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  • 1.
    Englund, Gunilla
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Jacobson, Annica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Rorsman, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Artursson, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Pharmacy.
    Kindmark, Andreas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Rönnblom, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Efflux transporters in ulcerative colitis: decreased expression of BCRP (ABCG2) and Pgp (ABCB1)2007In: Inflammatory Bowel Diseases, ISSN 1078-0998, E-ISSN 1536-4844, Vol. 13, no 3, p. 291-297Article in journal (Refereed)
    Abstract [en]

    Background: Efflux transport proteins are important components of the intestinal barrier against bacterial toxins, carcinogens, and drugs. This investigation was conducted to determine the expression of Breast Cancer Resistance Protein (BCRP/ABCG2), P-glycoprotein (Pgp/MDR1/ABCB1), and Multidrug Resistance Protein 2 (MRP2/ABCC2) in the gut mucosa of patients with ulcerative colitis (UC). Methods: Patients were thoroughly diagnosed according to well-established clinical, endoscopic, and histologic criteria to be included in the group of patients with active UC (n = 16) or UC in remission (n = 17). Colonic and rectal mucosa from patients with UC were compared with tissues from control subjects (n = 15). The mRNA expression (TaqMan) of the efflux transporters and the proinflammatory cytokines interleukin (IL)-1β and IL-6 was determined. Western blot was used in the analysis of protein expression and the tissue localization of BCRP was determined with confocal microscopy. Results: BCRP and Pgp expression was strongly reduced in individuals with active inflammation compared with controls and was negatively correlated with the levels of IL-6 mRNA. The BCRP staining of colonic epithelium seen in healthy mucosa was diminished in inflamed tissues, with concurrent disruption of epithelial F-actin structure. Conclusions: Two of the efflux transporters of importance for the barrier function of the gut mucosa, Pgp and BCRP, are expressed at strongly reduced levels during active inflammation in patients with UC. Investigations are warranted to determine whether the low levels of efflux transporters during active UC contribute to altered transport and tissue exposure of carcinogens, bacterial toxins, and drugs.

  • 2.
    Göransson, Viktoria
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Cell Biology.
    Johnsson, Cecilia
    Department of Surgical Sciences.
    Jacobson, Annica
    Department of Medical Sciences.
    Heldin, Paraskevi
    Ludwiginstitutet för Cancerforskning.
    Hällgren, Roger
    Department of Medical Sciences.
    Hansell, Peter
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Cell Biology.
    Renal hyaluronan accumulation and hyaluronan synthase expression after ischaemia-reperfusion injury in the rat.2004In: Nephrol Dial Transplant, ISSN 0931-0509, Vol. 19, no 4, p. 823-30Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Hyaluronan (HA) is a connective tissue component with unique water binding and pro-inflammatory properties. It has been suggested that HA is involved in normal renal water handling but also in several pathological conditions such as organ rejection and ischaemia-reperfusion (IR) injury. METHODS: In anaesthetized normal rats we investigated if renal cortical HA accumulation and the intrarenal distribution and expression of HA synthases (Has 1, 2 and 3) correlate with renal dysfunction after renal IR injury. After 20, 30 or 45 min of unilateral renal ischaemia and 72 h of reperfusion, renal function and cortical HA content were measured. Has 1, 2 and 3 mRNA were determined in control and IR kidneys subjected to 45 min ischaemia and 72 h reperfusion. RESULTS: IR kidneys had reduced urine concentrating ability, potassium excretion, glomerular filtration rate (GFR) and renal blood flow. On average, IR kidneys had more than 10 times higher amounts of cortical HA than the contralateral control kidney and their water content was elevated while medullary HA was largely unaffected. Has 2 expression in the cortex was heavily up-regulated in IR kidneys while Has 3 remained at control levels. Has 1 could never be detected. There was a direct correlation between the amount of cortical HA and the time period of ischaemia and also between the cortical amount of HA and depression of functional parameters. CONCLUSIONS: IR injury depresses parameters of renal function, which coincides with an elevated cortical HA content and Has 2 expression. The enhanced Has 2 expression indicates that the cortical HA accumulation is primarily dependent on increased HA synthesis and not impaired degradation/elimination. The water binding and pro-inflammatory properties of HA may contribute to renal dysfunction after IR.

