PMID:Hypophosphatasia. 1832 85

In 2003, we reported on a 12-yr-old boy who had developed osteopetrosis (OPT) while receiving pamidronate (PMD) for idiopathic bone pain and enigmatic elevation in circulating bone alkaline phosphatase. Now 17 yr of age, he was re-evaluated 6.5 yr after PMD exposure stopped. Our patient described less bone pain but further limb fractures. His growth plates were fused, yet hyperphosphatasemia persisted. Radiographs documented interval fractures of a metacarpal, an osteosclerotic distal radius, and a dense diaphyseal segment of an ulna where a "chalkstick" break remained incompletely healed after 2 yr. There was new L(4) spondylolysis, and previous L(5) spondylolysis had caused spondylolisthesis. Modeling disturbances of OPT persisted, but partial recovery was shown by metaphyseal surfaces with a unique concave shape. Metaphyseal osteosclerosis had remodeled imperfectly to become focal areas of dense, diaphyseal bone. Newer metaphyseal bone was unexpectedly osteopenic, especially in his distal femurs where cortices were thin and a paucity of trabeculae was documented by CT. Femoral necks had become short and wide with an abnormal contour. A "bone-within-bone" configuration was now present throughout his skeleton. In vertebrae, endplates were thin, and trabecular osteopenia was present central and peripheral to the bands of osteosclerosis. BMD Z-scores assessed by DXA had decreased into the normal range in his spine, hip, and whole body. Iliac crest biopsy showed active bone formation, with much less accumulated primary spongiosa than during the PMD infusions. Osteoclasts that had been dysmorphic, round cells without polarization and off of bone surfaces were now unremarkable in number, location, and appearance. In conclusion, bisphosphonate toxicity during childhood can impair skeletal modeling and remodeling with structural changes that evolve and carry into adult life.
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PMID:Bisphosphonate-induced osteopetrosis: novel bone modeling defects, metaphyseal osteopenia, and osteosclerosis fractures after drug exposure ceases. 1850 75

Postmenopausal bone loss is a major public health concern. Although drug therapies are available, women are interested in alternative/adjunct therapies to slow down the bone loss associated with ovarian hormone deficiency. The purpose of this study was to determine whether dietary supplementation of l-carnitine can influence bone density and slow the rate of bone turnover in an aging ovariectomized rat model. Eighteen-month-old Fisher-344 female rats were ovariectomized and assigned to two groups: (1) a control group in which rats were fed ad libitum a carnitine-free (-CN) diet (AIN-93M) and (2) another fed the same diet but supplemented with l-carnitine (+CN). At the end of 8 weeks of feeding, animals were sacrificed and bone specimens were collected for measuring bone mineral content (BMC) and density (BMD) using dual energy X-ray absorptiometry. Femoral microarchitectural properties were assessed by microcomputed tomography. Femoral mRNA levels of selected bone matrix proteins were determined by northern blot analysis. Data showed that tibial BMD was significantly higher in the rat fed the +CN diet than those fed the -CN (control) diet. Dietary carnitine significantly decreased the mRNA level of tartrate-resistant acid phosphatase (TRAP), an indicator of bone resorption by 72.8%, and decreased the mRNA abundance of alkaline phosphatase (ALP) and collagen type-1 (COL), measures of bone formation by 63.6% and 61.2%, respectively. The findings suggest that carnitine supplementation slows bone loss and improves bone microstructural properties by decreasing bone turnover.
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PMID:Dietary l-carnitine supplementation improves bone mineral density by suppressing bone turnover in aged ovariectomized rats. 1853 46

The goal of this study was to investigate the expression levels of interleukin 6 (IL-6), nuclear factor kappa beta (NF-kappabeta), bone-specific alkaline phosphatase (BALP), and bone osteocalcin (BGP) in rats with osteoporosis and their significance in the pathogenesis of osteoporosis. In all, 60 adult female SD rats were divided randomly into 3 groups of 20 rats each: normal control group (control), sham-operated group (sham), and ovariectomized group (OVX). In 2, 3, 4, 5, and 6 months after surgery, 4 rats were randomized from each group for assays of BMD, IL-6, BALP, and BGP. Then, the rats were sacrificed for the detection of IL-6 and NF-kappabeta expression levels in bone tissue by quantitative real-time RT-PCR analysis. Compared with the sham (0.097 +/- 0.04 g/cm2, 0.097 +/- 0.01 g/cm2, 0.095 +/- 0.07 g/cm2) and control group (0.107 +/- 0.01 g/cm2, 0.103 +/- 0.07 g/cm2, 0.108 +/- 0.06 g/cm2), the BMD of rats in the OVX group was reduced remarkably in 4, 5, and 6 months (0.082 +/- 0.05 g/cm2, 0.073 +/- 0.02 g/cm2, 0.061 +/- 0.05 g/cm2, respectively; P < 0.01); the serum IL-6 level increased significantly from 2 to 6 months after surgery (P < 0.01); and the serum levels of BALP and BGP were greater at 4, 5, and 6 months (P < 0.05). The quantitative real-time RT-PCR analysis demonstrated that IL-6 and NF-kappabeta mRNA levels in OVX group increased in a time-dependent manner. Moreover, the IL-6, NF-kappabeta, BALP, and BGP levels were correlated negatively with the BMD. Meanwhile, a positive correlation was observed between IL-6 and NF-kappabeta. In conclusion, the expression levels of IL-6, NF-kappabeta, and bone formation markers may increase significantly in the osteoporosis rats. These molecules could play a role in the pathogenesis.
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PMID:Expression characteristic and significance of interleukin-6, nuclear factor kappa beta, and bone formation markers in rat models of osteoporosis. 1859 33

