Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0029463 (osteosarcoma)
 16,637 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Amine-carboxyboranes have been shown to prevent osteoporosis and loss of bone mass in rodents. In vitro studies using CF1 mouse pup calvaria and rat UMR-106 osteosarcoma cells showed that amine-carboxyborane derivatives reduced significantly the loss of intracellular calcium into the growth medium from 10(-4) to 10(-8) M over 48 hours. Amine-carboxyborane derivatives were more effective than calcitonin or simple boron salts. Calcium incorporation into these cells and proline incorporation into collagen was accelerated in the presence of amine carboxyboranes. The amine-carboxyborane derivatives effectively inhibited lysosomal and proteolytic enzymes as well as activities of serine elastase, prostaglandin cyclooxygenase, and 5'-lipoxygenase in mouse macrophages, human PMNs, leukocytes and Be Sal cells. IC50 values were in the range of 10(-6) M. In lactating ovariectomized female rats after administered amine-carboxyboranes for 14 days at 8 mg/kg/day orally, the femur and humerus showed increased volume, weight, density and ash weight. Serum calcium levels were elevated significantly with minimum reductions on serum inorganic phosphate levels. Femur calcium levels were elevated after treatment with amine-carboxyborane derivatives, but not with etidronate. Humerus total lipids after 14 days were slightly elevated probably due to increased levels of triglycerides and phospholipids.
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PMID:The anti-osteoporotic activity of amine-carboxyboranes in rodents. 764 84

In order to test the hypothesis that salmon calcitonin has direct effects to modulate tyrosyl-protein phosphorylation in human osteosarcoma cells, SaOS-2 cells (with very high steady-state levels of skeletal alkaline phosphatase) were exposed to calcitonin, in duplicate serum-free cultures, at concentrations ranging from 10(-13) to 10(-9) mol/liter, for 0-60 minutes at 37 degrees C. Phospho-tyrosyl proteins were identified by autoradiography of Western blots after incubation with 125I-labeled antiphosphotyrosine antibodies (or with unlabeled antibodies and 125I-labeled protein A) and quantitated by laser densitometry. The results of these studies revealed (1) time-dependent effects of salmon calcitonin (sCt) (at 3 x 10(-12) mol/liter) to increase the level of tyrosylphosphorylation of at least six proteins, with apparent molecular weights of 20, 25, 27, 41, 48, and 135 kD (P < 0.05 for each); and (2) dose-dependent effects of sCt (during 15 minutes of exposure) to increase the level of tyrosyl-phosphorylation of at least 10 proteins with apparent molecular weights of 19, 20, 27, 35, 41, 102, 135, 195, 220, and 244 kD (P < 0.05 for each). A supplementary study of calcitonin effects on tyrosyl-protein phosphorylation in a subpopulation of SaOS-2 cells with very low steady-state levels of skeletal alkaline activity revealed similar responses--time and dose-dependent increases in the tyrosyl-phosphorylation of at least seven proteins with apparent molecular weights of 44, 48, 57, 62, 101, 244, and 280 kD (P < 0.05 for each).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Calcitonin acutely increases tyrosyl-phosphorylation of proteins in human osteosarcoma (SaOS-2) cells. 776 36

