Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0005940 (bone disease)
 7,459 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Histopathological and pathophysiological investigations including the genetic approach have been contributing to management of renal hyperparathyroidism (HPT). In renal failure, parathyroid glands initially proliferate diffusely and polyclonally, and then are transformed to monoclonal nodular hyperplasia with aggressive growth potential and diminished expression of both the vitamin D receptor and calcium-sensing receptor. When more than one parathyroid gland progresses to nodular hyperplasia, HPT is refractory to medical treatment. To prevent advanced renal HPT, progression to nodular hyperplasia should be avoided. Control of hyperphosphatemia is very important to prevent advanced renal HPT, but it is usually difficult. Administration of vitamin D metabolites constitutes the most promising form of prophylaxis and should be performed with monitoring of the PTH level to avoid adynamic bone disease. Calcitriol pulse therapy is effective for advanced renal HPT; however, when parathyroid glands progress to nodular hyperplasia, surgical treatment should be considered. Measuring parathyroid volume by ultrasonography is useful for detecting nodular glands and deciding treatment options. Parathyroidectomy (PTx) is an effective treatment for advanced renal HPT. However, the timing of the operation is important, because the improvement of skeletal deformity and vessel calcification inducing high mortality risk cannot be expected even after successful surgery. Total PTx with forearm autograft is a suitable procedure for renal HPT. Recently. selective percutaneous ethanol injection therapy has been adopted as an alternative treatment to PTx, and new vitamin D analogues, phosphate binders without calcium, and calcimimetics have been developed as new options for management of renal HPT.
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PMID:Management of renal hyperparathyroidism. 1091 87

The calcium-sensing receptor (CaR) is a G protein-coupled receptor that plays key roles in extracellular calcium ion (Ca(2+)(o)) homeostasis by enabling parathyroid, kidney, and other cells to directly "sense" changes in Ca(2+)(o). In multiple myeloma-associated bone disease, myeloma cells could raise the level of Ca(2+)(o) within their immediate vicinity in the bone marrow microenvironment, through their known capacity to cause bone destruction by stimulating osteoclastic bone resorption. Thus if myeloma cells expressed the CaR, they might sense these locally elevated levels of Ca(2+)(o), which could, in turn, potentially modify their function(s) in ways that could contribute to myeloma bone disease or other aspects of the pathophysiology of this disabling hematological malignancy. In this study, we examined the expression of the CaR in three myeloma cell lines, human U266, IM-9, and RPMI8226 cells. CaR protein was present in all three cell lines as assessed by immunocytochemistry and Western blot analysis using a monoclonal antibody specific for the CaR. Moreover, the use of reverse transcription-polymerase chain reaction (RT-PCR) with CaR-specific primers, followed by nucleotide sequencing of the amplified products, also identified CaR transcripts in the three cell lines. Exposure to known polycationic agonists of the CaR, including high Ca(2+)(o) (2.5mM), neomycin, and gadolinium (Gd(3+)) as well as a specific CaR activator, NPS R467, augmented cell proliferation in all three cell lines. RT-PCR revealed that U266 cells, but not IM-9 cells or RPMI8226 cells, expressed interleukin-6 (IL-6), the expression of which was not enhanced by treatments with CaR agonists. Therefore, taken together, our data first document the fact that the myeloma cell lines, U266, IM-9, and RPMI8226, all express CaR protein and mRNA. Moreover, the CaR expressed on myeloma cells could sense the locally high levels of Ca(2+)(o) in the vicinity of sites of osteoclastic bone resorption and stimulate their proliferation in an IL-6-independent manner. These processes may result in promoting further growth of the tumor and aggravating the associated bone disease.
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PMID:The extracellular calcium Ca2+o-sensing receptor is expressed in myeloma cells and modulates cell proliferation. 1245 70