  • 3.
    Hansell, Peter
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Rügheimer, Louise
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Johnsson, Cecilia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Jacobson, Annica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Heldin, Evi
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Hällgren, Roger
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Göransson, Viktoria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Hyaluronan and renal ischemic damage2005Book (Refereed)
  • 4.
    Jacobson, Annica
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis.
    Cunningham, Janet L
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Psychiatry, University Hospital.
    Connective tissue growth factor in tumor pathogenesis2012In: Fibrogenesis & Tissue Repair, ISSN 1755-1536, Vol. 5, no Suppl.1, p. S8-S8Article in journal (Refereed)
    Abstract [en]

    Key roles for connective tissue growth factor (CTGF/CCN2) are demonstrated in the wound repair process where it promotes myofibroblast differentiation and angiogenesis. Similar mechanisms are active in tumor-reactive stroma where CTGF is expressed. Other potential roles include prevention of hypoxia-induced apoptosis and promoting epithelial-mesenchymal transistion (EMT). CTGF expression in tumors has been associated to both tumor suppression and progression. For example, CTGF expression in acute lymphoblastic leukemia, breast, pancreas and gastric cancer correlates to worse prognosis whereas the opposite is true for colorectal, lung and ovarian cancer. This discrepancy is not yet understood.

    High expression of CTGF is a hallmark of ileal carcinoids, which are well-differentiated endocrine carcinomas with serotonin production originating from the small intestine and proximal colon. These tumors maintain a high grade of differentiation and low proliferation. Despite this, they are malignant and most patients have metastatic disease at diagnosis. These tumors demonstrate several phenotypes potentially related to CTGF function namely: cell migration, absent tumor cell apoptosis, as well as, reactive and well vascularised myofibroblast rich stroma and fibrosis development locally and in distal organs. The presence of CTGF in other endocrine tumors indicates a role in the progression of well-differentiated tumors.

  • 5.
    Jacobson, Annica
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Johansson, Sara
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Branting, Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Melhus, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Vitamin A differentiall regulates RANKL and OPG expression in human osteoblasts2004In: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, E-ISSN 1090-2104, Vol. 322, no 1, p. 162-167Article in journal (Refereed)
    Abstract [en]

    All-trans-retinoic acid (ATRA) induces bone resorption, but the molecular mechanisms are unknown. We have studied the effect of ATRA on osteoprotegerin (OPG) and receptor activator of NF-kappaB ligand (RANKL) expression in human MG-63 osteosarcoma cells and primary osteoblast-like cultures. ATRA dose-dependently down-regulated protein levels of OPG in MG-63 cells, with a maximum (-56%) observed at a dose of 10(-6)M. This effect was confirmed with quantitative real-time PCR, where OPG mRNA was decreased after 4h (-68%) in primary cultures and after 8h (-87%) in MG-63 cells. The reduction in OPG expression was inhibited by a retinoic acid receptor (RAR)-antagonist and was mimicked by a RARbeta,gamma-agonist, indicating that the ATRA effect is mediated by these receptors. In primary cultures we found a threefold induction of RANKL mRNA expression. Thus, the RANKL/OPG ratio was markedly increased, suggesting a potential mechanism of ATRA-induced bone resorption.

  • 6.
    Jacobson, Annica
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Melhus, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Wadelius, Mia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis.
    Can mutations in ELA2, neutrophil elastase expression or differential cell toxicity explain sulphasalazine-induced agranulocytosis?2004In: BMC Blood Disorders, ISSN 1471-2326, Vol. 4, no 1, p. 5-Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Drug-induced agranulocytosis, a severe side effect marked by a deficit or absolute lack of granulocytic white blood cells, is a rare side-effect of the anti-inflammatory drug sulphasalazine. Mutations in the human neutrophil elastase gene (ELA2), causing increased intracellular concentration of this serine protease, inhibits neutrophil differentiation in severe congenital neutropenia (SCN). Since the clinical symptoms of agranulocytosis and SCN are similar, we hypothesized that it may origin from a common genetic variation in ELA2 or that sulphasalazine may affect human neutrophil elastase activity and protein expression. METHODS: We screened for genetic differences in ELA2 in DNA from 36 patients who had suffered from sulphasalazine-induced agranulocytosis, and compared them with 72 patients treated with sulphasalazine without blood reactions. We also performed in vitro studies of the blood cell lines HL60 and U937 after sulphasalazine exposure with respect to cell survival index, neutrophil elastase protein expression and activity. RESULTS: None of the mutations in ELA2, which previously have been reported to be associated with SCN, was found in this material. Protein expression of human neutrophil elastase in lymphoma U937 cells was not affected by treatment with concentrations equivalent to therapeutic doses. Cell survival of lymphoma U937 and promyelocytic leukemia HL-60 cells was not affected in this concentration range, but exhibited a decreased proliferative capacity with higher sulphasalazine concentrations. Interestingly the promyelocytic cells were more sensitive to sulphasalazine than the lymphoma cell line. CONCLUSION: Neutrophil elastase expression and ELA2 mutations do, however, not seem to be involved in the etilogy of sulphasalazine-induced agranulocytosis. Why sulphasalazine is more toxic to promyelocytes than to lymphocytes remains to be explained.

