Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0235394 (wasting)
 8,040 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Tumor necrosis factor-alpha (TNF alpha), a product of activated monocytes, induces tissue wasting in certain solid tumors in vivo and in in vitro model systems. Recent studies indicate that TNF alpha also regulates cell replication and expression of differentiated function in a variety of nonneoplastic cell systems. Since monocyte products could accumulate in bone with trauma, inflammation, or other disease states, bone cell activity might be altered by the presence of these pathophysiological molecules. Using cells obtained by sequential enzyme release from fetal rat parietal bone, we find that TNF alpha has acute stimulatory and inhibitory effects on bone cell macromolecular synthesis. Within 24 h of exposure, recombinant human TNF alpha at 0.3-100 nM progressively increases the rate of DNA synthesis in osteoblast-enriched cell cultures up to 3- to 4-fold, and 3-100 nM TNF alpha reduces collagen production and alkaline phosphatase activity by 20-30%. These decreases are not altered by 1 mM hydroxyurea, which blocks the mitogenic effect of TNF alpha by 85-90%. In addition, hydroxyproline levels in the culture medium do not increase relative to the control value after TNF alpha treatment, suggesting that decreased collagen production results from less synthesis rather than increased collagen degradation. Hybridization studies with cDNA encoding the alpha 1-chain of rat type I collagen show that TNF alpha increases type I collagen mRNA to an extent similar to its effect on cell replication. Therefore, TNF alpha appears to inhibit collagen synthesis and alkaline phosphatase activity in osteoblast-enriched cell cultures by mechanisms that are not related to its effects on cell replication.
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PMID:Tumor necrosis factor-alpha inhibits collagen synthesis and alkaline phosphatase activity independently of its effect on deoxyribonucleic acid synthesis in osteoblast-enriched bone cell cultures. 340 90

Glucocorticoids, when administered over prolonged periods of time, cause protein wasting, osteoporosis, elevation of total cholesterol, and carbohydrate intolerance. Human GH is a potent anabolic agent known to stimulate protein synthesis and osteoblast activity. Chronic hypercortisolemia is associated with impaired GH secretion. The aim of our study was to evaluate the effects of short term administration of human recombinant GH on bone and fuel metabolism in patients receiving chronic glucocorticoid treatment and with suppressed GHRH-stimulated GH peaks (< 10 micrograms/L). We studied nine nonobese adult patients more than 70 yr of age (seven females and two males; age range, 41-68 yr; body mass index, 26 +/- 1.3 kg/m2) undergoing long term glucocorticoid therapy for nonendocrine diseases. After a 3-day stabilization period in the hospital, several parameters were evaluated in all patients: 1) protein, 2) bone, 3) lipid, 4) carbohydrate metabolism, and 5) immune system function under baseline conditions. At 1800 h on the fifth day of hospitalization, the patients began treatment with a daily sc injection of 0.1 IU/kg (0.037 mg/kg) recombinant human GH (Humatrope, Eli Lilly Co.) for 7 days. GH administration caused a significant increase in nitrogen balance (from -0.12 +/- 0.04 to -0.03 +/- 0.02 g/kg.day; P < 0.05), osteocalcin, carboxy-terminal propeptide of type I procollagen, and carboxy-terminal telopeptide of type I collagen with respect to basal levels. After GH administration, total, high density lipoprotein, and low density lipoprotein cholesterol levels were significantly lowered, and serum triglyceride levels were increased in all patients. Normal blood glucose levels during GH administration were observed in our patients concomitantly with a slight increase in insulin secretion. After GH treatment, the T-helper/T-suppressor cell ratio significantly increased with respect to basal levels (2.5 +/- 0.4 vs. 2.2 +/- 0.3; P < 0.05). Our data suggest that in patients receiving chronic glucocorticoid treatment, GH administration may significantly antagonize several side-effects of long term glucocorticoid administration, such as protein wasting, osteoporosis, and hyperlipidemia.
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PMID:Effects of recombinant human growth hormone (GH) on bone and intermediary metabolism in patients receiving chronic glucocorticoid treatment with suppressed endogenous GH response to GH-releasing hormone. 782

Loss of lean tissue often accompanies human immunodeficiency virus (HIV) infection. Exogenous human recombinant GH (hrGH) has been shown to be beneficial in reversing this wasting. However, catabolic effects of hrGH on muscle protein metabolism have also been reported. Therefore, the responsiveness of other GH-sensitive tissues, including bone formation and albumin synthesis, has been examined. Anabolic activity in bone, from serum levels of carboxy-terminal propeptide of type I collagen, was stimulated by 2 weeks of hrGH in controls (56 +/- 15%, P = 0.002), patients with asymptomatic HIV (24 +/- 10%, not significant), patients with AIDS (47 +/- 7%, P < 0.001), and patients with AIDS and > 10% weight loss (21 +/- 12%, P = 0.02). Albumin synthesis, determined from the incorporation of L-[2H5]phenylalanine, was increased in response to hrGH in controls (23 +/- 7%, P < 0.05), HIV+ subjects (39 +/- 16%, P < 0.05), and patients with AIDS (25 +/- 7%, P < 0.01). Patients with AIDS and weight loss, however, did not increase albumin synthesis (-0.6 +/- 12%) in response to hrGH. The results indicate variable anabolic responses to hrGH. Bone collagen synthesis remained sensitive to hrGH, whereas, the anabolic action of hrGH on the synthesis of albumin diminished with severity of disease. However unlike muscle protein synthesis, albumin synthesis was not depressed below basal levels by hrGH.
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PMID:Albumin synthesis and bone collagen formation in human immunodeficiency virus-positive subjects: differential effects of growth hormone administration. 974 2

