Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.1.3.1 (alkaline phosphatase)
 47,916 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The bisphosphonates, which are chemically related to pyrophosphate, have been studied extensively both in vivo and in vitro to elucidate their effects on bone tissues and cells. However, because these agents have important effects on bone resorption, the majority of investigations have focused on this area. Few studies regarding direct bisphosphonate effects on bone formation have been carried out in the past and, thus, we chose to use the chick periosteal osteogenesis (CPO) in vitro model system to test the direct effects of pyrophosphate and the bisphosphonates ethane-1-hydroxy-1,1-diphosphate (HEBP) and disodium-1-hydroxy-1-amino-propylidine (APD) on various parameters of osteogenesis in vitro. The data show that the bisphosphonate HEBP inhibits bone mineralization reversibly while APD, at low doses, may actually enhance mineralization of bone. Similarly, pyrophosphate (PPi) will prevent mineralization in CPO cultures. However, CPO cultures can circumvent PPi-mediated blockage of mineralization with longer-term, continuous (10-day) incubation, whereas this does not occur if cultures are incubated continuously with bisphosphonates. Both drugs appear to be able to reverse beta-glycerophosphate-induced changes in alkaline phosphatase activity, but do not appear on their own to regulate the activity of this enzyme. The findings show that in addition to their well-known effects on resorption, bisphosphonates have significant and direct effects on mineralization in bone-forming cultures. Their direct effects on osteoblastic activity and differentiation remain to be determined.
 ...
PMID:Effects of bisphosphonates and inorganic pyrophosphate on osteogenesis in vitro. 163 72

Effects of chlorpromazine on the mineralization and alkaline phosphatase activity (ALP) in the tooth germ were examined and compared with those of retinoic acid and HEBP (1-hydroxyethylidene-1, 1-bisphosphonate). Mandibular first molars from 17-day-old mouse embryos were cultured with or without drugs. Calcium content and ALP in the tooth germ increased gradually from 0 to 7 days in culture, the increase of calcium being preceded by that of ALP. Retinoic acid suppressed increases of calcium and ALP in the tooth germ but not in the specimens precultured for 2 days, suggesting that retinoic acid inhibits the mineralization at an early developmental stage of the tooth. HEBP, a physiochemical inhibitor of mineralization, suppressed the increase of calcium, but significantly enhanced the increased of ALP in the tooth germ. Chlorpromazine, which has an antagonistic action towards calmodulin, also suppressed the increases of calcium and ALP in the tooth germ. Calmodulin antagonists W-7 and W-5 similarly suppressed the increases of calcium and ALP; W-5 had less effects on both calcium and ALP. These results indicate that calmodulin may be involved in the regulation of the mineralization in the tooth germ. These drugs are shown to possess different modes of inhibitory action on the mineralization.
 ...
PMID:[In vitro effect of chlorpromazine on the mineralization of tooth germ in mice--comparison with that of retinoic acid and HEBP]. 190 64

The present study was undertaken to test whether long term administration of HEBP could prevent the progress of bone loss induced by ovariectomy in rats. Administration of HEBP was started from day 111 after ovariectomy. The animals received subcutaneous injections of HEBP, at a dose of 0, 2, 4, or 8 mg/kg, every other day for 92 days. Tibiae, femora and incisor teeth were investigated by chemical analyses and by contact microradiography. Effects on calcium, phosphorus, and alkaline phosphatase activity in the plasma were also examined. Progress in the loss of bone density and ash content caused by ovariectomy was prevented by the administration of 2 mg/kg HEBP for 92 days and was partially prevented by the administration of 4 mg/kg. At a dose of 8 mg/kg, however, HEBP did not prevent the bone loss but, rather, potentiated it. These chemical findings were qualitatively confirmed by contact microradiography. A dose-dependent inhibition was observed in the mineralization of incisor dentin. These results suggest that HEBP, at least at low dose levels in which the inhibition of mineralization is not predominant, has a potency to prevent the progress of bone loss induced by ovariectomy. At higher doses, however, this compound seems not to be effective, because of the severe inhibition of mineralization.
 ...
PMID:Effect of HEBP (1-hydroxyethylidene-1,1-bisphosphonate) on experimental osteoporosis induced by ovariectomy in rats. 190 20

HEBP (1-hydroxy, ethylidene-1, 1-biphosphonate) inhibited mineralization and was observed in matrix-induced heterotopic bone in rabbits. In one group of rabbits, HEBP was administered continuously until sacrifice 20 weeks after the operation. Another group of animals received HEBP for the first four weeks only. The effect of HEBP on de novo bone formation was determined by histologic and biochemical analyses. Implant alkaline and acid phosphatase levels and implant calcium and phosphate contents were measured. The implants of HEBP-treated animals showed diminished implant resorption and, at the same time, formation of atypical osteoid tissue. Quantitative measurements revealed a decrease of acid phosphatase activity, whereas implant alkaline phosphatase activity was unaffected. The mineralization, as depicted by the implant calcium and phosphate content, was almost completely inhibited during HEBP-administration. These effects were completely reversible after the withdrawal of the drug. Remineralization began directly after discontinuation, and recovered only 12 weeks later. The results of this study confirm reports that HEBP cannot prevent the formation of heterotopic ossification. The only effect would be a delay of mineralization during its administration.
 ...
PMID:The effect of biphosphonate on induced heterotopic bone. 193 42