Musculoskeletal problems remain among the main limitations of the quality of life of renal failure patients, in particular of those treated with long-term maintenance dialysis. Renal osteodystrophy continues to receive great attention. The mechanisms of uremic skeletal resistance to parathormone (PTH) are further investigated. The assay used for the dosage of "intact PTH" has been found to detect 7-84 fragments with an inhibitory effect on the action of the whole hormone. A decrease in the density of PTH receptor on osteoblasts is another recently evidenced factor. Investigations of the recently described RANK-RANKL system have demonstrated an increase in serum osteprotegerin levels, which, together with the two above-mentioned abnormalities, may explain bone resistance to PTH. These are important advances in the understanding of renal osteodystrophy as skeletal resistance to PTH appears to play an important part in the pathophysiology of secondary hyperparathyroidism and of adynamic bone disease. Because of this skeletal resistance, it has been recommended for several years that serum PTH level be monitored and kept twofold to threefold above the upper value of the normal level to maintain normal bone turnover in dialysis patients. Relative hypoparathyroidism has recently been found to be associated with increased spontaneous fracture rate and mortality, so this recommendation appears to hold adequate, despite the demonstration that serum PTH levels in this range are a poor predictor of bone turnover and that chronic parathyroid gland hyperplasia is likely to favor parathyroid gland autonomization. Recent publications have insisted on the role that hyperphosphatemia plays not only in the development of secondary hyperparathyroidism, but also of vascular, especially coronary, calcification and as a predictor of mortality. This "silent killer" of uremic patients is one of the main targets for therapeutic intervention. Extensive use of calcium-containing phosphate binders has been recently criticized as calcium overload appears to favor vascular calcification. Sevelaner (RenaGel) is a calcium- and aluminum-free phosphate binder that is an important advance in the management of renal osteodystrophy, especially in patients with extraskeletal calcification and hypercalcemia. The use of vitamin D derivatives has also raised concern because they enhance calcium and phosphorus absorption and reduce bone turnover. New metabolites with fewer hypercalcemic effects have been developed. Calcium-sensing receptor agonists are stimulating interest and are likely to take an important place in the future management of renal osteodystrophy. Uremic myopathy has received recent attention. Impaired muscle capillary oxygen transfer has been identified as a pathophysiologic factor, and progressive resistance training has been shown to improve the condition. Finally, a new entity, nephrogenic fibrosing dermopathy, has been described, which must be distinguished from calciphylaxis and scleromyxedema.
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PMID:Musculoskeletal manifestations of chronic renal failure. 1249 10

Our knowledge of the mineral metabolism disturbances and skeletal disorders in patients with chronic renal insufficiency has advanced significantly in the last years. Probably the most important what we have learned is, that apart of bone disease, hyperparathyroidism and its treatment can also lead to severe extra-skeletal complications, contributing to the progression of cardiovascular disease in this population. This fact has fundamentally changed our approach to the treatment, and - as a result - the new clinical practice guidelines on the management of mineral metabolism and bone disease in chronic renal failure have been developed. Mainstays of the new approach are lower recommended serum calcium and calcium-phosphate product. However, these targets are very difficult to achieve in clinical practice. During the last decade, some additional therapeutic agents have been welcomed. There are two effective calcium-free, aluminium-free phosphate binders, sevelamer hydrochloride, and lanthanum carbonate, four vitamin D analogues of newer generation, and--last but not least--modulators of calcium-sensing receptor, calcimimetics. Future studies will be needed to determine how these recent developments will be helpful. The optimal therapy for all end-stage renal failure complications is definitely renal transplantation.
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PMID:[New aspects in the management of renal osteodystrophy]. 1566 6