Insulin-like growth factor-I (IGF-I) and IGF-II have powerful, well defined effects on osteoblastic cells, stimulating their proliferation and inducing collagen synthesis, but the role of IGF-I and -II in modulating osteoclast differentiation and activity remains unclear. We first examined the bone-resorptive effects of IGF-I and IGF-II by assessing 45Ca2+ release from neonatal mouse calvarial bones. Both IGFs dose dependently stimulated bone resorption, with an EC50 of 8 x 10(-9) M for IGF-I and 2 x 10(-8) M for IGF-II. We then tested the effects of the IGFs on bone resorption by rat isolated osteoclasts cultured on ivory slices. Neither IGF-I nor IGF-II stimulated isolated osteoclast activity. However, in the presence of either primary mouse osteoblasts or human osteosarcoma MG 63 cells, both IGFs enhanced osteoclast resorptive activity, with an EC50 of 5 x 10(-10) M for IGF-I and 10(-9) M for IGF-II. Stimulation was not mediated by BALB/c/3T3 cells, a nonosteoblastic cell line. The effects of the IGFs were blocked by alpha IR-3, an antibody to the type I IGF receptor, but not by beta-galactosidase, a lysosomal enzyme that competes with IGF-II for the type II IGF receptor. We then examined the effects of the IGFs on the formation of osteoclast-like multinucleate cells (MNCs) in mouse bone marrow cultures. IGF-I and -II dose dependently increased the number of tartrate-resistant acid phosphatase (TRAP)-positive MNCs, although their effects were less than that of 1,25-dihydroxyvitamin D3 (a hormone that induces osteoclast differentiation). No TRAP-positive MNCs appeared in the absence of these hormones. Like authentic osteoclasts, the TRAP-positive MNCs formed in response to IGF-I and -II bound [125I]salmon calcitonin. When mouse bone marrow cells were cultured on ivory slices in the presence of either IGF-I or IGF-II for 10 days, numerous resorption lacunae were formed. beta-Galactosidase had no effect on IGF-mediated osteoclast formation. These results are strong evidence that both IGF-I and IGF-II stimulate bone resorption in vitro by enhancing osteoclast formation and function. Our data also suggest that the IGFs act through the intermediary of osteoblastic cells to stimulate osteoclast activity and that the type I, but not the type II, IGF receptor is involved in their responses. We propose that the local production of IGF-I and IGF-II may modulate both osteoblast-osteoclast interactions and osteoclast formation and play an important role in bone remodeling.
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PMID:Osteoblasts mediate insulin-like growth factor-I and -II stimulation of osteoclast formation and function. 782 21

Calcium and phosphorus metabolism is mainly regulated by PTH through its actions on kidney and bone. PTHrP, which is associated with the hypercalcemia of malignancy syndrome, binds to and activates the same receptor that PTH does. cDNA clones of PTH/PTHrP receptors from rat osteosarcoma (ROS 17/2.8) and opossum kidney (OK) cells are highly homologous and are members of a novel G protein-linked receptor family that includes calcitonin, glucagon, GLP-1, GHRH, VIP, and secretin receptors. Analysis of the protein sequence predicts a receptor with 7 transmembrane domains, a 155 amino acids (aa) extracellular (EC) N-terminal, and 130aa intracellular C-terminal domaina. The extracellular domain has 6 conserved cysteines and 4 potential glycosylation sites. When transfected in COS cells, both receptors are able to bind PTH and PTHrP active fragments with equal affinity. Likewise, agonists activate both adenylate cyclase and phospholipase C efficiently. The N-terminal EC domain and the first EC loop seem to determine the receptor binding capacity with the agonists. Activation of adenylate cyclase and phospholipase C might involve multiple sites between the 3rd helix and the C-terminal tail. Partial characterization of the rat PTH/PTHrP receptor gene demonstrates the existence of at least 15 exons. The first six transmembrane domains are encoded by separated exons. The PTH/PTHrP receptor mRNA is expressed mainly in kidney and bone, and also is widely expressed in many tissues, but not all. A major 2.3-2.5 kb transcript is observed in all these tissues. Nevertheless, 2 larger transcripts are observed in kidney and liver, and multiple smaller mRNA species are observed in kidney, skin, and testis.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[Mode of action of parathyroid hormone (PTH) and PTH-related peptide (PTHrP) in target organs]. 785 77

The authors treated 18 patients with Paget's disease of bone (12 men and 6 women, age 65 +/- 5 years) with pamidronate (bisphosphonate of the second generation). Three patients from this group were treated previously without success with calcitonin or bisphosphonate of the first generation (etidronate) 50% of the patients suffered from the polyostotic form of the disease. In one patient a rare combination of primary hyperparathyroidism with Paget's bone disease was found and in another patient later an osteosarcoma developed in the affected bone. To all patients sodium pamidronate was administered (Aredia, Ciba-Geigy) 30 mg per day by i.v. infusion for 2 hours during three days. Four patients developed fever, two patients phlebitis at the site of injection. These side-effects are described by the manufacturer. Two patients developed transient regional alopecia, not described so far. Subjective pain relief of the affected skeleton occurred in one patient after one month of treatment, after three months in 78%. Laboratory manifestations of activity of the disease (serum activity of alkaline phosphatase, tartrate resistant acid phosphatase and hydroxyprolinuria) declined gradually from the 1st to the 6th month after onset of treatment. There was a less marked decline of the osteocalcin serum concentration. The concentration of calcium, phosphorus and vitamin D metabolites did not change markedly. Twelve months after treatment 14.7% of the patients were inactive according to laboratory tests, 73% however experienced another rise of parameters of osteoresorption and osteoformation. Pamidronate treatment in patients with Paget's disease of bone is effective and safe.
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PMID:[Paget's disease of bone and treatment with pamidronate]. 837 65

