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)

It has been reported that osteopontin (OPN) plays an important role during urolithiasis as well as bone formation. Generation of stones in the urinary tract may be associated with osteoporosis and bisphosphonates are potent inhibitors of bone resorption, being used with effect in the management of bone disease. We therefore investigated the relationship between alendronate, a bisphosphonate derivative, and OPN expression in the kidney. Alendronate was administered to rats made hypercalcemic by treatment with parathyroid hormone-related peptide (PTHrP). The renal expression of OPN was then evaluated at both protein and mRNA levels. OPN expression was enhanced in the distal tubular cells of hypercalcemic rats and was decreased by alendronate. The observed inhibition of OPN expression suggests an ability of alendronate and other bisphosphonates to act as inhibitors of stone formation in the urinary tract.
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PMID:Alendronate inhibits osteopontin expression enhanced by parathyroid hormone-related peptide (PTHrP) in the rat kidney. 984 Mar 46

Oncogenic hypophosphatemic osteomalacia (OHO) is characterized by a renal phosphate leak, hypophosphatemia, low-serum calcitriol (1,25-vitamin-D3), and abnormalities in skeletal mineralization. Resection of OHO tumors results in remission of the symptoms, and there is evidence that a circulating phosphaturic factor plays a role in the bone disease. This paper describes the characterization and cloning of a gene that is a candidate for the tumor-secreted phosphaturic factor. This new gene has been named MEPE (matrix extracellular phosphoglycoprotein) and has major similarities to a group of bone-tooth mineral matrix phospho-glycoproteins (osteopontin (OPN; HGMW-approved symbol SPP1), dentin sialo phosphoprotein (DSPP), dentin matrix protein 1 (DMP1), bone sialoprotein II (IBSP), and bone morphogenetic proteins (BMP). All the proteins including MEPE contain RGD sequence motifs that are proposed to be essential for integrin-receptor interactions. Of further interest is the finding that MEPE, OPN, DSPP, DMP1, IBSP, and BMP3 all map to a defined region in chromosome 4q. Refined mapping localizes MEPE to 4q21.1 between ESTs D4S2785 (WI-6336) and D4S2844 (WI-3770). MEPE is 525 residues in length with a short N-terminal signal peptide. High-level expression of MEPE mRNA occurred in all four OHO tumors screened. Three of 11 non-OHO tumors screened contained trace levels of MEPE expression (detected only after RT-PCR and Southern 32P analysis). Normal tissue expression was found in bone marrow and brain with very-low-level expression found in lung, kidney, and human placenta. Evidence is also presented for the tumor secretion of clusterin (HGMW-approved symbol CLU) and its possible role as a cytotoxic factor in one of the OHO patients described.
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PMID:MEPE, a new gene expressed in bone marrow and tumors causing osteomalacia. 1094 70

Tissue nonspecific alkaline phosphatase (TNAP) knockout (ko) mice manifest defects in bone mineralization that mimic the phenotypic abnormalities of infantile hypophosphatasia. In this article, we have searched for phenotypic differences between calvarial osteoblasts and osteoclasts in wild-type (wt), heterozygous and homozygous TNAP null mice. In vitro release of 45Ca from calvarial bones, with and without stimulation with parathyroid hormone (PTH), revealed no functional difference between osteoclasts from the three TNAP genotypes. Studies of primary cultures of TNAP+/+, TNAP+/-, and TNAP-/- calvarial osteoblasts revealed no differences in the rate of protein synthesis or in the expression levels of messenger RNAs (mRNAs) for osteopontin (OP), osteocalcin (OC), collagen type I, core binding factor alpha1 (Cbfa 1), N-cadherin, Smad 5, and Smad 7. Release of interleukin-6 (IL-6) from calvarial osteoblasts under basal conditions and after stimulation with PTH, tumor necrosis factor alpha (TNF-alpha) or IL-1beta was similar in all genotypes. The amount of cyclic adenosine monophosphate (cAMP) accumulation also was comparable. However, although cultures of primary TNAP-/- osteoblasts were able to form cellular nodules as well as TNAP positive osteoblasts do, they lacked the ability to mineralize these nodules in vitro. Mineralization also was delayed in TNAP+/- osteoblast cultures compared with cultures of wt osteoblasts. Incubation with media supplemented with recombinant TNAP, but not with enzymatically inactive TNAP, restored mineralization in ko osteoblast cultures. Our data provide evidence that osteoblasts in TNAP null mice differentiate normally but are unable to initiate mineralization in vitro. The fact that even heterozygous osteoblasts show delayed mineralization provides a rationale for the presence of bone disease in carriers of hypophosphatasia.
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PMID:Functional characterization of osteoblasts and osteoclasts from alkaline phosphatase knockout mice. 1102 39

