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 extremely poor prognosis of patients with metastatic osteosarcoma indicates the need for novel therapeutic approaches. Ectodysplasin-A2 (EDA-A2) is a recently isolated member of the tumor necrosis factor superfamily that binds to X-linked ectodermal dysplasia receptor (XEDAR). In this report, we have analyzed the biological activity of EDA-A2 against osteosarcoma-derived cell lines. We report that XEDAR is expressed in cell lines derived from osteosarcoma and adenoviral-mediated expression of EDA-A2 in these cells results in the induction of apoptosis via caspase activation and cell-cycle arrest in the G(0)/G(1) phase. Treatment with EDA-A2 also upregulates the expression of alkaline phosphatase, a marker of osteogenic differentiation, in a caspase-dependent fashion. Collectively, our results suggest that EDA-A2 may be a promising agent for the gene therapy of osteosarcoma.
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PMID:Adenoviral-mediated gene transfer of ectodysplasin-A2 results in induction of apoptosis and cell-cycle arrest in osteosarcoma cell lines. 1769 91

This paper summarizes the clinical features, causative genes and treatment progress of patients with rickets-like genetic diseases, including X-linked hypophosphatemic rickets (XLH), hypophosphatasia, achondroplasia, vitamin D-dependent rickets, pycnodysostosis and ectodermal dysplasia, who visited the pediatric or child health clinic due to the symptoms of rickets, including bow legs, delayed closure of the anterior fontanelle, and sparse hair. Children with XLH usually go to hospital for bow legs and short stature, and biochemical evaluation reveals significantly low serum phosphorus so it is easily diagnosed. This disease is treated using phosphate mixture and 1,25(OH)2D3, which is different from the treatment of nutritional vitamin D deficiency rickets. Hypophosphatasia is characterized by a significant decrease in serum alkaline phosphatase, as well as normal serum calcium and phosphorus. The disease is caused by mutations in TNSALP gene. Patients with achondroplasia show short-limbed dwarfism and special face in addition to bow legs, but with normal serum calcium, phosphorus and alkaline phosphatase. Bone X-ray and FGFR3 gene test contribute to the diagnosis. Vitamin D-dependent rickets is an autosomal recessive disease, and active vitamin D supplement is effective in treatment of the disease. Patients with pycnodysostosis may be first seen at hospital because of large anterior fontanelle; in addition, they also show obtuse mandibular angle, dental abnormalities and dysplastic nails, which are caused by mutations in TSK gene. Children with ectodermal dysplasia may see a doctor for sparse hair, and they are easily misdiagnosed with nutritional vitamin D deficiency rickets. Ectodermal dysplasia is related to EDA, EDAR, EDARADD and WNT 10A genes.
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PMID:[Rickets-like genetic diseases]. 2422 81

Circulating plasma fibronectin (pFN), produced by hepatocytes, is a major component of the noncollagenous bone matrix where it was recently shown in vivo in mice to control the biomechanical quality as well as the mineral-to-matrix ratio in bone. FN fibrillogenesis is a process generally requiring FN binding to cellular integrins, and cellular tension to elongate and assemble the molecule. Whether soluble pFN undergoes cell-mediated assembly in bone is not fully established. FN is a well-known substrate for transglutaminases (TGs), which are protein-crosslinking enzymes capable of stabilizing macromolecular structures. The role of this modification regarding the function of FN in bone matrix has remained unknown. Osteoblasts express two TGs-transglutaminase 2 and Factor XIIIA-and we have shown that Factor XIIIA is the main TG active during osteoblast differentiation. In the present study, conducted using MC3T3-E1 osteoblast cultures and bone marrow stromal cells, we demonstrate that pFN requires a TG-mediated crosslinking step to form osteoblast matrix in vitro. This modification step is specific for pFN; cellular FN (EDA-FN) does not serve as a TG substrate. Inhibition of pFN assembly using a TG inhibitor, or depletion of pFN from cell culture serum, dramatically decreased total FN matrix assembly in the osteoblast cultures and affected both the quantity and quality of the type I collagen matrix, and decreased lysyl oxidase and alkaline phosphatase levels, resulting in decreased mineralization. Experiments with isozyme-specific substrate peptides showed that FXIIIA is responsible for the crosslinking of pFN. Addition of exogenous preactivated FXIIIA to osteoblast cultures promoted pFN assembly from the media into matrix. Exogenous TG2 had no effect. Analysis of pFN and EDA-FN fibrils by immunofluorescence microscopy demonstrated that they form distinct matrix network, albeit with minor overlap, suggesting different functions for the two FN forms. Further analysis using EDA-FN blocking antibody showed that it regulated preosteoblast proliferation whereas pFN depletion from the serum had no effect on this process. In conclusion, our study shows that pFN assembly into bone matrix in vitro requires FXIIIA transglutaminase activity making pFN assembly an active, osteoblast-mediated process.
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PMID:Transglutaminase activity arising from Factor XIIIA is required for stabilization and conversion of plasma fibronectin into matrix in osteoblast cultures. 2424 48


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