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)

Genistein, a major phytoestrogen of soy, is considered a potential drug for prevention and treatment of postmenopausal osteoporosis. The aim of the present study was to compare the effects of genistein, estradiol and raloxifene on the skeletal system in vivo and in vitro. Genistein (5 mg/kg), estradiol (0.1 mg/kg) or raloxifene hydrochloride (5 mg/kg) were administered daily by a stomach tube to mature ovariectomized Wistar rats for 4 weeks. Bone mass, mineral and calcium content, macrometric parameters and mechanical properties were examined. Also the effects of genistein, estradiol and raloxifene (10(-9)-10(-7) M) on the formation of osteoclasts from neonatal mouse bone marrow cells and the activity of osteoblasts isolated from neonatal mouse calvariae were compared. In vivo, estrogen deficiency resulted in the impairment of bone mineralization and bone mechanical properties. Raloxifene but not estradiol or genistein improved bone mineralization. Estradiol fully normalized the bone mechanical properties, whereas genistein augmented the deleterious effect of estrogen-deficiency on bone strength. In vitro, genistein, estradiol and raloxifene inhibited osteoclast formation from mouse bone marrow cells, decreasing the ratio of RANKL mRNA to osteoprotegerin mRNA expression in osteoblasts. Genistein, but not estradiol or raloxifene, decreased the ratio of alkaline phosphatase mRNA to ectonucleotide pyrophosphatase phosphodiesterase 1 mRNA expression in osteoblasts. This difference may explain the lack of genistein effect on bone mineralization observed in ovariectomized rats in the in vivo study. Concluding, our experiments demonstrated profound differences between the activities of genistein, estradiol and raloxifene towards the osseous tissue in experimental conditions.
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PMID:A comparative study of the effects of genistein, estradiol and raloxifene on the murine skeletal system. 1940 87

Diabetes results in increased fracture risk, and advance glycation endproducts (AGEs) have been implicated in this pathophysiology. S100 proteins are ligands for the receptor of AGEs (RAGE). An intracellular role of the S100 family member S100A4 (Mts1) to suppress mineralization has been described in pre-osteoblastic MC3T3-E1 cells. However, S100 proteins could have additional effects on bone. The goal of the current study was to determine effects of increased extracellular S100 on osteoclastogenesis. We first determined the direct effects of S100 on pre-osteoclast proliferation and osteoclastic differentiation. RANKL-treated RAW 264.7 cell proliferation and TRAP activity were significantly inhibited by S100, and the number and size of TRAP-positive multinucleated cells were decreased. We then determined whether S100 could affect osteoclastogenesis by an indirect process by examining effects of conditioned media from S100-treated MC3T3-E1 cells on osteoclastogenesis. In contrast to the direct inhibitory effect of S100, the conditioned media promoted RAW 264.7 cell proliferation and TRAP activity, with a trend toward increased TRAP-positive multinucleated cells. S100 treatment of the MC3T3-E1 cells for 14 days did not significantly affect alkaline phosphatase, M-CSF, or OPG gene expression. RANKL was undetectable in both untreated and treated cells. The treatment slightly decreased MC3T3-E1 cell proliferation. Interestingly, S100 treatment increased expression of RAGE by the MC3T3-E1 cells. This suggested the possibility that S100 could increase soluble RAGE, which acts as a decoy receptor for S100. This decrease in availability of S100, an inhibitor of pre-osteoclast proliferation, could contribute to osteoclastogenesis, ultimately resulting in increased bone resorption.
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PMID:Direct inhibitory and indirect stimulatory effects of RAGE ligand S100 on sRANKL-induced osteoclastogenesis. 1941 76