  • 7.
    Jacobson, Annica
    et al.
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Salnikov, Alexei
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Lammerts, Ellen
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Roswall, Pernilla
    Department of Genetics and Pathology.
    Sundberg, Christian
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Heldin, Paraskevi
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Ludwiginstitutet för Cancerforskning.
    Rubin, Kristofer
    Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Heldin, Nils-Erik
    Department of Genetics and Pathology.
    Hyaluronan content in experimental carcinoma is not correlated to interstitial fluid pressure.2003In: Biochem. Biophys. Res. Commun., Vol. 305, p. 1017-1023Article in journal (Refereed)
    Abstract [en]

    Mechanism(s) for generation of the high tumor interstitial fluid pressure (TIFP) that is characteristic of carcinoma is not known. We investigated the role of hyaluronan, the major water-binding polysaccharide of the extracellular matrix, for the generation of a high TIFP. A human anaplastic thyroid carcinoma (KAT-4) xenografted to athymic mice and a syngeneic rat colon carcinoma (PROb) were used. Neither KAT-4 nor PROb cells produced hyaluronan (HA) in culture, however, both cell lines produced factors that stimulated HA-synthesis by cultured fibroblasts. Modulating hyaluronan levels by transfection of PROb carcinoma cells with hyaluronan synthase-2 revealed no correlation between hyaluronan content and TIFP. Furthermore, lowering of TIFP by treating KAT-4 tumors with a specific inhibitor of TGF-beta 1 and -beta 3 did not change the concentration of hyaluronan in the tumors. In summary, our results suggest that a modulation of hyaluronan content is not a major pathogenetic mechanism for the generation of the characteristically high TIFP in malignant carcinomas.

  • 8.
    Khoschnau, Shwan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Melhus, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Jacobson, Annica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Rahme, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Bengtsson, Henrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Ribom, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Grundberg, Elin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Mallmin, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Michaëlsson, Karl
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Type I collagen alpha1 Sp1 polymorphism and the risk of cruciate ligament ruptures or shoulder dislocations2008In: American Journal of Sports Medicine, ISSN 0363-5465, E-ISSN 1552-3365, Vol. 36, no 12, p. 2432-2436Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Cruciate ligament ruptures and shoulder dislocations are often caused by trauma, but predisposing intrinsic factors might also influence the risk. These injuries are more common in those with a previously injured sibling, an observation that might indicate a genetic predisposition. It is well known that polymorphisms in the collagen I gene are associated not only with osteoporosis and osteoporotic fracture risk, but also with osteoarthritis.

    HYPOTHESIS: Because collagen I is abundant in ligaments and tendons, the authors hypothesized that collagen I alpha1 Sp1 polymorphism also was related to the occurrence of cruciate ligament ruptures and shoulder dislocations.

    STUDY DESIGN: Case-control study; Level of evidence, 3.

    METHODS: A total of 358 patients and 325 randomly selected population-based female controls were included in the study. Of the cases, 233 had a cruciate ligament rupture and 126 had had a shoulder dislocation. Age-adjusted odds ratios (ORs) with 95% confidence intervals (CIs) estimated by unconditional logistic regression were used as measures of association.

    RESULTS: Compared with the homozygous SS category, the heterozygous participants displayed a similar risk (OR, 1.06; 95% CI, 0.76-1.49), whereas the ss genotype was underrepresented in the injured population compared with the controls (OR, 0.15; 95% CI, 0.03-0.68). This latter estimate was similar for both cruciate ligament ruptures and shoulder dislocations, and was furthermore not modified by general joint laxity.

    CONCLUSION: The authors found a substantially decreased risk of these injuries associated with collagen type I alpha1 Sp1 polymorphism. The study might encourage other investigators to consider further research in the area of genes and soft tissue injuries.