Hyperparathyroidism (HPT) is a significant clinical concern for patients with a variety of diseases, notably the secondary HPT associated with chronic kidney disease requiring dialysis. Secondary HPT is associated with elevated para-thyroid hormone (PTH) levels, decreased levels of 1,25 dihydroxyvitamin D, and disordered mineral levels (usually high calcium and phosphorus). If not controlled, secondary HPT can result in bone disease, vascular calcification, and ultimately, patient mortality. Established, conventional therapies, such as 1,25dihydroxyvitamin D analogues (vitamin D analogues) and phosphate binders, have proven to be inadequate in enabling patients to meet the National Kidney Foundation's-Kidney Disease Outcomes Quality Initiative (NKF-K/DOQI) treatment goals for PTH, calcium and phosphorus levels. A novel therapeutic, cinacalcet HCl (formerly AMG 073; Sensipar in the US and Mimpara in Europe; Amgen, Inc.), binds directly to the calcium-sensing receptor (CaR) on the cells of the parathyroid gland, increasing the receptor's sensitivity to calcium and reducing PTH, serum calcium and phosphorus levels. Treatment with cinacalcet in clinical trials has safely and effectively improved achievement of the NKF-K/DOQI goals. Cinacalcet has also reduced serum calcium levels in patients with primary HPT, including parathyroid carcinoma, in the clinical trial setting. Evidence suggesting the utility of cinacalcet in these diseases and the potential for additional therapeutic applications will be discussed.
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PMID:Cinacalcet HCl: a novel therapeutic for hyperparathyroidism. 1579 35

The parathyroid gland (PTG) is a unique endocrine organ in which the quiescent glandular cells begin to proliferate in response to the demand for maintaining calcium (Ca) homeostasis in the progressive course of renal failure, leading to secondary hypereparathyroidism (SHPT). SHPT is characterized with continuous over-secretion of parathyroid hormone (PTH) and high turn-over bone disease, osteitis fibrosa, and the major factors include a deficiency of active vitamin D, hypocalcemia, and phosphate retention. With long-term end-stage renal failure, SHPT becomes resistant to conventional medical treatment such as phosphate binders and active vitamin D supplementation, and the growth of the PTG accelerates with the pattern of hyperplasia changing from diffuse to nodular type. In this process, the sigmoid curve between extracellular Ca concentration (exCa) and the plasma level of PTH shifts to the upper-rightward, indicating both an absolute increase in PTH secretion and the resistance of PT cells to exCa. Many experimental and human studies have revealed down-regulation of vitamin D receptor (VDR), calcium-sensing receptor (CaSR), and retinoid X receptor (RXR) in PT cells. The sustained proliferation of PT cells after obtaining autonomicity is another characteristic feature of SHPT. In this context, it has been demonstrated that the cell cycle is markedly progressed, where the expression of cyclin-dependent kinase inhibitor (CDKI), p21 and p27, is depressed in a VDR-dependent manner. These pathological features are most evident in nodular hyperplasia, in which monoclonal proliferation is obvious, indicating the phenotypic changes have occured in PT cells. It has been observed by Fukagawa and colleagues that pharmacologically high dose of active vitamin D administered orally can cause small-size PTG hyperplasia to regress in patients with advanced SHPT. Successful renal transplantation may also restore VDR and CaSR expressions in the diffuse type, in association with increasing TUNEL-positive cells. Thus, it is important to vigorously treat SHPT when the PT cell proliferation is in the reversible stage of diffuse hyperplasia.
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PMID:Parathyroid cell growth in patients with advanced secondary hyperparathyroidism: vitamin D receptor, calcium sensing receptor, and cell cycle regulating factors. 1610 39