The approach of gene-targeted animal models is likely the most important experimental tool contributing to recent advances in skeletal biology. Modifying the expression of a gene in vivo, and the analysis of the consequences of the mutation, are central to the understanding of gene function during development and physiology, and therefore to our understanding of the gene's role in disease states. Researchers had been limited to animal models primarily involving pharmaceutical manipulations and spontaneous mutations. With the advent of gene targeting, however, animal models that impact our understanding of metabolic bone disease have evolved dramatically. Interestingly, some genes that were expected to yield dramatic phenotypes in bone, such as estrogen receptor-alpha or osteopontin, proved to have subtle phenotypes, whereas other genes, such as interleukin-5 or osteoprotegerin, were initially identified as having a role in bone metabolism via the analysis of their phenotype after gene ablation or overexpression. Particularly important has been the advance in knowledge of osteoblast and osteoclast independent and dependent roles via the selective targeting of genes and the consequent disruption of bone formation, bone resorption, or both. Our understanding of interactions of the skeletal system with other systems, ie, the vascular system and homeostatic controls of adipogenesis, has evolved via animal models such as the matrix gla protein, knock-out, and the targeted overexpression of Delta FosB. Challenging transgenic models such as the osteopontin-deficient mice with mediators of bone remodeling like parathyroid hormone and mechanical stimuli and extending phenotype characterization to mechanistic in vitro studies of primary bone cells is providing additional insight into the mechanisms involved in pathologic states and their potentials for therapeutic strategies. This review segregates characterization of transgenic models based on the category of gene altered, eg, reproductive hormones, calcitropic hormones, growth factors and cytokines, signaling molecules, extracellular matrix molecules and "other" genes. Models are also segregated based on phenotypes that are primarily osteoclastic, osteoblastic or mixed. As the technical ability to alter gene expression negatively or positively and in a tissue-specific and temporal manner continues to evolve, there are endless possibilities for generating genetically altered animal models with which to gain insight into metabolic bone diseases.
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PMID:Transgenic mouse models of metabolic bone disease. 1155 36

We have examined several analogs of 1alpha,25-dihydroxyvitamin D(3) [1,25-(OH)(2)D(3)] in an animal model of osteoporosis (ovariectomized rats) to identify a compound with a greater therapeutic range than 1,25-(OH)(2)D(3) for treatment of this bone disease. Here, we report that one analog, Ro-26-9228, had a bone-protecting effect but did not induce hypercalcemia at a wide concentration range. Analysis of biochemical markers and the bone histomorphometry of analog-treated rats suggested that Ro-26-9228 acted by inhibiting bone resorption and increasing the number of differentiated osteoblasts. To determine the basis for the segregation between hypercalcemia and bone-protecting action, we examined gene expression in tissues that regulate calcium homeostasis. We found that 1,25-(OH)(2)D(3) induced 24-hydroxylase mRNA expression in the duodena of ovariectomized rats, but Ro-26-9228 did not. Furthermore, in the duodena of intact animals, 1,25-(OH)(2)D(3) induced a significant increase in calbindin D 9K and plasma membrane calcium pump 1 mRNAs, but Ro-26-9228 had no effect on these mRNAs. On the other hand, the osteoblast-specific gene products osteocalcin and osteopontin were significantly up-regulated in trabecular bone by both the natural hormone and Ro-26-9228. Further investigation of gene-regulatory events in trabecular bone revealed that both 1,25-(OH)(2)D(3) and Ro-26-9228 up-regulated TGF beta1 and beta2 mRNAs. We concluded that the unique properties of Ro-26-9228 include preferential gene regulation in osteoblasts over duodenum and effective induction of growth factors in bone.
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PMID:Cellular and molecular events associated with the bone-protecting activity of the noncalcemic vitamin D analog Ro-26-9228 in osteopenic rats. 1195 43