  • 9.
    Lejonklou, Margareta Halin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Occupational and Environmental Medicine.
    Karimullina, Elina
    Larsson, Sune
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Lind, Thomas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis.
    Melhus, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis.
    Jacobson Rasmusson, Annica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis.
    Rönn, Monika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Occupational and Environmental Medicine.
    Risérus, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Public Health and Caring Sciences, Clinical Nutrition and Metabolism.
    Blumberg, Bruce
    Lind, P. Monica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Occupational and Environmental Medicine.
    Does developmental exposure to bisphenol A induce bone and adipose tissue disturbances?2014In: Toxicology Letters, ISSN 0378-4274, E-ISSN 1879-3169, Vol. 229, p. S243-S243Article in journal (Other academic)
  • 10.
    Lejonklou, Margareta Halin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Occupational and Environmental Medicine.
    Lind, Thomas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis.
    Rasmusson, Annica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis.
    Larsson, Sune
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Melhus, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis.
    Lind, Monica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Occupational and Environmental Medicine.
    Developmental low-dose exposure to bisphenol A results in gender-specific and non-monotonic effects on Fischer F344 rat bone2015In: Toxicology Letters, ISSN 0378-4274, E-ISSN 1879-3169, Vol. 238, no 2, p. S255-S255Article in journal (Other academic)
  • 11.
    Lind, Thomas
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Hu, Lijuan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Lind, Monica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Occupational and Environmental Medicine.
    Sugars, Rachael
    Andersson, Göran
    Jacobson, Annica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Melhus, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Microarray Profiling of Diaphyseal Bone of Rats Suffering from Hypervitaminosis A2012In: Calcified Tissue International, ISSN 0171-967X, E-ISSN 1432-0827, Vol. 90, no 3, p. 219-229Article in journal (Refereed)
    Abstract [en]

    Vitamin A is the only known compound that produces spontaneous fractures in rats. In an effort to resolve the molecular mechanism behind this effect, we fed young male rats high doses of vitamin A and performed microarray analysis of diaphyseal bone with and without marrow after 1 week, i.e., just before the first fractures appeared. Of the differentially expressed genes in cortical bone, including marrow, 98% were upregulated. In contrast, hypervitaminotic cortical bone without marrow showed reduced expression of 37% of differentially expressed genes. Gene ontology (GO) analysis revealed that only samples containing bone marrow were associated with a GO term, which principally represented extracellular matrix. This is consistent with the histological findings of increased endosteal/marrow osteoblast number. Fourteen genes, including Cyp26b1, which is known to be upregulated by vitamin A, were selected and verified by real-time PCR. In addition, immunohistochemical staining of bone sections confirmed that the bone-specific molecule osteoadherin was upregulated. Further analysis of the major gene-expression changes revealed apparent augmented Wnt signaling in the sample containing bone marrow but reduced Wnt signaling in cortical bone. Moreover, induced expression of hypoxia-associated genes was found only in samples containing bone marrow. Together, these results highlight the importance of compartment-specific analysis of bone and corroborate previous observations of compartment-specific effects of vitamin A, with reduced activity in cortical bone but increased activity in the endosteal/marrow compartment. We specifically identify potential key osteoblast-, Wnt signaling-, and hypoxia-associated genes in the processes leading to spontaneous fractures.

  • 12.
    Lind, Thomas
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis.
    Lejonklou, Margareta Halin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Occupational and Environmental Medicine.
    Dunder, Linda
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Occupational and Environmental Medicine.
    Rasmusson, Annica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis.
    Larsson, Sune
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Melhus, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis.
    Lind, P. Monica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Occupational and Environmental Medicine.
    Low-dose developmental exposure to bisphenol A induces sex-specific effects in bone of Fischer 344 rat offspring2017In: Environmental Research, ISSN 0013-9351, E-ISSN 1096-0953, Vol. 159, p. 61-68, article id S0013-9351(17)30727-2Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Bisphenol A (BPA) is a component of polycarbonate plastics to which humans are regularly exposed at low levels, and an endocrine disruptor with effects on several hormonal systems. Bone is a sensitive hormone target tissue, and we have recently shown that in utero and lactational exposure to 25µg BPA/kg BW/day alters femoral geometry in rat offspring.

    OBJECTIVE: To investigate bone effects in rat offspring after developmental exposure to a BPA dose in the range of human daily exposure (0.1-1.5µg/kg BW/day) as well as a dose to corroborate previous findings.

    METHODS: Pregnant Fischer 344 rats were exposed to BPA via drinking water corresponding to 0.5µg/kg BW/day: [0.5], (n=21) or 50µg/kg BW/day: [50], (n = 16) from gestational day 3.5 until postnatal day 22, while controls were given only vehicle (n = 25). The offspring was sacrificed at 5 weeks of age. Bone effects were analyzed using peripheral quantitative computed tomography (pQCT), the 3-point bending test, plasma markers of bone turnover, and gene expression in cortical bone and bone marrow.

