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Uticaj statusa vitamina D na metaboličku aktivnost kosti i koštanu masu kod bolesnika sa alkoholnom cirozom jetre / Effects of vitamin D status on bone metabolism and bone mass in patients with alcoholic liver cirrhosisSavić Željka 27 October 2014 (has links)
<p>Uvod: Hepatička osteodistrofija je termin koji obuhvata metaboličke bolesti kosti udružene sa hroničnim bolestima jetre. U alkoholnoj cirozi (AC) jetre postoji visoka zastupljenost deficijencije vitamina D proporcionalna stepenu disfunkcije jetre, ali njena uloga u patogenezi hepatičke osteodistrofije nije dovoljno objašnjena. Nivo 25(OH)D odražava status vitamina D. Kod AC jetre izmenjena je metabolička aktivnost kosti i suprimirano je formiranje kosti što dovodi do smanjenja koštane mase. U centru interesovanja je postizanje optimalnog statusa vitamina D. Stavovi o suplementaciji vitaminom D kod AC jetre nisu jasno definisani. Cilj rada: Utvrditi nivo vitamina D, ispitati metaboličku aktivnost kosti i mineralnu gustinu kosti kod bolesnika sa AC jetre. Utvrditi efekte suplementacije sa 1000 IU vitamina D3 na dan tokom godinu dana u odnosu na metaboličku aktivnost kosti i mineralnu gustinu kosti kod ispitivanih bolesnika. Bolesnici i metode: Istraživanje je sprovedeno na Klinici za gastroenterologiju i hepatologiju Kliničkog centra Vojvodine u Novom Sadu kao prospektivna intervencijska studija sa primenom suplementacije sa 1000 IU vitamina D3 na dan kod bolesnika sa AC jetre. Grupu bolesnika koja je uključena u istraživanje (1) činilo je 70 bolesnika muškog pola sa dijagnozom AC jetre. Bolesnici su imali četiri pregleda (P), odnosno tačke studije: P1-uključivanje bolesnika i započinjanje suplementacije vitaminom D; P2, P3 i P4 posle tri, šest i dvanaest meseci suplementacije vitaminom D, redom. Prilikom svakog pregleda rađene su analize funkcije jetre, metabolizma kosti i statusa vitamina D. Na početku (P1) i na kraju istraživanja (P4) vršeno je merenje mineralne gustine kosti (BMD) DXA metodom. Gubitak bolesnika od P1 do P4 bio je dvadeset, na različitim tačkama studije. Prvi deo istraživanja odnosi se na Grupu bolesnika koja je uključena u istraživanje (1) i završila prvi pregled (P1). Pedeset bolesnika je završilo kompletno istraživanje po predviđenom protokolu i oni se zbog realizacije svih pregleda i ponovljenih merenja posmatraju kao: Grupa bolesnika koja je završila istraživanje (2). Rezultati: (1): Kod bolesnika sa AC jetre utvrđena je deficijencija vitamina D, snižen nivo osteokalcina, normalni nivoi CrossLapsa, PTH, ukupnog i jonizovanog kalcijuma, fosfora i magnezijuma. Osteopeniju je imalo 42,65% a osteoporozu 14,71% ispitanika. Kod svih ispitanika najniži BMD izmeren je na vratu femura. (2): Suplementacija vitaminom D dovela je do značajnog porasta 25(OH)D. U odnosu na osteokalcin konstatovana je pozitivna razlika vrednosti P1/P4, iako je nivo ostao ispod donje granice normale. Kod nivoa CrossLapsa i PTH razlika P1/P4 je negativna, ali su nivoi u sva četiri merenja u okviru referentnih vrednosti. Na lumbalnoj kičmi došlo je do poboljšanja BMD za 0.87%, a pogoršanja su na vratu femura -1.87 % i kuku -1.65%. Konstatovano je i poboljšanje funkcije jetre. Zaključci: Kod bolesnika sa AC jetre poboljšanje statusa vitamina D dovodi do povećanja formiranja kosti i poboljšanja koštane mase na lumbalnoj kičmi. Neophodno je određivanje statusa vitamina D kod svih bolesnika sa AC jetre i uvođenje suplementacije vitaminom D kod bolesnika koji imaju nivo 25(OH)D < 80 nmol/l, uz tromesečne kontrole efekta. Kod postavljanja dijagnoze AC jetre potrebno je inicijalno određivanje BMD. Kod suplementacije vitaminom D nakon inicijalnog DXA pregleda sledeći se preporučuje nakon jedne do dve godine.</p> / <p>Introduction: The term Hepatic osteodystrophy defines a group of metabolic bone diseases associated with underlying chronic liver disease. Alcoholic liver cirrhosis (ALC) is characterized by high incidence of vitamin D deficiency that is proportional to the level of liver failure; however, its role in the pathogenesis of hepatic osteodystrophy has not yet been fully elucidated. The level of 25(OH)D best reflects the vitamin D status. ALC is characterized by changed bone metabolic activity and suppressed bone formation, resulting in the decrease in bone mass. The key topic of interest is the achievement of optimal vitamin D status. The attitude of health professionals towards vitamin D supplementation in alcoholic liver cirrhosis has not yet been clearly defined. The aim of the research: Determining of vitamin D levels, investigating the metabolic activity of the bone and bone mass in patients with alcoholic liver cirrhosis (ALC); Determining the effects of vitamin D3 supplementation at the dose 1000 IU/day during a one-year period in relation to metabolic activity of the bone and bone mineral density (BMD) in the investigated patient population. Patients and methods: The research was conducted at the Clinic for Gastroenterology and Hepatology of the Clinical Centre of Vojvodina in Novi Sad. The research was designed as a prospective interventional study implicating vitamin D3 supplementation at the dose 1000 IU/day to patients with ALC. The investigated patient population (1) encompassed 70 male patients diagnosed with ALC. The patients underwent four examinations (P), that is, research phases: P1 – inclusion of the patient into the study and introduction of vitamin D supplementation; P2, P3 and P4 after 3, 6 and 12 months of vitamin D supplementation treatment, respectively. Each examination included the analysis