Although the primary skeletal action of exogenous calcitonin is to inhibit bone resorption, calcitonin also has effects on bone formation. In-vitro data indicate that the latter may include direct effects on bone cells of osteoblastic lineage. In the current studies, we examined the effects of calcitonin on cyclic adenosine monophosphate (cAMP) and PGE2 synthesis and 45Ca uptake in human osteosarcoma cells, specifically, TE-85 cells and subpopulations of SaOS-2 cells with low-, intermediate-, and high-steady-state levels of skeletal alkaline phosphatase (ALP) activity. Since previous in-vivo studies had shown that calcitonin could acutely decrease skeletal ALP activity in rat periosteal osteoblasts, we also measured the effects of calcitonin treatment on ALP specific activity. Neither salmon nor human calcitonin altered the net synthesis of cAMP or PGE2 by SaOS-2 cells, but human calcitonin gene-related peptide increased both (P < .001 and P < .005, respectively). Both salmon and human calcitonin had short-term effects to alter ALP activity in TE-85 and SaOS-2 cells. The effects were different in SaOS-2 subpopulations with different pretreatment ALP levels. Four hours of exposure to salmon calcitonin had dose-dependent, biphasic effects on ALP levels in SaOS-2 cells with intermediate pretreatment ALP levels, increasing ALP at doses between 0.16 and 1.6 nmol/L (P < .005) and decreasing ALP at higher concentrations (P < .05). Both salmon and human calcitonin, but not human calcitonin gene-related peptide, also had short-term effects to increase net 45Ca uptake by SaOS-2 cells; these effects were dose-dependent and long-lasting.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Calcitonin acutely increases net 45Ca uptake and alters alkaline phosphatase specific activity in human osteosarcoma cells. 838 75

Components of the extracellular matrices (ECM) exert pleiotropic effects in many cell systems, but little is known of the effect of ECM on hormone signal transduction. We have investigated the effect of ECM substrates on cell growth and signal transduction by calcitonin (CT) and parathyroid hormone (PTH) using the rat osteosarcoma cell line, UMR 106-06. Type I collagen (collagen[I]) and Matrigel changed the morphology of the cells and significantly inhibited cell growth by 37% or 23%, respectively, compared with control. None of laminin, fibronectin, or type IV collagen affected cell shape or proliferation. Cells cultured on collagen (I)-coated plates showed increased specific binding of labeled CT compared with cells on plastic plates. The effect was apparent by 24 h and persisted for at least 72 h. None of the other ECM affected CT binding. Scatchard analysis revealed that collagen(I) increased CT receptor numbers but not receptor affinity. Consistent with increased binding capacity, cells plated on collagen(I) had increased responses to each of CT and PTH in terms of cyclic adenosine monophosphate (cAMP) production compared to control cells. In addition, cAMP production by prostaglandin E2, cholera toxin, and forskolin was increased by 30-70% compared to control. These data suggest that collagen(I) had effects not only on membrane receptors but on guanosine triphosphate (GTP) binding proteins (G proteins). The effect of collagen(I) on CT binding was no longer present when the cells were freed from the plates by enzymatic dispersion and binding measured in cell suspensions. In UMR 106-01 cells transiently transfected with the porcine CT receptor cDNA, binding was similarly induced by collagen(I). These data are the first demonstration that collagen(I) may play an important role in signal transduction, affecting both receptors and G proteins in UMR 106-06 cells. These results draw attention to the potential role of the ECM of bone in hormone-induced responses.
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PMID:Type I collagen substrate increases calcitonin and parathyroid hormone receptor-mediated signal transduction in UMR 106-06 osteoblast-like cells. 839 Oct 4