The purpose of this study was to investigate various serum markers of bone turnover in non-small cell lung cancer patients (NSCLC) in the presence or absence of bone metastasis. Our retrospective study included 79 newly diagnosed NSCLC patients. Group A included 51 patients with bone metastasis and group B included 28 patients that never developed bone metastasis. The measurement of bone formation markers, bone resorptive markers and osteoclastogenesis markers as well as routine biochemical analysis was determined. Patients with bone metastasis had an increase in receptor activator of nuclear factor kappaB ligand, osteopontin and osteoprotegerin. Patients who later developed bone metastasis had decreased osteocalcin and tartrate-resistant acid phosphatase isoform 5b levels (TRACP-5b). We also found an unusually low TRACP-5b/RANKL ratio for patients who have or later developed metastasis. In patients that never developed bone metastases, cross-linked carboxy-terminal telopeptide of type I collagen was increased. Positive correlations were found between osteopontin and TRACP-5b, and also between bone alkaline phosphatase with osteocalcin and TRACP-5b. In conclusion, serum markers of bone turnover may be able to determine the time-to-tumor progression, metastatic potential and overall survival of the NSCLC patient. In addition, they may contribute to a more accurate follow-up and tailored treatment options.
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PMID:The clinical significance of serum markers of bone turnover in NSCLC patients: surveillance, management and prognostic implications. 1944 81

Overexpression of dickkopf (DKK)-1 in pagetic osteoblast cultures resulted in stimulation of osteoclast proliferation and inhibition of osteoblast growth. The aim of this study was to evaluate for the first time in Paget's disease of bone (PDB): 1) the serum levels of DKK1; 2) the association of DKK-1 with receptor activator of nuclear factor kappa B (RANKL) and osteoprotegerin (OPG); and 3) the effect of zoledronic acid (ZOL) on serum DKK-1, RANKL, and OPG. The study was conducted as a prospective open-label cohort study. Eleven patients with PDB (median age 60 years) were recruited. Twelve age- gender- and body mass index (BMI)-matched healthy individuals were used as controls at baseline. Blood samples were obtained before treatment (baseline) and after 3, 6, 12, and 18 months following ZOL infusion in patients with PDB. Patients with PDB had significantly higher RANKL (p=0.002), OPG (p=0.001), and bone markers (total alkaline phosphatase and C-terminal cross-linking telopeptide of type I collagen) compared with controls at baseline. There was no difference between groups in DKK-1 at baseline. Bone markers were both significantly decreased after therapy. Serum OPG, RANKL, RANKL:OPG ratio, and DKK-1 remained unaffected throughout the study. No correlations were found between OPG, RANKL, RANKL:OPG ratio, and DKK-1 at baseline nor between their changes during the study. Although both OPG and RANKL were increased in patients with PDB, ZOL had no effect on their serum levels. Serum DKK-1 was neither increased in patients with PDB nor related to OPG and RANKL, and was unaffected by ZOL.
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PMID:The effect of zoledronic acid on serum dickkopf-1, osteoprotegerin, and RANKL in patients with Paget's disease of bone. 1967 Jan 54

To evaluate serum levels of osteoprotegerin (OPG), soluble receptor activator of the nuclear factor-kappaB (RANKL), and their relationship with FGF-23, lumbar bone mineral density (BMD), and bone turnover markers, five patients with tumor-induced osteomalacia (TIO) and 40 healthy controls were studied. TIO patients were followed for 360 days after surgical removal of underlying tumor (n = 2) or beginning of therapy with phosphate and calcitriol when surgical treatment was impossible (n = 3). At diagnosis, TIO patients had higher levels of FGF-23 and bone-specific alkaline phosphatase (bALP) and lower levels of cathepsin K (CathK), RANKL, and RANKL/OPG ratio compared to controls. During the follow-up, FGF-23 decreased significantly only in patients who underwent a surgical excision, while phosphate and BMD increased in all patients. The increases in BMD, phosphate, and renal phosphate reabsorption rate were directly related. In the first 60 days of follow-up, we observed a prolonged inhibition of RANKL, CathK, and bone resorption markers associated with a persistence of TIO symptoms and an increase in bALP. From day 60, levels of bone turnover markers returned progressively within the normal range and a clinical remission was observed. The inhibition of the RANKL/OPG pathway and the uncoupling of bone formation and resorption observed in patients with active TIO may be a compensatory mechanism, attempting to reduce worsening of osteomalacia. The BMD increase during TIO treatment is related to the improvement of phosphate rather than FGF-23 levels. A "hungry bone"-like syndrome was observed after surgical or pharmacological treatment.
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PMID:Bone turnover and the osteoprotegerin-RANKL pathway in tumor-induced osteomalacia: a longitudinal study of five cases. 1976 78

