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:2.7.7.49 (reverse transcriptase)
31,746 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In the field of rickets and osteomalacia, progress has been made mainly in the mapping of vitamin D-dependency rickets or "pseudodeficiency rickets" type I to chromosome 12q14, and the further identification of a variety of abnormalities in the calcitriol receptor complex responsible for hereditary resistance to 1,25-dihydroxyvitamin D. The study of the molecular basis of this latter inherited disorder has important implications for a better understanding of the physiologic role of 1,25-dihydroxyvitamin D. Concerning osteopetrosis, the finding of a reverse transcriptase activity in a patient with the benign form of this disorder opens new perspectives such as the possibility that retroviral infection may be the origin of at least some type(s) of osteopetrosis. Moreover, impairment of macrophage colony-stimulating factor production appears to be a key event in the pathogenesis of the osteopetrotic op/op mutation in rodents.
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PMID:Rickets, osteomalacia, and osteopetrosis. 188 5

HEM-1 was isolated as a putative factor responsible for oncogenic osteomalacia by Kumar et al. (Proc Assoc Am Phys 107:296-305; 1995). The cDNA was identified on the basis of PTH-like immunoreactivity; however, no studies have been reported of the expression of HEM-1 mRNA in oncogenic osteomalacia tumors. In this study, expression of HEM-1 mRNA was investigated in two oncogenic osteomalacia tumors and in a series of normal tissues. An HEM-1 PCR product was amplified from a cDNA library from one of the tumors, with six base changes identified, as compared with the published sequence. No expression was detected, however, in the oncogenic osteomalacia tumors either by Northern blot analysis or by reverse transcriptase PCR. This indicates that, although a region of HEM-1 sequence is present in the tumor cell cDNA library, any HEM-1 expression must be at very low levels. It is unlikely, therefore, that the HEM-1 product is the active factor responsible for oncogenic osteomalacia. In the normal tissues examined, human placenta, fibroblasts, parathyroid gland, liver, fetal bone, and rat kidney cortex, HEM-1 mRNA was not detected, suggesting that it does not have a physiological role in these tissues.
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PMID:Tumor expression studies indicate that HEM-1 is unlikely to be the active factor in oncogenic osteomalacia. 985 64

The reverse transcriptase inhibitor 9-[2-(phosphonomethoxy)propyl]adenine (PMPA; tenofovir) was previously found to offer strong prophylactic and therapeutic benefits in an infant macaque model of pediatric human immunodeficiency virus (HIV) infection. We now summarize the toxicity and safety of PMPA in these studies. When a range of PMPA doses (4 to 30 mg/kg of body weight administered subcutaneously once daily) was administered to 39 infant macaques for a short period of time (range, 1 day to 12 weeks), no adverse effects on their health or growth were observed; this included a subset of 12 animals which were monitored for more than 2 years. In contrast, daily administration of a high dose of PMPA (30 mg/kg subcutaneously) for prolonged periods of time (>8 to 21 months) to 13 animals resulted in a Fanconi-like syndrome (proximal renal tubular disorder) with glucosuria, aminoaciduria, hypophosphatemia, growth restriction, bone pathology (osteomalacia), and reduced clearance of PMPA. The adverse effects were reversible or were alleviated following either complete withdrawal of PMPA treatment or reduction of the daily regimen from 30 mg/kg to 2.5 to 10 mg/kg subcutaneously. Finally, to evaluate the safety of a prolonged low-dose treatment regimen, two newborn macaques were started on a 10-mg/kg/day subcutaneous regimen; these animals are healthy and have normal bone density and growth after 5 years of daily treatment. In conclusion, our findings suggest that chronic daily administration of a high dose of PMPA results in adverse effects on kidney and bone, while short-term administration of relatively high doses and prolonged low-dose administration are safe.
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PMID:Biological effects of short-term or prolonged administration of 9-[2-(phosphonomethoxy)propyl]adenine (tenofovir) to newborn and infant rhesus macaques. 1510 94

MEPE, 56.6 kDa protein isolated from tumors associated with hypophosphatemic osteomalacia, increases renal phosphate excretion and is expressed in normal human bone cells. AC-100, a central 23-amino acid fragment of MEPE, contains motifs that are important in regulating cellular activities in the bone microenvironment. Thus, we assessed in vitro effects of AC-100 on multipotential normal human marrow stromal (hMS) cells that have the capacity to differentiate into mature osteoblasts. Proliferation was quantified by [H3]thymidine uptake and cell counting and differentiation by the levels of mRNA for the alpha2-chain of type I procollagen (COL1A2), alkaline phosphatase (AP), and osteocalcin (OC) measured using real time reverse transcriptase PCR (RT-PCR) and by the formation of mineralized nodules. AC-100 increased proliferation by 257 +/- 89% (P < 0.005), increased gene expression of COL1A2 by 339 +/- 85% (P < 0.005), AP by 1,437 +/- 40% (P < 0.001), and OC by 1,962 +/- 337% (P < 0.001). In addition, it increased mineralized nodule formation by 81 +/- 14% (P < 0.001) in a dose- and time-dependent fashion. In equimolar dosages, the parent compound, MEPE, had the full activity of the AC-100 fragment. AC-100 elicited a comparable response to both IGF-I and BMP-2 with respect to proliferation and differentiation of hMS cells. Using gene expression microarray analysis, we demonstrated that AC-100 increased (by approximately 3-fold) the mRNA for cyclooxgenase-2 (COX-2), an inducible enzyme required for prostaglandin synthesis. Moreover, NS-398, a specific inhibitor of COX-2 action completely blocked AC-100-induced increases in proliferation and differentiation. Thus, AC-100 has potent anabolic activity on osteoblast precursor cells in vitro and these effects require the induction of COX-2.
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PMID:A fragment of the hypophosphatemic factor, MEPE, requires inducible cyclooxygenase-2 to exert potent anabolic effects on normal human marrow osteoblast precursors. 1544 21