Osteoporosis is associated with the pathogenesis of urinary stone formation. Urinary stones are similar to bone diseases such as osteoporosis and bone metabolism in terms of pathogenesis. Bisphosphonates are potent inhibitors of bone resorption, and are used in the management of bone disease. Furthermore, bisphosphonates have a strong affinity for calcium, and a reported inhibitory effect on calcium oxalate crystallization in vitro. Thus, bisphosphonates might also inhibit urinary stone formation. Madin-Darby canine kidney (MDCK) cells form calcium phosphate microliths at the basolateral side in vitro. We investigated the inhibitory effects of new generation bisphosphonates (alendronate and incadronate) on calcium phosphate microlith formation and on the expression of osteopontin, which is an important urinary stone matrix. MDCK cells formed two types of colonies in three-dimensional soft agar culture; dark colonies containing calcium phosphate microliths and clear colonies free from microliths. We applied purified alendronate and incadronate at concentrations of 10(-11), 10(-9), 10(-7) and 10(-5) M to MDCK cells cultured in three-dimensional soft agar and investigated the efficiency of colony formation and the dark colony ratio (number of dark colonies relative to the total number of colonies). The administration of 10(-9) and 10(-7) M alendronate decreased the dark colony ratio compared with controls, whereas incadronate did not significantly alter this colony ratio compared with controls. The expression of osteopontin in cultured cells was inhibited by the 10(-7) M alendronate administration. The present findings show that alendronate inhibits calcium stone formation, suggesting that it is effective in the prevention of urolithiasis.
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PMID:Alendronate inhibits urinary calcium microlith formation in a three-dimensional culture model. 1506 76

Our previous report on bone histomorphometry in patients with distal renal tubular acidosis (dRTA) revealed decreased bone formation rate (BFR) when compared to healthy subjects. The abnormality improved significantly after alkaline therapy. The modest increase in osteoblastic surface, after correction of metabolic acidosis, could not explain the striking improvement in bone formation, suggesting additional influence of metabolic acidosis on osteoblast function and/or bone matrix mineralization. Osteoblasts and, to a lesser extent, osteoclasts synthesize and secrete bone matrix including type I collagen and various noncollagenous proteins (NCPs). Substantial evidence suggested diverse functions of NCPs related to bone formation, resorption, and mineralization. Metabolic acidosis, through its effect on bone cells, may result in an alteration in the production of NCPs. Our study examined bone histomorphometry with detailed analysis on the mineralization parameters and NCPs expression within the bone matrix of patients with dRTA before and after treatment with alkaline. Seven dRTA patients underwent bone biopsy at their initial diagnosis and again 12 months after alkaline therapy. Bone mineral density (BMD) and bone histomorphometry were obtained at baseline and after the treatment. The expression of NCPs was examined by immunohistochemistry, quantitated by digital image analysis, and reported as a percentage of area of positive staining or mineralized trabecular bone area. Alkaline therapy normalized the low serum phosphate and PTH during acidosis. The reduction in BMD at baseline improved significantly by the treatment. Bone histomorphometry demonstrated the increase in osteoid surface and volume without significant alteration after acidosis correction. In comparison to the normal subjects, osteoid thickness was slightly but insignificantly elevated. Osteoblast and osteoclast populations and their activities were suppressed. The reduction in mineral apposition rate and adjusted apposition rate were observed in conjunction with the prolongation of mineralization lag time. Alkaline therapy improved the mineralization parameters considerably. In addition to the increase in BFR relative osteoblast number after acidosis correction, osteocalcin expression in the bone matrix increased significantly from 16.7% to 22.3%. Six of seven patients had decreased osteopontin expression. In conclusion, the abnormal bone remodeling in dRTA is characterized by low turnover bone disease with some degree of defective mineralization. Alteration of NCPs expression suggested the effect of metabolic acidosis on bone cells. Alkaline therapy increased bone mass through the restoration of bone mineral balance and, perhaps, improved osteoblast function.
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PMID:Alteration of noncollagenous bone matrix proteins in distal renal tubular acidosis. 1533 95