    RESULTS: Compared to controls, male offspring developmentally exposed to BPA had shorter femurs. pQCT analysis revealed effects in the [0.5] group, but not in the [50] group; BPA reduced both trabecular area (-3.9%, p < 0.01) and total cross sectional area (-4.1%, p < 0.01) of femurs in the [0.5] group, whereas no effects were seen on bone density. Conversely, bone length and size were not affected in female offspring. However, the procollagen type I N-terminal propeptide (P1NP), a peptide formed during type 1 collagen synthesis, was increased in plasma (42%: p < 0.01) in female offspring exposed to [0.5] of BPA, although collagen gene expression was not increased in bone. The biomechanical properties of the bones were not altered in either sex. Bone marrow mRNA expression was only affected in male offspring.

    CONCLUSIONS: Developmental low-dose exposure to BPA resulted in sex-specific bone effects in rat offspring. A dose approximately eight times lower than the current temporary EFSA human tolerable daily intake of 4µg/kg BW/day, reduced bone length and size in male rat offspring. Long-term studies are needed to clarify whether the increased plasma levels of P1NP in female offspring reflect development of fibrosis.

  • 13.
    Lind, Thomas
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Lind, Monica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Occupational and Environmental Medicine.
    Jacobson, Annica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Hu, Lijuan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Sundqvist, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    Risteli, Juha
    Yebra-Rodriguez, Africa
    Larsson, Sune
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Rodriguez-Navarro, Alejandro
    Andersson, Göran
    Melhus, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Pharmacology.
    High dietary intake of retinol leads to bone marrow hypoxia and diaphyseal endosteal mineralization in rats2011In: Bone, ISSN 8756-3282, E-ISSN 1873-2763, Vol. 48, no 3, p. 496-506Article in journal (Refereed)
    Abstract [en]

    Vitamin A (retinol) is the only molecule known to induce spontaneous fractures in laboratory animals and we have identified retinol as a risk factor for fracture in humans. Since subsequent observational studies in humans and old animal data both show that high retinol intake appears to only have small effects on bone mineral density (BMD) we undertook a mechanistic study of how excess retinol reduces bone diameter while leaving BMD essentially unaffected. We fed growing rats high doses of retinol for only 1week. Bone analysis involved antibody-based methods, histology, pQCT, biomechanics and bone compartment-specific PCR together with Fourier Transform Infrared Spectroscopy of bone mineral. Excess dietary retinol induced weakening of bones with little apparent effect on BMD. Periosteal osteoclasts increased but unexpectedly endosteal osteoclasts disappeared and there was a reduction of osteoclastic serum markers. There was also a lack of capillary erythrocytes, endothelial cells and serum retinol transport protein in the endosteal/marrow compartment. A further indication of reduced endosteal/marrow blood flow was the increased expression of hypoxia-associated genes. Also, in contrast to the inhibitory effects in vitro, the marrow of retinol-treated rats showed increased expression of osteogenic genes. Finally, we show that hypervitaminotic bones have a higher degree of mineralization, which is in line with biomechanical data of preserved stiffness in spite of thinner bones. Together these novel findings suggest that a rapid primary effect of excess retinol on bone tissue is the impairment of endosteal/marrow blood flow leading to hypoxia and pathological endosteal mineralization.

  • 14.
    Lind, Thomas
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis.
    Sundqvist, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research.
    Hu, Lijuan
    Pejler, Gunnar
    Andersson, Goran
    Jacobson, Annica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis.
    Melhus, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis.
    Vitamin A Is a Negative Regulator of Osteoblast Mineralization2013In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 12, p. e82388-Article in journal (Refereed)
    Abstract [en]

    An excessive intake of vitamin A has been associated with an increased risk of fractures in humans. In animals, a high vitamin A intake leads to a reduction of long bone diameter and spontaneous fractures. Studies in rodents indicate that the bone thinning is due to increased periosteal bone resorption and reduced radial growth. Whether the latter is a consequence of direct effects on bone or indirect effects on appetite and general growth is unknown. In this study we therefore used pair-feeding and dynamic histomorphometry to investigate the direct effect of a high intake of vitamin A on bone formation in rats. Although there were no differences in body weight or femur length compared to controls, there was an approximately halved bone formation and mineral apposition rate at the femur diaphysis of rats fed vitamin A. To try to clarify the mechanism(s) behind this reduction, we treated primary human osteoblasts and a murine preosteoblastic cell line (MC3T3-E1) with the active metabolite of vitamin A; retinoic acid (RA), a retinoic acid receptor (RAR) antagonist (AGN194310), and a Cyp26 inhibitor (R115866) which blocks endogenous RA catabolism. We found that RA, via RARs, suppressed in vitro mineralization. This was independent of a negative effect on osteoblast proliferation. Alkaline phosphatase and bone gamma carboxyglutamate protein (Bglap, Osteocalcin) were drastically reduced in RA treated cells and RA also reduced the protein levels of Runx2 and Osterix, key transcription factors for progression to a mature osteoblast. Normal osteoblast differentiation involved up regulation of Cyp26b1, the major enzyme responsible for RA degradation, suggesting that a drop in RA signaling is required for osteogenesis analogous to what has been found for chondrogenesis. In addition, RA decreased Phex, an osteoblast/osteocyte protein necessary for mineralization. Taken together, our data indicate that vitamin A is a negative regulator of osteoblast mineralization.