Children and adolescents with poorly controlled type 1 diabetes mellitus (T1DM) are at risk for decreased bone mass. Growth hormone (GH) and its mediator, IGF-1, promote skeletal growth. Recent observations have suggested that children and adolescents with T1DM are at risk for decreased bone mineral acquisition. We examined the relationships between metabolic control, IGF-1 and its binding proteins (IGFBP-1, -3, -5), and bone mass in T1DM in adolescent girls 12-15 yr of age with T1DM (n = 11) and matched controls (n = 10). Subjects were admitted overnight and given a standardized diet. Periodic blood samples were obtained, and bone measurements were performed. Serum GH, IGFBP-1 and -5, glycosylated hemoglobin (HbA(1c)), glucose, and urine magnesium levels were higher and IGF-1 values were lower in T1DM compared with controls (p < 0.05). Whole body BMC/bone area (BA), femoral neck areal BMD (aBMD) and bone mineral apparent density (BMAD), and tibia cortical BMC were lower in T1DM (p < 0.05). Poor diabetes control predicted lower IGF-1 (r(2) = 0.21) and greater IGFBP-1 (r(2) = 0.39), IGFBP-5 (r(2) = 0.38), and bone-specific alkaline phosphatase (BALP; r(2) = 0.41, p < 0.05). Higher urine magnesium excretion predicted an overall shorter, lighter skeleton, and lower tibia cortical bone size, mineral, and density (r(2) = 0.44-0.75, p < 0.05). In the T1DM cohort, earlier age at diagnosis was predictive of lower IGF-1, higher urine magnesium excretion, and lighter, thinner cortical bone (r(2) >or=0.45, p < 0.01). We conclude that poor metabolic control alters the GH/IGF-1 axis, whereas greater urine magnesium excretion may reflect subtle changes in renal function and/or glucosuria leading to altered bone size and density in adolescent girls with T1DM.
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PMID:IGF-1 and IGF-binding proteins and bone mass, geometry, and strength: relation to metabolic control in adolescent girls with type 1 diabetes. 1884 35

Vitamin D is suggested to have a role in the coupling of bone resorption and formation. Compared with women, men are believed to have more stable bone remodeling, and thus, are considered less susceptible to the seasonal variation of calcitropic hormones. We examined whether seasonal variation exists in calcitropic hormones, bone remodeling markers, and BMD in healthy men. Furthermore, we determined which vitamin D intake is required to prevent this variation. Subjects (N = 48) were healthy white men 21-49 yr of age from the Helsinki area with a mean habitual dietary intake of vitamin D of 6.6 +/- 5.1 (SD) microg/d. This was a 6-mo double-blinded vitamin D intervention study, in which subjects were allocated to three groups of 20 microg (800 IU), 10 microg (400 IU), or placebo. Fasting blood samplings were collected six times for analyses of serum (S-)25(OH)D, iPTH, bone-specific alkaline phosphatase (BALP), and TRACP. Radial volumetric BMD (vBMD) was measured at the beginning and end of the study with pQCT. Wintertime variation was noted in S-25(OH)D, S-PTH, and S-TRACP (p < 0.001, p = 0.012, and p < 0.05, respectively) but not in S-BALP or vBMD in the placebo group. Supplementation inhibited the winter elevation of PTH (p = 0.035), decreased the S-BALP concentration (p < 0.05), but benefited cortical BMD (p = 0.09) only slightly. Healthy men are exposed to wintertime decrease in vitamin D status that impacts PTH concentration. Vitamin D supplementation improved vitamin D status and inhibited the winter elevation of PTH and also decreased BALP concentration. The ratio of TRACP to BALP shows the coupling of bone remodeling in a robust way. A stable ratio was observed among those retaining a stable PTH throughout the study. A daily intake of vitamin D in the range of 17.5-20 microg (700-800 IU) seems to be required to prevent winter seasonal increases in PTH and maintain stable bone turnover in young, healthy white men.
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PMID:Wintertime vitamin D supplementation inhibits seasonal variation of calcitropic hormones and maintains bone turnover in healthy men. 1884 21