Osteoprotegerin (OPG) is a potent antiresorptive molecule that binds NF-kappaB ligand, the final effector for osteoclastogenesis. OPG production is regulated by a number of cytokines and hormones. Osteopontin (OPN) is a secreted adhesive glycoprotein involved in tumour angiogenesis, and also a non-collagenous protein involved in bone turnover. OPN serum value is associated with tumour burden and survival in advanced breast cancer patients. The short-term effects of anastrozole on OPG and OPN serum values, and the usefulness of these analytes during follow-up were studied in 34 consecutive advanced breast cancer patients receiving anastrozole 1 mg/day. Blood samples were taken before treatment and at 2, 4, 8 and 12 weeks. OPG and OPN values were measured by ELISA. The results were analysed for all patients, and also separately for patients with (group A, 22 patients) and without (group B, 12 patients) bone metastasis. Whether the survival of all patients was related to their OPN serum values was also tested by placing patients into three groups (terciles) according to their baseline OPN values. No significant changes in OPG and OPN values were observed in the complete patient group. There was no difference in baseline OPG and OPN serum values between patients in groups A and B. In group A, a significant percentage increase in both OPG and OPN values from baseline was detected during treatment. No significant changes were reported for group B patients. Furthermore, in group A, a significant increase in both analytes was evident only for patients with progressive disease (PD). The Kaplan-Meier adjusted survival estimates for patients grouped according to tercile OPN values differed significantly (P = 0.001, log rank test). In conclusion, in the short term, anastrozole does not seem to affect OPG and OPN serum values in patients without bone disease. OPG and OPN appear to be useful predictors of the outcome of skeletal disease and elevated OPN values may be associated with short survival in advanced breast cancer patients.
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PMID:Osteoprotegerin and osteopontin serum values in postmenopausal advanced breast cancer patients treated with anastrozole. 1561 51

The aim of this study was the evaluation of the effect of intermediate doses of thalidomide with dexamethasone (Thal/Dex) on disease course and bone disease in patients with refractory/relapsed myeloma who were under zoledronic acid therapy. We studied 35 patients, who received thalidomide at a dose of 200 mg/daily. We measured, pre-, 3 and 6 months post-treatment soluble receptor activator of nuclear factor-kappaB ligand (sRANKL), osteoprotegerin (OPG), osteopontin (OPN), markers of bone resorption and formation. Before treatment, patients had increased levels of sRANKL/OPG ratio, bone resorption markers and OPN, while they had suppressed bone formation. The pretreatment sRANKL/OPG ratio correlated with the extent of bone disease. Thal/Dex administration resulted in a significant reduction of sRANKL/OPG ratio, and bone resorption. Bone formation, OPG and OPN did not show any alteration. Changes of sRANKL/OPG ratio correlated with changes of bone resorption markers. Thal/Dex was given for a median time of 10 months and the median follow-up period was 22 months. The response rate was 65.7%. The median survival was 19.5 months. beta2-microglobulin, type of response and International Staging System predicted for survival. These results suggest that the combination of intermediate dose of Thal/Dex is effective in patients with refractory/relapsed myeloma and improves abnormal bone remodeling through the reduction of sRANKL/OPG ratio.
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PMID:The combination of intermediate doses of thalidomide with dexamethasone is an effective treatment for patients with refractory/relapsed multiple myeloma and normalizes abnormal bone remodeling, through the reduction of sRANKL/osteoprotegerin ratio. 1607 95

Osteolytic bone disease is a major clinical feature of multiple myeloma (MM). Mechanisms of bone destruction are related to increased osteoclastic activity, which is not accompanied by a comparable increase in bone formation, as osteoblasts are functionally exhausted. Thus the lesions rarely heal and bone scans are often negative in myeloma patients with extensive lytic lesions, offering very little in the follow-up of bone disease. Biochemical markers of bone resorption, such as N- and C-terminal cross-linking telopeptide of type I collagen (NTX, CTX/ICTP, respectively), tartrate resistant acid phosphatase isoform-5b, bone formation (bone-specific alkaline phosphatase [BAP]), and osteocalcin provide useful information on bone dynamics. Several studies have shown that NTX, CTX, and ICTP are elevated in myeloma patients, reflect the extent of bone disease, and correlate with survival. Furthermore, they are useful in monitoring bone destruction during antimyeloma or bisphosphonate treatment. Markers of bone formation have produced conflicting results in trials. However, BAP correlates with bone pain, lytic lesions, and fractures in quite a few studies of MM. Novel markers, such as bone sialoprotein, receptor activator of nuclear factor-kappa B ligand (RANKL), osteoprotegerin, osteopontin, dickkopf-1, and soluble Frizzle-related protein-2 have been found of value in assessing bone lytic disease in MM, but their promising results must be confirmed in large trials. In conclusion, although no marker provides optimal analysis of MM or of MM treatments, combinations of markers have at times helped in assessing MM stages and lytic bone disease and in monitoring specific treatment modalities. The need for further research in this field is clear.
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PMID:Biochemical markers of bone metabolism in multiple myeloma. 1668 Aug 33


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