  • 15.
    Lind, Thomas
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis.
    Öhman, Caroline
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Applied Materials Sciences.
    Calounova, Gabriela
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Rasmusson, Annica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis.
    Andersson, Goran
    Karolinska Univ Hosp Huddinge, Karolinska Inst, Div Pathol, Dept Lab Med, Stockholm, Sweden..
    Pejler, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Department of Biomedical Science and Veterinary Public Health, Swedish University of Agricultural Sciences, Uppsala.
    Melhus, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis.
    Excessive dietary intake of vitamin A reduces skull bone thickness in mice2017In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 12, no 4, article id e0176217Article in journal (Refereed)
    Abstract [en]

    Calvarial thinning and skull bone defects have been reported in infants with hypervitaminosis A. These findings have also been described in humans, mice and zebrafish with loss-of-function mutations in the enzyme CYP26B1 that degrades retinoic acid (RA), the active metabolite of vitamin A, indicating that these effects are indeed caused by too high levels of vitamin A and that evolutionary conserved mechanisms are involved. To explore these mechanisms, we have fed young mice excessive doses of vitamin A for one week and then analyzed the skull bones using micro computed tomography, histomorphometry, histology and immunohistochemistry. In addition, we have examined the effect of RA on gene expression in osteoblasts in vitro. Compared to a standard diet, a high dietary intake of vitamin A resulted in a rapid and significant reduction in calvarial bone density and suture diastasis. The bone formation rate was almost halved. There was also increased staining of tartrate resistant acid phosphatase in osteocytes and an increased perilacunar matrix area, indicating osteocytic osteolysis. Consistent with this, RA induced genes associated with bone degradation in osteoblasts in vitro. Moreover, and in contrast to other known bone resorption stimulators, vitamin A induced osteoclastic bone resorption on the endocranial surfaces.

  • 16.
    Michaëlsson, Karl
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Jacobson, Annica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis.
    Wolk, Alicja
    Byberg, Liisa
    Mitchell, Adam
    Melhus, Håkan
    The Free Hormone Hypothesis: Is Free Serum 25-Hydroxyvitamin D a Better Marker for Bone Mineral Density in Older Women?2018In: JBMR plus, ISSN 2473-4039, Vol. 2, no 6, p. 367-374Article in journal (Refereed)
    Abstract [en]

    It is presently unclear whether free serum 25-hydroxyvitamin D (S-25(OH)D) better reflects bone health than total S-25(OH)D. We have previously shown that summer total S-25(OH)D values are more useful to predict bone mineral density (BMD) than winter values. Our objective was therefore to compare the relative importance of free and total S-25(OH)D for BMD by season. BMD was measured by dual-energy X-ray absorptiometry (DXA) in 5002 Swedish women (mean age 68 years) randomly selected from a large population-based longitudinal cohort study. Free S-25(OH)D was analyzed by a commercial ELISA and total S-25(OH)D by HPLC-tandem mass spectrometry (MS/MS). Free and total S-25(OH)D co-varied with season, with 26% and 29% higher values in August compared with those in January-March (nadir). There were no differences in mean BMD between categories of free or total S-25(OH)D in samples collected during winter. Women with higher total S-25(OH)D measured during summer had higher BMD at the total hip. Compared with women who had total S-25(OH)D values above 80 nmol/L during summer, adjusted BMD at the total hip was 6% (95% CI, 1% to 11%) lower for S-25(OH)D concentrations between 30 and 40 mmol/L, and 11% (95% CI, 3% to 19%) lower for those with total S-25(OH)D <30 nmol/L. In contrast, free S-25(OH)D measured during summer was not associated with BMD. Compared with women who had highest free S-25(OH)D measured during summer (>8.8 pmol/L), those with intermediate (2.4-3.5 pmol/L) and lowest (<2.4 pmol/L) free S-25(OH)D during summer did not have lower total hip BMD values (3% [95% CI, -2% to 7%] and -2% [95% CI, -8% to 4%]). In addition, we found no added value for the prediction of BMD with the combined measurement of total and free S-25(OH)D during summer or winter. We conclude that vitamin D status assessed by direct measurements of free S-25(OH)D does not reflect BMD better than total S-25(OH)D. © 2018 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.