Human skeletal progenitors were engineered to stably express R201C mutated, constitutively active Gs alpha using lentiviral vectors. Long-term transduced skeletal progenitors were characterized by an enhanced production of cAMP, indicating the transfer of the fundamental cellular phenotype caused by activating mutations of Gs alpha. Like skeletal progenitors isolated from natural fibrous dysplasia (FD) lesions, transduced cells could generate bone but not adipocytes or the hematopoietic microenvironment on in vivo transplantation. In vitro osteogenic differentiation was noted for the lack of mineral deposition, a blunted upregulation of osteocalcin, and enhanced upregulation of other osteogenic markers such as alkaline phosphatase (ALP) and bone sialoprotein (BSP) compared with controls. A very potent upregulation of RANKL expression was observed, which correlates with the pronounced osteoclastogenesis observed in FD lesions in vivo. Stable transduction resulted in a marked upregulation of selected phosphodiesterase (PDE) isoform mRNAs and a prominent increase in total PDE activity. This predicts an adaptive response in skeletal progenitors transduced with constitutively active, mutated Gs alpha. Indeed, like measurable cAMP levels, the differentiative responses of transduced skeletal progenitors were profoundly affected by inhibition of PDEs or lack thereof. Finally, using lentiviral vectors encoding short hairpin (sh) RNA interfering sequences, we demonstrated that selective silencing of the mutated allele is both feasible and effective in reverting the aberrant cAMP production brought about by the constitutively active Gs alpha and some of its effects on in vitro differentiation of skeletal progenitors.
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PMID:Transfer, analysis, and reversion of the fibrous dysplasia cellular phenotype in human skeletal progenitors. 1987 99

Citrus fruit hesperidin is hydrolyzed by gut microflora into aglycone form (hesperetin) and then conjugated mainly into glucuronides. We previously demonstrated that hesperetin enhanced osteoblast differentiation. In this study, we examined the effect of hesperetin-7-O-glucuronide (Hp7G) on primary rat osteoblast proliferation and differentiation. The impact of Hp7G on specific bone signaling pathways was explored. Osteoblasts were exposed to physiological concentrations of 1 (Hp7G1) and 10 (Hp7G10) microM of conjugate. The glucuronide did not affect proliferation but enhanced differentiation by significantly increasing alkaline phosphatase (ALP) activity from day 14 of exposure. Hp7G significantly induced mRNA expression of ALP, Runx2, and Osterix after 48 h of exposure. Moreover, phosphorylation of Smad1/5/8 was enhanced by Hp7G, while ERK1/2 remained unchanged after 48 h. Hp7G decreased RANKL gene expression. These results suggest that Hp7G may regulate osteoblast differentiation through Runx2 and Osterix stimulation, and might be implicated in the regulation of osteoblast/osteoclast communication.
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PMID:Molecular mechanism of hesperetin-7-O-glucuronide, the main circulating metabolite of hesperidin, involved in osteoblast differentiation. 1992 38