Osteomalacia has multiple aetiologies including the least common, tumour-induced osteomalacia (TIO). Recently, most cases of TIO have been confirmed to be due to phosphaturic mesenchymal tumour of mixed connective tissue type (PMTMCT). Most cases of TIO are the result of production of the fibroblast growth factor-23 (FGF-23) by the tumour. The authors recently showed reverse transcriptase PCR (RT-PCR) for FGF-23 to be valuable in the diagnosis of PMTMCT. However, the authors also noted FGF-23 expression in some cases of aneurysmal bone cyst (ABC) and chondromyxoid fibroma (CMF). For the present study, the authors studied FGF-23 expression by RT-PCR in 19 cases of ABC and eight cases of CMF, all with typical clinical and radiographic features and without evidence of TIO. Seven of 16 (44%) ABC and two of seven (29%) CMF were positive for FGF-23. These results confirm that ABC and CMF not uncommonly express FGF-23. These results strongly suggest caution and careful integration with all other clinical and radiographic data in the use of FGF-23 RT-PCR for the diagnosis of PMTMCT.
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PMID:Frequent expression of fibroblast growth factor-23 (FGF23) mRNA in aneurysmal bone cysts and chondromyxoid fibromas. 2293 46

We report the case of a 66-year-old woman with tumor-induced osteomalacia (TIO) caused by fibroblast growth factor 23 (FGF-23) secreting mesenchymal tumor localized in a lumbar vertebra and review other cases localized to the axial skeleton. She presented with nontraumatic low back pain and spontaneous bilateral femur fractures. Laboratory testing was remarkable for low serum phosphorus, phosphaturia, and significantly elevated serum FGF-23 level. Magnetic resonance imaging (MRI) of the lumbar spine showed a focal lesion in the L-4 vertebra which was hypermetabolic on positron emission tomography (PET) scan. A computed tomography (CT) guided needle biopsy showed a low grade spindle cell neoplasm with positive FGF-23 mRNA expression by reverse transcriptase polymerase chain reaction (RT-PCR), confirming the diagnosis of a phosphaturic mesenchymal tumor mixed connective tissue variant (PMTMCT). The patient elected to have surgery involving anterior resection of L-4 vertebra with subsequent normalization of serum phosphorus. Including the present case, we identified 12 cases of neoplasms localized to spine causing TIO. To our knowledge, this paper represents the first documented case of lumbar vertebra PMT causing TIO. TIO is a rare metabolic bone disorder that carries a favorable prognosis. When a lesion is identifiable, surgical intervention is typically curative.
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PMID:Tumor-induced osteomalacia caused by primary fibroblast growth factor 23 secreting neoplasm in axial skeleton: a case report. 2334 26

Hypophosphatemia with osteomalacia may be due to a neoplasm that produces fibroblast growth factor 23 (FGF-23), which inhibits phosphate reabsorption in the kidneys. Most of these tumors occur in bone or soft tissue and occasionally in the head, although intracranial occurrence is very rare. This report describes a tumor that caused hypophosphatemia and osteomalacia and was located entirely in the right anterior cranial fossa. Radiologically, the tumor resembled a meningioma; histologically, it was a low-grade phosphaturic mesenchymal tumor, mixed connective tissue variant (PMTMCT). After gross-total resection, the patient's symptoms abated and laboratory values normalized. The authors also studied another PMTMCT initially diagnosed as a hemangiopericytoma that involved the left anterior cranial fossa and ethmoid sinus, and reviewed reports of 6 other intracranial tumors that induced osteomalacia, 3 entirely in the anterior cranial fossa, 2 involving the anterior cranial fossa and ethmoid sinus, and 1 in the cavernous sinus. In older children or adults who have hypophosphatemia with osteomalacia and no personal or family history of metabolic, renal, or malabsorptive disease, a neoplasm should be suspected and an imaging workup that includes the brain is warranted, with particular attention to the anterior cranial fossa. Additionally, because there are some overlapping histological features between PMTMCTs and hemangiopericytomas, it may be helpful to assess tumoral FGF-23 expression by reverse transcriptase polymerase chain reaction or immunohistochemical analysis in patients with oncogenic osteomalacia from an intracranial tumor diagnosed as, or resembling, hemangiopericytoma.
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PMID:Intracranial phosphaturic mesenchymal tumors: report of 2 cases. 2335 Jul 80