  • 17.
    Michaëlsson, Karl
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Wolk, Alicja
    Jacobsson, Annica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Kindmark, Andreas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Grundberg, Elin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Stiger, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Mallmin, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Ljunghall, Sverker
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Melhus, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    The positive effect of dietary vitamin D intake on bone mineral density in men is modulated by the polyadenosine repeat polymorphism of the vitamin D receptor2006In: Bone, ISSN 8756-3282, E-ISSN 1873-2763, Vol. 39, no 6, p. 1343-1351Article in journal (Refereed)
    Abstract [en]

    INTRODUCTION: Few studies have considered the dietary influence of vitamin D intake on bone mineral density (BMD). Numerous studies have examined the association between VDR polymorphism and BMD, but no previous study has examined the joint influence of dietary vitamin D intake and VDR polymorphism on BMD. METHODS: We therefore conducted a study in 230 men aged 41-76 years of age. BMD was measured with DXA. A second bone scan was performed on average 2.7 years after the first investigation. Dietary habits were assessed by 14 dietary 24-h recall interviews. The polyadenosine (A) VDR genotypes were determined. RESULTS: Dietary vitamin D intake was associated with BMD at all sites, also after multivariate adjustment. Those in the highest quintile of intake had 9% higher femoral neck BMD (p = 0.004), 6% higher BMD at the lumbar spine (p = 0.06) and 5% higher total body BMD (p = 0.003) compared to men in the lowest quintile of dietary vitamin D intake. However, the positive association between vitamin D intake and BMD was especially apparent among those with the L/L polyadenosine (A) VDR genotype explaining between 10 and 15% of the variability in BMD depending on site (p < 0.004). There was furthermore a trend, in the lumbar spine, of less reduction in BMD with increasing vitamin D intake (p = 0.07) but not at the other sites. Calcium intake conferred no association with BMD. CONCLUSIONS: Our results indicate that the extent of positive association between dietary vitamin D intake and BMD in men is dependent on VDR polymorphism, a novel conceivable important gene-environmental interaction.

  • 18.
    Montazerolghaem, Maryam
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Applied Materials Sciences.
    Jacobson Rasmusson, Annica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis.
    Melhus, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis.
    Engqvist, Håkan
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Applied Materials Sciences.
    Karlsson Ott, Marjam
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Applied Materials Sciences.
    Simvastatin-doped pre-mixed calcium phosphate cement inhibits osteoclast differentiation and resorption2016In: Journal of materials science. Materials in medicine, ISSN 0957-4530, E-ISSN 1573-4838, Vol. 27, no 5, article id 83Article in journal (Refereed)
    Abstract [en]

    Simvastatin, a cholesterol lowering drug, has been shown to have positive effects on fracture healing and bone regeneration based on its dual effect; bone anabolic and anti-resorptive. In this study the focus has been on the anti-resorptive effect of the drug and its impact on the degradation of acidic calcium phosphate cement. The drug was added to the pre-mixed acidic cement in three different doses (0.1, 0.25 and 0.5 mg/g cement) and the release was measured. Furthermore the effect of the loaded cements on osteoclast differentiation and resorption was evaluated by TRAP activity, number of multinucleated cells, gene expression and calcium ion concentration in vitro using murine bone marrow macrophages. The simvastatin did not affect the cell proliferation while it clearly inhibited osteoclastic differentiation at all three doses as shown by TRAP staining, TRAP activity and gene expression. Consistent with these results, simvastatin also impaired resorption of cements by osteoclasts as indicated by reduced calcium ion concentrations. In conclusion, our findings suggest that simvastatin-doped pre-mixed acidic calcium phosphate cement inhibits the osteoclastic mediated resorption of the cement thus slowing down the degradation rate. In addition with simvastatin's bone anabolic effect it makes the cement-drug combination a promising bone graft material, especially useful for sites with compromised bone formation.