1. The effects of retinoids on bone metabolism were examined in newborn mouse calvaria. 2. Incubation of calvaria with 0.01-1 microM retinoic acid for 4 days decreased their alkaline phosphatase (ALP) activity, mineral content and collagen content in a concentration-dependent fashion. 3. With treatment for 2 days, retinoic acid (1 microM) decreased the ALP activity and collagen content, but not the mineral content. 4. All these inhibitory effects were observed in calvaria from 0-day-old mice, but no inhibition of ALP activity was observed in calvaria from 14-day-old mice. 5. 1-Hydroxyethylidene-1,1-bisphosphonate (HEBP, 1 mM), which inhibits bone resorption, prevented the effect of retinoic acid (1 microM) on the bone mineral content, but not the effects on ALP and collagen (synthesized by osteoblasts). HEBP (1 mM) alone had no effect on the calvarial mineral and collagen contents. 6. These findings indicate that retinoic acid both stimulates bone resorption and inhibits osteoblastic activity by different mechanisms, and that stimulation of bone resorption by retinoic acid is inhibited by HEBP.
 ...
PMID:Effects of retinoic acid on bone formation and resorption in cultured mouse calvaria. 205 23

When HEBP (1-hydroxyethylidene-1, 1-biphosphonic acid) was administered to young rats in large doses over a short period rickets was consistently produced. When HEBP was administered concomitantly with 1,25 (OH)2D3 or calcitonin (CT), calcification appeared in the growth-plate cartilage where there had been an increase in thickness due to the inhibition of calcification. This experiment was done in an attempt to clarify differences in the calcification-promoting mechanisms of 1,25 (OH)2D3 and CT. The serum alkaline phosphatase level was reduced in rats with an accelerated calcification following the administration of 1,25 (OH)2D3, but there was no reduction in the serum alkaline phosphatase level in rats in which the calcification was accelerated by the administration of CT. The mode of appearance of calcification in the growth-plate cartilage by 1,25 (OH)2D3 or CT differed, depending on the time of administration. These results suggest that mechanisms involved in the enhancement of calcification by 1,25 (OH)2D3 and CT differ in cases where rickets are induced by HEBP.
 ...
PMID:A comparative study of the calcification-promoting action of 1,25 (OH)2D3 and calcitonin on the growth cartilage of rats with 1-hydroxyethylidene-1, 1-biphosphonic acid (HEBP)-induced rickets. 310 19

Although the effects of the bisphosphonates on resorption have been well documented, their effects on bone formation are not as clear. Therefore, this investigation was undertaken to elucidate the role played by bisphosphonates in the regulation of bone formation in vitro. To evaluate bisphosphonate-mediated regulation of bone formation in vitro, the effects of two drugs, ethane-1-hydroxy,1-diphosphate (Etidronate) (HEBP), and the second-generation bisphosphonate, disodium-1-hydroxy-1-aminopropylidine-1,1-diphosphate (Pamidronate) (APD), were assessed in the chick periosteal osteogenesis (CPO) model. In this study, drug-induced changes in alkaline phosphatase were assessed at the cellular level by means of quantitative fluorescence histochemistry. Cellular proliferation was quantified by means of autoradiography ([3H]thymidine). Mineralization and matrix production were measured morphometrically, whereas collagen synthesis and degradation were measured biochemically. The data suggest that in addition to their effects on bone resorption, the bisphosphonates have marked and direct effects on bone formation and other parameters of osteogenesis. HEBP may affect cellular proliferation (75-80% reduction, p < 0.05) in zones distant from bone; alkaline phosphatase positive cell numbers were increased in the osteoblastic layer of cells (twofold relative to control, p < 0.05) in 12-day cultures. HEBP, but not APD, prevented mineralization-induced suppression of matrix synthesis in early stages of culture. In 6-day cultures induced to mineralize with beta-glycerophosphate, (GP) cotreatment with HEBP induced a 70% increase in collagen synthesis. In addition, degradation of collagen in the CPO cultures was inhibited by HEBP (25%) and to a lesser extent by APD (8%). Although there were no differences in bone-osteoid areas measured in 12-day cultures treated with various regimens of bisphosphonate or GP, a clear increase in bone-osteoid area was detected in 6-day cultures treated with GP and HEBP as compared to GP only. This may suggest that initially, osteoblasts may be induced to synthesize increased volumes of bone matrix when mineralization is inhibited (e.g., with HEBP), but that over time the osteoblasts make the same amount of matrix. Taken together, these findings indicate that whereas the bisphosphonates do have well-documented effects on bone resorption, their effects on bone formation may also be important.(ABSTRACT TRUNCATED AT 400 WORDS)
 ...
PMID:Effects of bisphosphonates APD and HEBP on bone metabolism in vitro. 762 21