Glucocorticoid (GC) effects on skeletal development have not been established. The objective of this pQCT study was to assess volumetric BMD (vBMD) and cortical dimensions in childhood steroid-sensitive nephrotic syndrome (SSNS), a disorder with minimal independent deleterious skeletal effects. Tibia pQCT was used to assess trabecular and cortical vBMD, cortical dimensions, and muscle area in 55 SSNS (age, 5-19 yr) and >650 control participants. Race-, sex-, and age-, or tibia length-specific Z-scores were generated for pQCT outcomes. Bone biomarkers included bone-specific alkaline phosphatase and urinary deoxypyridinoline. SSNS participants had lower height Z-scores (p < 0.0001) compared with controls. In SSNS, Z-scores for cortical area were greater (+0.37; 95% CI = 0.09, 0.66; p = 0.01), for cortical vBMD were greater (+1.17; 95% CI = 0.89, 1.45; p < 0.0001), and for trabecular vBMD were lower (-0.60; 95% CI, = -0.89, -0.31; p < 0.0001) compared with controls. Muscle area (+0.34; 95% CI = 0.08, 0.61; p = 0.01) and fat area (+0.56; 95% CI = 0.27, 0.84; p < 0.001) Z-scores were greater in SSNS, and adjustment for muscle area eliminated the greater cortical area in SSNS. Bone formation and resorption biomarkers were significantly and inversely associated with cortical vBMD in SSNS and controls and were significantly lower in the 34 SSNS participants taking GCs at the time of the study compared with controls. In conclusion, GCs in SSNS were associated with significantly greater cortical vBMD and cortical area and lower trabecular vBMD, with evidence of low bone turnover. Lower bone biomarkers were associated with greater cortical vBMD. Studies are needed to determine the fracture implications of these varied effects.
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PMID:Divergent effects of glucocorticoids on cortical and trabecular compartment BMD in childhood nephrotic syndrome. 1901 83

Poor vitamin D status is common in the elderly and is associated with bone loss and fractures. The aim was to assess worldwide vitamin D status in postmenopausal women with osteoporosis according to latitude and economic status, in relation to parathyroid function, bone turnover markers, and BMD. The study was performed in 7441 postmenopausal women from 29 countries participating in a clinical trial on bazedoxifene (selective estrogen receptor modulator), with BMD T-score at the femoral neck or lumbar spine <or= -2.5 or one to five mild or moderate vertebral fractures. Serum 25(OH)D, PTH, alkaline phosphatase (ALP), bone turnover markers osteocalcin (OC) and C-terminal cross-linked telopeptides of type I collagen (CTX), and BMD of the lumbar spine, total hip, femoral neck, and trochanter were measured. The mean serum 25(OH)D level was 61.2 +/- 22.4 nM. The prevalence of 25(OH)D <25, 25-50, 50-75, and >75 nM was 5.9%, 29.4%, 43.5%, and 21.2%, respectively, in winter and 3.0%, 22.2%, 47.2%, and 27.5% in summer. Worldwide, a negative correlation between 25(OH)D and latitude was observed. With increasing 25(OH)D categories of <25, 25-50, 50-75, and >75 nM, mean PTH, OC, and CTX were decreasing (p < 0.001), whereas BMD of all sites was increasing (p < 0.001). A threshold in the positive relationship between 25(OH)D and different BMD parameters was visible at a 25(OH)D level of 50 nM. Our study showed a high prevalence of low 25(OH)D in postmenopausal women with osteoporosis worldwide. Along with latitude, affluence seems to be an important factor for serum 25(OH)D level, especially in Europe, where it is strongly correlated with latitude.
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PMID:Vitamin D status, parathyroid function, bone turnover, and BMD in postmenopausal women with osteoporosis: global perspective. 1904 41

Low vitamin K status is associated with low BMD and increased fracture risk. Additionally, a specific menaquinone, menatetrenone (MK4), may reduce fracture risk. However, whether vitamin K plays a role in the skeletal health of North American women remains unclear. Moreover, various K vitamers (e.g., phylloquinone and MK4) may have differing skeletal effects. The objective of this study was to evaluate the impact of phylloquinone or MK4 treatment on markers of skeletal turnover and BMD in nonosteoporotic, postmenopausal, North American women. In this double-blind, placebo-controlled study, 381 postmenopausal women received phylloquinone (1 mg daily), MK4 (45 mg daily), or placebo for 12 mo. All participants received daily calcium and vitamin D(3) supplementation. Serum bone-specific alkaline phosphatase (BSALP) and n-telopeptide of type 1 collagen (NTX) were measured at baseline and 1, 3, 6, and 12 mo. Lumbar spine and proximal femur BMD and proximal femur geometry were measured by DXA at baseline and 6 and 12 mo. At baseline, the three treatment groups did not differ in demographics or study endpoints. Compliance with calcium, phylloquinone, and MK4 treatment was 93%, 93%, and 87%, respectively. Phylloquinone and MK4 treatment reduced serum undercarboxylated osteocalcin but did not alter BSALP or NTX. No effect of phylloquinone or MK4 on lumbar spine or proximal femur BMD or proximal femur geometric parameters was observed. This study does not support a role for vitamin K supplementation in osteoporosis prevention among healthy, postmenopausal, North American women receiving calcium and vitamin D supplementation.
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PMID:Vitamin K treatment reduces undercarboxylated osteocalcin but does not alter bone turnover, density, or geometry in healthy postmenopausal North American women. 1911 22


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