of liver function, bone metabolism and vitamin D status. At the beginning (P1) and at the end (P4) of the investigation period, bone mineral density (BMD) was measured by means of dual-energy x-ray absorptiometry (DXA) method. Twenty patients dropped out from the research at different stages throughout the investigation period (P1 to P4). The first part of the investigation pertains to the Group of patients who were included into the study (1) and completed the first examination (P1). Fifty patients have completed the entire research according to the foreseen protocol encompassing all examinations and repeated measurements. These patients are considered a Group of patients who completed the research (2) Results: (1): In ALC patients, vitamin D deficiency and decreased osteocalcin levels were established, as well as normal levels of CrossLaps, PTH, total and ionized calcium, phosphorus and magnesium. Osteopenia and osteoporosis were established in 42.65% and 14.71% of patients, respectively. The lowest BMD was measured in the femoral neck in all patients. (2): Vitamin D supplementation resulted in significant increase in 25(OH)D. Analysis of osteocalcin level revealed positive P1/P4 difference, even though the level remained below the lower normal limit. The levels of CrossLaps and PTH revealed negative P1/P4 difference; however, the levels determined at all four measurements were within the reference values. An improvement of BMD for 0.87% was established in lumbar spine, whereas a decrease was noticed in femoral neck (1.87%) and hip (1.65%). Furthermore, an improvement of liver function was established. Conclusions: Improvement of vitamin D status in ALC patients results in an increase of bone formation and improvement of body mass in lumbar spine. Determining the vitamin D status in all patients with ALC is of outmost importance, as well as the vitamin D supplementation of patients with levels of 25(OH)D < 80 nmol/l along with the monitoring of treatment outcome at three-month intervals. Establishment of the diagnosis of alcoholic liver cirrhosis should encompass initial measurement of BMD. In case of vitamin D supplementation treatment, the initial DXA examination should be repeated after the period of one to two years.</p>
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Bone Metabolism: The Role of STAT3 and Reactive Oxygen SpeciesNewnum, America Bethanne 14 August 2013 (has links)
Indiana University-Purdue University Indianapolis (IUPUI) / Signal Transducers and Activators of Transcription 3 (STAT3), a transcription factor expressed in many cell types, including osteoblasts and osteoclasts, is emerging as a key regulator of bone mass and strength. STAT3 mutations cause a rare human immunodeficiency disease characterized by extremely elevated levels of IgE in serum that have associated craniofacial and skeletal features, such as reduced bone mineral density and recurrent pathological fractures. Our microarray data and immunohistochemical staining using a normal rat model have shown that STAT3 mRNA and protein levels markedly increase in response to mechanical loading. In addition, as indicated by STAT3 phosphorylation in MC3T3-E1 osteoblastic cells, STAT3 activity significantly increases in response to 30 to 90 minutes fluid shear stress. In order to further study the role that STAT3 plays in bone responsiveness to loading, tissue-selective STAT3 knockout (KO) mice, in which inactivation of STAT3 occurs in osteoblasts, were generated by breeding the transgenic mice in which Cre recombinase cDNA was cloned downstream of a 3.6 or 2.3 kb fragment of the rat Col1a1 promoter (Col3.6-Cre and Col2.3-Cre, respectively) with a strain of floxed mice in which the two loxP sites flank exons 18-20 of the STAT3 gene were used. Mice engineered with bone selective inactivation of STAT3 in osteoblasts exhibited significantly lower bone mineral density (7-12%, p<0.05) and reduced ultimate force (21-34%, p<0.01) compared to their age-matched littermate controls. The right ulnae of 16-week-old bone specific STAT3 KO mice and the age-matched control mice were loaded with peak forces of 2.5 N and 2.75 N for female and male mice, respectively, at 2 Hz, 120 cycles/day for 3 consecutive days. Mice with inactivation of STAT3 specific in bone were significantly less responsive to mechanical loading than the control mice as indicated by decreased relative mineralizing surface (rMS/BS, 47-59%, p<0.05) and relative bone formation rate (rBFR/BS, 64-75%, p<0.001). Bone responsiveness was equally decreased in mice in which STAT3 is inactivated either in early osteoblasts (Col3.6-Cre) or in mature osteoblasts (Col2.3-Cre).
Accumulating evidence indicates that bone metabolism is significantly affected by activities in mitochondria. For instance, although STAT3 is reported to be involved in bone formation and resorption through regulation of nuclear genes, inactivation of STAT3 is shown to disrupt mitochondrial activities and result in an increased level of reactive oxygen species (ROS). Inactivation of STAT3 suppressed load-driven mitochondrial activity, which led to an elevated level of ROS in cultured primary osteoblasts. Oxidative stress induced by administration of buthionine sulfoximine (BSO) significantly inhibits load-induced bone formation in wild type mice. Taken together, the results support the notion that the loss-of-function mutation of STAT3 in osteoblasts and osteocytes diminishes load-driven bone formation and impairs the regulation of oxidative stress in mitochondria.
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