Hypovitaminosis D is a very common disorder, regarding both Western and developing countries. A growing amount of data over the last years have shown vitamin D deficiency to be high prevalent among HIV-positive subjects. In addition to "classic" risk factors, such as female sex, low dietary intake, dark skin pigmentation and low sun exposure, HIV-related factors, including immune activation and antiretroviral adverse effects, may affect vitamin D status. Even if both protease inhibitors and non-nucleoside reverse transcriptase inhibitors have been associated with low vitamin D levels, available evidences have failed to univocally associate hypovitaminosis D with specific antiretroviral class effects. Low vitamin D is known to have a negative impact not only on bone health, but also on neurocognitive, metabolic, cardiovascular and immune functions. Similarly to the general population, several studies conducted on HIV-infected subjects have associated hypovitaminosis D with a greater risk of developing osteopenia/osteoporosis and fragility fractures. Analogously, vitamin D deficiency has been described as an independent risk factor for cardiovascular disease and metabolic disorders, such as insulin resistance and type 2 diabetes mellitus. Last EACS guidelines suggest to screen for hypovitaminosis D every HIV-positive subject having a history of bone disease, chronic kidney disease or other known risk factors for vitamin D deficiency. Vitamin D repletion is recommended when 25-hydroxyvitamin D levels are below 10 ng/ml. Furthermore, it may be indicated in presence of 25OHD values between 10 and 30 ng/ml, if associated with osteoporosis, osteomalacia or increased parathyroid hormone levels. The optimal repletion and maintenance dosing regimens remain to be established, as well as the impact of vitamin D supplementation in preventing comorbidities.
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PMID:Vitamin D deficiency in HIV infection: an underestimated and undertreated epidemic. 2369 Jan 92

Vitamin D deficiency in HIV infection has attracted much interest. The best known clinical outcomes of vitamin D deficiency are rickets (children) and osteomalacia (adults). Several non-skeletal disorders have also been linked to suboptimal vitamin D levels in the general population. The prevalence of vitamin D deficiency varies widely (6-100%) across diverse patient populations, with no evidence that it is higher in HIV-positive versus noninfected adults. Vitamin D deficiency may blunt immune restoration and exacerbate HIV complications (e.g. opportunistic infections, poor perinatal outcomes, wasting, HIV disease progression, AIDS events, and death). The nonnucleoside reverse transcriptase inhibitor efavirenz was associated with a relatively high risk of vitamin D deficiency; nevirapine, etravirine, and rilpivirine were noted to have less or no impact on vitamin D versus efavirenz in the limited data available. Protease inhibitors have either no or a low association with vitamin D deficiency. Nucleoside/nucleotide reverse transcriptase inhibitors (with the possible exception of zidovudine) also did not appear to be associated with vitamin D deficiency. Management of vitamin D deficiency in HIV-positive adults has not been rigorously evaluated; some guidelines recommend more vitamin D supplementation for HIV-positive adults on antiretrovirals versus the general population (e.g. 2-3 times higher vitamin D daily intake for the age group; loading dose up to 10,000 IU/day for 8-10 weeks and a maintenance dose of 800-2,000 IU/day). In conclusion, although vitamin D deficiency in HIV-positive adults can be prevalent, current evidence for its causes and impact is relatively weak. More data, particularly from large, controlled, long-term trials, regarding the benefits of correcting vitamin D levels in HIV-positive adults are needed.
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PMID:Vitamin D deficiency in HIV: a shadow on long-term management? 2475 52

Tumour-induced osteomalacia (TIO) is a rare paraneoplastic syndrome of humans. Some mesenchymal tumours (often resembling haemangiopericytomas) express molecules that normally regulate phosphorus metabolism; most frequently, fibroblast growth factor 23. Patients develop renal phosphate wasting and inappropriately low serum concentrations of 1, 25 (OH)2 vitamin D3 , leading to osteomalacia. Surgical removal of the tumour is curative. The authors examined expression of canine fibroblast growth factor 23 in 49 soft tissue sarcomas, and control tissues from normal adult dogs. RNA extracted from bone or formalin-fixed, paraffin-embedded tissues was analysed by end point and quantitative reverse transcriptase-polymerase chain reaction. Fibroblast growth factor 23 expression was detected in bone, lung, kidney, lymph node and thymus. Fifteen of 49 sarcomas (31%) expressed fibroblast growth factor 23, three of these had high relative expression and some features resembling phosphatonin-expressing mesenchymal tumours of humans. Further work is required to determine whether TIO may occur in dogs.
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PMID:Expression of fibroblast growth factor 23 by canine soft tissue sarcomas. 2492 16


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