It was recently shown that interleukin-6 (IL-6) is produced by bone and bone marrow-derived stromal cells and that it plays an important role in osteoclast development. Here we examined whether parathyroid hormone (PTH), calcitonin (CT), or the calcitonin gene-related peptide (CGRP) influence IL-6 production by two murine bone marrow-derived stromal cell lines: the preadipocyte-like stromal cell line +/+ LDA11 and the fibroendothelial stromal cell line MBA 13.2. We found that CGRP (but not PTH or CT) exerted a dose-dependent increase in cAMP and IL-6 production in the +/+ LDA11 cells. In addition, CGRP had an inhibiting effect on the proliferation of this stromal cell line. CGRP, however, did not affect cAMP or IL-6 in the rat osteogenic sarcoma cell line UMR-106-06, which exhibits CT receptors, whereas CT stimulated both cAMP and IL-6 by the UMR-106-01 cells. In contrast to the specificity of the IL-6 response of the +/+ LDA11 cells to CGRP, IL-6 production by the MBA 13.2 stromal cells was stimulated by PTH whereas CGRP or CT had no effect. These data suggest that bone marrow-derived stromal cells express receptors for either CGRP or PTH in a phenotype-specific manner and that, acting via these receptors, CGRP and PTH stimulate IL-6 production by stromal cells. In addition, the evidence for specific receptors for the neuropeptide CGRP in bone marrow stromal cells and an effect of CGRP on IL-6 raises the possibility for a role of cytokines in a putative interplay between neuronal stimuli and bone.
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PMID:Stimulation of interleukin-6 production by either calcitonin gene-related peptide or parathyroid hormone in two phenotypically distinct bone marrow-derived murine stromal cell lines. 839 39

In certain neurons, alternative RNA processing generates calcitonin gene-related peptide (CGRP) from the same gene that encodes the hormone calcitonin. As CGRP-containing nerve fibers are prominent in skeleton, we evaluated the effects of CGRP on osteoblasts. Because the vasodilatory effect of neural CGRP in smooth muscle probably involves inhibition of unstimulated Ca2+ uptake, we examined the acute effects of CGRP on this parameter in rat osteoblastic cells. CGRP inhibits 45Ca2+ uptake in both UMR 106 osteosarcoma and RCOB-3 osteoblastic cells. This inhibition is rapid (0.5 min), occurs with an EC50 of 1 nM, and cannot be demonstrated in the presence of 0.1 mM diltiazem, a blocker of voltage-dependent Ca2+ channels. Depolarization of bone cells with high extracellular potassium (K+) also blocks the effect of CGRP on 45Ca2+ uptake, suggesting a central role for K+ channels in mediating this action. In agreement with this hypothesis, the effect of CGRP is blocked by 1 microM glybenclamide, a specific inhibitor of ATP-sensitive potassium (K(ATP)) channels, or by pretreatment of cells with 1 mM iodoacetic acid to deplete intracellular ATP. Blocking Ca2+-activated potassium channels with 1 mM tetraethylammonium does not prevent CGRP's effect. Pinacidil, a specific activator of K(ATP) channels, mimics CGRP's effect. Both CGRP and pinacidil also produce a small significant stimulation of cellular Ca2+ efflux in UMR 106 cells. These data suggest that inhibition of diltiazem-sensitive Ca2+ channels occurs secondary to the hyperpolarization engendered by CGRP activation of K(ATP) channels in osteoblastic cells, an effect similar to that of CGRP on smooth muscle cells.
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PMID:Calcitonin gene-related peptide rapidly inhibits calcium uptake in osteoblastic cell lines via activation of adenosine triphosphate-sensitive potassium channels. 860 12

In human periosteum-derived osteoblastic cells (SaM-1) and human osteosarcoma-derived cells (SaOS-2, HOS, MG-63), the mRNA expressions of calcitonin gene-related peptide receptor (CGRP-R), substance P receptor (SP-R), neuropeptide Y receptor (NPY-R), beta-adrenergic receptors (beta1-R, beta2-R, beta3-R), vasoactive intestinal polypeptide type 1 and type 2 receptors (VIP-1R, VIP-2R) and pituitary adenylate cyclase activating polypeptide receptor (PACAP-R) were examined by reverse transcription-polymerase chain reaction (RT-PCR). According to the magnitude of the mRNA expression of alkaline phosphatase (ALP), the relative state of commitment of these osteoblastic cell lines to the osteoblast lineage was SaM-1 > SaOS-2 > HOS > MG-63. CGRP-R, NPY-R, VIP-1R and beta2-R, but not SP-R, VIP-2R, PACAP-R, beta1-R and beta3-R, were expressed in osteoblasts as well as osteosarcoma cells. Expression of these receptors seems to be a common feature in osteoblastic cells, but the magnitude of expression was not dependent upon the relative state of commitment of the osteoblastic cells to the osteoblast lineage. In addition, VIP mRNA was not expressed in osteoblastic cells, suggesting the absence of an autocrine system of VIP in osteoblasts. These observations suggest that these neuropeptides and norepinephrine are involved in local regulation of human bone metabolism.
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PMID:Expression of mRNAs for neuropeptide receptors and beta-adrenergic receptors in human osteoblasts and human osteogenic sarcoma cells. 935 Aug 48


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