Renal stone disease (nephrolithiasis) affects 5% of adults and is often associated with hypercalciuria. Hypercalciuric nephrolithiasis is a familial disorder in more than 35% of patients, and may occur as a monogenic disorder, or as a polygenic trait involving 3 to 5 susceptibility loci in man and rat, respectively. Studies of monogenic forms of hypercalciuric nephrolithiasis in man, for example, Bartter syndrome, Dent's disease, autosomal dominant hypocalcemic hypercalciuria (ADHH), hypercalciuric nephrolithiasis with hypophosphatemia, and familial hypomagnesemia with hypercalciuria have helped to identify a number of transporters, channels, and receptors that are involved in regulating the renal tubular reabsorption of calcium. Thus, Bartter syndrome, an autosomal recessive disease, is caused by mutations of the bumetanide-sensitive Na-K-Cl (NKCC2) cotransporter, the renal outer-medullary potassium channel (ROMK), the voltage-gated chloride channel, CLC-Kb, or in its beta subunit, Barttin. Dent's disease, an X-linked disorder characterized by low molecular weight proteinuria, hypercalciuria, and nephrolithiasis, is due to mutations of the chloride/proton antiporter, CLC-5; ADHH is associated with activating mutations of the calcium-sensing receptor, which is a G protein-coupled receptor; hypophosphatemic hypercalciuric nephrolithiasis associated with rickets is due to mutations in the type 2c sodium-phosphate cotransporter (NPT2c); and familial hypomagnesemia with hypercalciuria is due to mutations of paracellin-1, which is a member of the claudin family of membrane proteins that form the intercellular tight junction barrier in a variety of epithelia. These studies have provided valuable insights into the renal tubular pathways that regulate calcium reabsorption and predispose to kidney stones and bone disease.
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PMID:Genetics of hypercalciuric nephrolithiasis: renal stone disease. 1787 84

Successful kidney transplantation reverses mineral and bone disorder including secondary hyperparathyroidism, but persistent hyperparathyroidism with subsequent hypercalcemia emerges in a significant number of allograft patients. Among kidney-transplanted patients, approximately 5% will later require parathyroidectomy. Recently, the calcimimetic agent cinacalcet offers a novel therapeutic option to treat post-transplant hypercalcemia where parathyroidectomy might be considered. Despite persistent down-regulation of vitamin D receptor and calcium-sensing receptor in nodular hyperplasia even after successful kidney transplantation, calcimimetics has been shown to be efficacious in reducing serum calcium levels in such patients. However, there still remain several problems of calcimimetics, such as long-term efficacy, safety, optimal time point for cessation, and long-term effect on cardiovascular morbidity and allograft function after kidney transplantation. Furthermore, surgical in dication for persistent hyperparathyroidism is also a clinically important question. Further researches are needed to elucidate these issues.
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PMID:[Basic and clinical aspects of calcimimetics. Calcimimetics : a promising treatment for persistent hypercalcemia after kidney transplantation]. 1817 73

Experiments performed in mice in which expression of the extracellular calcium-sensing receptor (CaSR) was completely nullified specifically in parathyroid cells, chondrocytes, or cells of the osteoblast lineage have identified phenotypes that indicate a key role for the CaSR in embryonic development of the skeleton, postnatal bone formation, and osteoblast differentiation that are independent of the calcitropic hormone axis. These long-awaited studies further clarify the signaling relationships between the parathyroid gland, kidney, and metabolic bone disease in patients with mutations in the gene encoding the CaSR, and they provide new insights into understanding the signaling pathways involving the CaSR in skeletal cells.
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PMID:New insights in bone biology: unmasking skeletal effects of the extracellular calcium-sensing receptor. 1876 30

Calcium and phosphorus homeostasis relies on a complex, tightly regulated system involving many ions and hormones. The regulation of calcium and phosphorus is controlled by the actions of these ions and hormones on the intestine, kidneys and bone. Disturbances in the serum level of calcium and/or phosphorus can lead to significant pathology, including kidney stones and bone disease. In addition to parathyroid hormone and vitamin D, recently identified factors such as fibroblast growth factors and klotho play an important role in maintaining mineral ion homeostasis. The identification of subfamily V transient receptor potential cation channels (TRPV channels), Na/P(i) cotransporters, the vitamin D receptor and the calcium-sensing receptor have further advanced our understanding of this complex physiology. In this review we discuss the current understanding of the relationships between the ions, hormones, and transporters that maintain calcium and phosphorus homeostasis.
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PMID:Calcium and phosphorus homeostasis. 1929 93


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