  • 19.
    Montazerolghaem, Maryam
    et al.
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Applied Materials Sciences.
    Karlsson Ott, Marjam
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Applied Materials Sciences.
    Engqvist, Håkan
    Uppsala University, Disciplinary Domain of Science and Technology, Technology, Department of Engineering Sciences, Applied Materials Sciences.
    Melhus, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis.
    Jacobson Rasmusson, Annica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis.
    Resorption of Monetite Calcium Phosphate Cement by Mouse Bone Marrow derived Osteoclasts2015In: Materials science & engineering. C, biomimetic materials, sensors and systems, ISSN 0928-4931, E-ISSN 1873-0191, Vol. 52, p. 212-218Article in journal (Refereed)
  • 20.
    Sundberg, Isak
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Psychiatry, University Hospital.
    Jacobson, Annica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Ramklint, Mia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Psychiatry, University Hospital.
    Ekselius, L
    Cunningham, Janet
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Psychiatry, University Hospital.
    Daytime Melatonin Levels in Saliva are Associated with Inflammatory Markers and Anxiety Disorders in Young Adults with Psychiatric DiseaseManuscript (preprint) (Other academic)
    Abstract [en]

    The bidirectional interaction between melatonin and the immune system has largely gone unexplored in a clinical context and especially in a psychiatric population. This study explored the association between melatonin during the day and inflammatory cytokines in young adult patients seeking psychiatric care. Samples and data were collected from 108 young adults (mean age 21, SD=2) at an outpatient clinic for affective disorders. Daytime saliva melatonin levels were analyzed with enzyme-linked immunosorbent assay in relation to normalized serum expression levels of 72 inflammatory markers in a proximity extension assay. In a post hoc analysis, the markers with a significant association with melatonin were tested in a generalized linear model to see whether there is a relationship to anxiety disorder or depression. After Bonferroni correction for multiple testing, melatonin levels at 11:00 were positively correlated with cluster of differentiation 5 (CD5; p=4.2e-4, p adj=0.03). Melatonin levels after lunch were correlated with monocyte chemoattractant protein-1 (MCP-1; p=4.2e-4p adj=0.03), monocyte inflammatory protein-1 alpha (MIP-1α; p=6.5e-4p adj=0.047) and vascular endothelial growth factor A (VEGF-A; p=5.3e-6p adj=0.004). In the generalized linear model, positive associations were found between the presence of any anxiety disorder after lunch and melatonin (p=0.046), VEGF-A (p=0.001) and MIP-1α (p=0.001). Daytime saliva levels of melatonin were related to several inflammatory markers in psychiatric patients. This observation likely reflects the bidirectional relationship between melatonin production and the immune system. These findings may have relevance for the understanding of psychiatric disorders and other disorders associated with the same underlying pathogenesis, including low-grade inflammation.

  • 21.
    Söderquist, Fanny
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Psychiatry, University Hospital.
    Tiensuu Janson, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine oncology.
    Rasmusson, Annica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical pharmacogenomics and osteoporosis.
    Alit, Abir
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Endocrine oncology.
    Stridsberg, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Biochemical endocrinology.
    Cunningham, Janet L.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Psychiatry, University Hospital.
    Melatonin Immunoreactivity in Malignant Small Intestinal Neuroendocrine Tumours2016In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 11, no 10, article id e0164354Article in journal (Refereed)
    Abstract [en]

    Background/ Aims Small intestinal neuroendocrine tumours (SI-NETs) are derived from enterochromaffin cells. After demonstrating melatonin in enterochromaffin cells, we hypothesized that SI-NETs may express and secrete melatonin, which may have an impact on clinical factors and treatment response. Methods Tumour tissue from 26 patients with SI-NETs, representing paired sections of primary tumour and metastasis, were immunohistochemically stained for melatonin and its receptors, MT1 and MT2. Plasma melatonin and immunoreactivity (IR) for melatonin, MT1 and MT2 in tumour cells were compared to other tumour markers and clinical parameters. Melatonin was measured at two time points in fasting morning plasma from 43 patients with SI-NETs. Results Melatonin IR was found in all SI-NETS. Melatonin IR intensity in primary tumours correlated inversely to proliferation index (p = 0.022) and patients reported less diarrhoea when melatonin IR was high (p = 0.012). MT1 IR was low or absent in tumours. MT2 expression was medium to high in primary tumours and generally reduced in metastases (p = 0.007). Plasma-melatonin ranged from 4.5 to 220.0 pg/L. Higher levels were associated with nausea at both time points (p = 0.027 and p = 0.006) and flush at the second sampling. In cases with disease stabilization or remission (n = 34), circulating melatonin levels were reduced in the second sample (p = 0.038). Conclusion Immunoreactive melatonin is present in SI-NETs. Circulating levels of melatonin in patients with SI-NETs are reduced after treatment. Our results are congruent with recent understanding of melatonin's endocrine and paracrine functions and SI-NETs may provide a model for further studies of melatonin function.

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