Pharmacological doses of glucocorticosteroids given chronically are associated with a variety of negative side effects which impact the prolonged use of these potent anti-inflammatory agents. They have catabolic effects on protein, resulting in poor tissue healing, an increased incidence of infections and accelerated bone loss. Insulin resistance to both hepatic and peripheral tissues is a common consequence of chronic steroid use, leading at times to impaired carbohydrate metabolism. Steroids affect both the release and the effects of growth hormone (GH) at the target sites, hence becoming functional GH antagonists. When administered to growing children the side effects of glucocorticosteroid treatment are further compounded by a potent and significant suppression of linear growth. Ample experimental and clinical data support a role for GH therapy in counteracting some of the effects of glucocorticosteroids. Using isotope dilution methods we have previously shown that both GH and insulin-like growth factor (IGF)-I can decrease the protein wasting effects of prednisone administration in man. IGF-I has also been shown to enhance type I collagen formation in hydrocortisone-treated human osteoblasts. GH (through IGF-I) significantly enhances linear growth; thus, in states of "functional" GH deficiency, such as that observed in chronic steroid use, GH may also have a potentially beneficial effect. Studies in children on chronic prednisone doses with cystic fibrosis, chronic renal failure or juvenile rheumatoid arthritis have all shown beneficial effects on linear growth after prolonged GH therapy. Data from a recent study of ours using GH in children with steroid-dependent inflammatory bowel disease showed that GH treatment was associated with increased lean body mass, decreased adiposity and increased linear growth. Marked increases in IGF-I concentrations and in kinetic measures of bone calcium accretion (using calcium tracers) were also observed, without any deterioration of disease activity scores or carbohydrate tolerance. In conclusion, GH therapy may play a role in the treatment of children on chronic steroids both as a growth promoting agent and as an anabolic agent on whole body protein and bone. Longer term studies will be needed to better define the safety and efficacy of this approach.
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PMID:Growth hormone therapy in the glucocorticosteroid-dependent child: metabolic and linear growth effects. 1178 79

FGF2 transgenic mice were developed in which type I collagen regulatory sequences drive the nuclear high molecular weight FGF2 isoforms in osteoblasts (TgHMW). The phenotype of TgHMW mice included dwarfism, decreased bone mineral density (BMD), osteomalacia, and decreased serum phosphate (P(i)). When TgHMW mice were fed a high P(i) diet, BMD was increased, and dwarfism was partially reversed. The TgHMW phenotype was similar to mice overexpressing FGF23. Serum FGF23 was increased in TgHMW mice. Fgf23 mRNA in bones and fibroblast growth factor receptors 1c and 3c and Klotho mRNAs in kidneys were increased in TgHMW mice, whereas the renal Na(+)/P(i) co-transporter Npt2a mRNA was decreased. Immunohistochemistry and Western blot analyses of TgHMW kidneys showed increased KLOTHO and decreased NPT2a protein. The results suggest that overexpression of HMW FGF2 increases FGF23/FGFR/KLOTHO signaling to down-regulate NPT2a, causing P(i) wasting, osteomalacia, and decreased BMD. We assessed whether HMW FGF2 expression was altered in the Hyp mouse, a mouse homolog of the human disease X-linked hypophosphatemic rickets/osteomalacia. Fgf2 mRNA was increased in bones, and Western blots showed increased FGF2 protein in nuclear fractions from osteoblasts of Hyp mice. In addition, immunohistochemistry demonstrated co-localization of FGF23 and HMW FGF2 protein in osteoblasts and osteocytes from Hyp mice. This study reveals a novel mechanism of regulation of the FGF23-P(i) homeostatic axis.
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PMID:Nuclear isoforms of fibroblast growth factor 2 are novel inducers of hypophosphatemia via modulation of FGF23 and KLOTHO. 1993 69

We examined, in immobilization, the effect of a diet high in sodium chloride (NaCl) on bone markers, nitrogen balance, and acid-base status. Eight healthy male test subjects participated in a 14-day head-down-tilt bed rest (HDBR) study. During the bed rest period they received, in a randomized crossover design, a high (7.7 meq Na(+)/kg body wt per day) and a low (0.7 meq Na(+)/kg body wt per day) NaCl diet. As expected, 24-h excretion of urinary calcium was significantly greater in the high-NaCl-intake HDBR phase than in the low-NaCl-intake HDBR phase (P < 0.001). High NaCl intake caused a 43-50% greater excretion of the bone resorption markers COOH- (CTX) and NH(2)- (NTX) terminal telopeptide of type I collagen in HDBR than low NaCl in HDBR (CTX/NTX: P < 0.001). Serum concentrations of the bone formation markers bone-specific alkaline phosphatase (bAP) and NH(2)-terminal propeptide of type I procollagen (PINP) were identical in both NaCl intake phases. High NaCl intake led to a more negative nitrogen balance in HDBR (P < 0.001). Changes were accompanied by increased serum chloride concentration (P = 0.008), reduced blood bicarbonate (P = 0.017), and base excess (P = 0.009) whereas net acid excretion was lower during high than during low NaCl intake in immobilization (P < 0.001). High NaCl intake during immobilization exacerbates disuse-induced bone and muscle loss by causing further protein wasting and an increase in bone resorption. Changes in the acid-base status, mainly caused by disturbances in electrolyte metabolism, seem to determine NaCl-induced degradation processes.
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PMID:High sodium chloride intake exacerbates immobilization-induced bone resorption and protein losses. 2159 17