The aim of this study was to determine how low-intensity intermittent negative pressure affects the differentiation and proliferation of human mesenchymal stem cells (MSCs), as well of OPG and OPGL mRNA expression in MSCs. MSCs were isolated from adult marrow using the density gradient separation method, passaged for three generations, and divided into the vacuum group, which was administrated at pressure of -50 kPa, for 30 min at a frequency of 2/d, and a control group. The differentiation of MSCs was examined through inverted phase contrast microscopy, measurement of alkaline phosphatase activity, alizarin-red staining, and immunohistochemistry for type I collagen, hypoxia-inducible factor-1alpha (HIF-1a), and vascular endothelial growth factor (VEGF). The MTT assay and flow cytometry were used to measure proliferation and apoptosis. Real-time PCR detected the expression of mRNA from OPG/OPGL. Compared to the control group, there was a decrease in the proliferation of cells in the vacuum group. The number of cells in S phase was reduced by 62.4%, while the rate of apoptosis, the activity of ALP, and calcium release all increased under vacuum conditions. Calcium nodes could be observed through alizarin-red staining, and the expression of collagen type I, VEGF, and HIF-1a were increased significantly. Expression of OPG mRNA was increased and the expression of OPGL mRNA decreased in the vacuum group relative to the control group. In conclusion, low-intensity intermittent negative pressure can inhibit the proliferation of human MSCs, induce differentiation to bone cells, promote the OPG mRNA expression, and reduce OPGL mRNA expression.
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PMID:Effect of negative pressure on human bone marrow mesenchymal stem cells in vitro. 2006 12

The vanilloid type 1 ion channel (TRPV1) is known to play an important role in the regulation of pain and inflammation. Pharmacological ligands of TRPV1 regulate human osteoclast formation in vitro, but the effects of these agents on osteoblast function have not been studied and their effects on bone loss in vivo are unknown. Here we examined the effects of the TRPV1 ion channel antagonist capsazepine on mouse osteoclast and osteoblast differentiation in vitro and ovariectomy induced bone loss in vivo. Capsazepine inhibited osteoclast formation and bone resorption in a dose dependent manner in bone marrow-osteoblast co-cultures and RANKL generated osteoclast cultures, whereas the TRPV1 agonist capsaicin enhanced RANKL and M-CSF stimulated osteoclast formation. Capsazepine also suppressed RANKL induced IkappaB and ERK1/2 phosphorylation and caused apoptosis of mature osteoclasts and also inhibited alkaline phosphatase activity and bone nodule formation in calvarial osteoblast cultures. Studies in vivo showed that capsazepine (1mg/kg/day) inhibited ovariectomy induced bone loss in mice and histomorphometric analysis showed inhibitory effects on indices of bone resorption and bone formation. We conclude that pharmacological blockade of TRPV1 ion channels by capsazepine inhibits osteoclastic bone resorption and protects against ovariectomy induced bone loss in mice, but also inhibits osteoblast activity and bone formation.
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PMID:The TRPV1 ion channel antagonist capsazepine inhibits osteoclast and osteoblast differentiation in vitro and ovariectomy induced bone loss in vivo. 2009 13

Mechanical loading is known to be important for maintaining the formation and resorption rates of bone. To study the mechanisms by which mechanical loading regulates osteogenesis, we investigated the role of the Wnt pathway in C2C12 cells committed to osteogenic differentiation in response to cyclic mechanical stretching. Osteoprotegerin (OPG) acts as a decoy receptor for RANKL to inhibit osteoclastogenesis and resorption of bone. Our results demonstrate that stretching leads to a sustained increase in OPG expression in C2C12 cells. The expression of osteogenic marker genes, such as osteocalcin and alkaline phosphatase, was transiently decreased by stretching at 24 hours and returned to control levels at 48 hours. The addition of inhibitors of the canonical Wnt/beta-catenin pathways, such as the secreted FZD-related peptide sRFP2, as well as siRNA-mediated knockdown, did not inhibit the effect of stretching on OPG expression. In contrast, treatment with inhibitors of noncanonical Wnt signaling, including KN93, and siRNA for Nemo-like kinase (NLK) blocked most of the mechanical inductive effect on OPG. Furthermore, stretching-induced OPG production in the culture medium was able to inhibit the osteoclast formation of bone marrow macrophages. These results suggest that mechanical stretching may play an important role in bone remodeling through the upregulation of OPG and that the mechanical signaling leading to OPG induction involves the noncanonical Wnt pathway.
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PMID:Mechanical stretching induces osteoprotegerin in differentiating C2C12 precursor cells through noncanonical Wnt pathways. 2020 Sep 98


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