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  • 1.
    Alfredson, Håkan
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Sports Medicine.
    Lorentzon, Mattias
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Sports Medicine.
    Bäckman, Stina
    Umeå University, Faculty of Medicine, Department of Odontology, Oral Cell Biology.
    Bäckman, Assar
    Umeå University, Faculty of Medicine, Department of Odontology, Oral Cell Biology.
    Lerner, Ulf H
    Umeå University, Faculty of Medicine, Department of Odontology, Oral Cell Biology.
    cDNA-arrays and real-time quantitative PCR techniques in the investigation of chronic Achilles tendinosis.2003In: Journal of Orthopaedic Research, ISSN 0736-0266, E-ISSN 1554-527X, Vol. 21, no 6, p. 970-975Article in journal (Refereed)
    Abstract [en]

    The aetiology and pathogenesis of chronic painful Achilles tendinosis are unknown. This investigation aimed to use cDNA arrays and real-time quantitative polymerase chain reaction (real-time PCR) technique to study tendinosis and control tissue samples. Five patients (females mean age 57.1+/-4.3 (years+/-SD)) with chronic painful Achilles tendinosis were included. From all patients, one biopsy was taken from the area with tendinosis and one from a clinically normal area (control) of the tendon. The tissue samples were immediately immersed in RNAlater and frozen at -80 degrees C until RNA extraction. Portions of pooled RNA from control and tendinosis sites, respectively, were transcribed to cDNA, radioactively labelled (32P), hybridized to cDNA expression arrays, and exposed to phosphoimager screens over night. Expressions of specific genes, shown to be regulated in the cDNA array analysis, were analyzed in the individual samples using real-time PCR. cDNA arrays showed that gene expressions for matrix-metalloproteinase-2 (MMP-2), fibronectin subunit B (FNRB), vascular endothelial growth factor (VEGF), and mitogen-activated protein kinase p38 (MAPKp38) were up-regulated, while matrix-metalloproteinase-3 (MMP-3) and decorin were down-regulated, in tendinosis tissue compared with control tissue. Using real-time PCR, 4/5 and 3/5 patients showed up-regulation of MMP-2 and FNRB mRNA, respectively. For decorin, VEGF, and MAPKp38, real-time PCR revealed a great variability among patients. Interestingly, the mRNAs for several cytokines and cytokine receptors were not regulated, indicating the absence of an inflammatory process in chronic painful Achilles tendinosis. In conclusion, cDNA-arrays and real-time PCR can be used to study differences in gene expression levels between tendinosis and control tendon tissue.

  • 2. Andersson, MK
    et al.
    Lundberg, Pernilla
    Umeå University, Faculty of Medicine, Odontology, Oral Cell Biology.
    Ohlin, A
    Perry, MJ
    Lie, Anita
    Umeå University, Faculty of Medicine, Odontology, Oral Cell Biology.
    Stark, A
    Lerner, Ulf
    Umeå University, Faculty of Medicine, Odontology, Oral Cell Biology.
    Effects on osteoclast and osteoblast activities in cultured mouse calvarial bones by synovial fluids from patients with a loose joint prosthesis and from osteoarthritis patients.2007In: Arthritis Research & Therapy, ISSN 1478-6354, E-ISSN 1478-6362, Vol. 9, no 1, p. R18-Article in journal (Refereed)
    Abstract [en]

    Aseptic loosening of a joint prosthesis is associated with remodelling of bone tissue in the vicinity of the prosthesis. In the present study, we investigated the effects of synovial fluid (SF) from patients with a loose prosthetic component and periprosthetic osteolysis on osteoclast and osteoblast activities in vitro and made comparisons with the effects of SF from patients with osteoarthritis (OA). Bone resorption was assessed by the release of calcium 45 (45Ca) from cultured calvariae. The mRNA expression in calvarial bones of molecules known to be involved in osteoclast and osteoblast differentiation was assessed using semi-quantitative reverse transcription-polymerase chain reaction (PCR) and real-time PCR. SFs from patients with a loose joint prosthesis and patients with OA, but not SFs from healthy subjects, significantly enhanced 45Ca release, effects associated with increased mRNA expression of calcitonin receptor and tartrate-resistant acid phosphatase. The mRNA expression of receptor activator of nuclear factor-kappa-B ligand (rankl) and osteoprotegerin (opg) was enhanced by SFs from both patient categories. The mRNA expressions of nfat2 (nuclear factor of activated T cells 2) and oscar (osteoclast-associated receptor) were enhanced only by SFs from patients with OA, whereas the mRNA expressions of dap12 (DNAX-activating protein 12) and fcrgamma (Fc receptor common gamma subunit) were not affected by either of the two SF types. Bone resorption induced by SFs was inhibited by addition of OPG. Antibodies neutralising interleukin (IL)-1alpha, IL-1beta, soluble IL-6 receptor, IL-17, or tumour necrosis factor-alpha, when added to individual SFs, only occasionally decreased the bone-resorbing activity. The mRNA expression of alkaline phosphatase and osteocalcin was increased by SFs from patients with OA, whereas only osteocalcin mRNA was increased by SFs from patients with a loose prosthesis. Our findings demonstrate the presence of a factor (or factors) stimulating both osteoclast and osteoblast activities in SFs from patients with a loose joint prosthesis and periprosthetic osteolysis as well as in SFs from patients with OA. SF-induced bone resorption was dependent on activation of the RANKL/RANK/OPG pathway. The bone-resorbing activity could not be attributed solely to any of the known pro-inflammatory cytokines, well known to stimulate bone resorption, or to RANKL or prostaglandin E2 in SFs. The data indicate that SFs from patients with a loose prosthesis or with OA stimulate bone resorption and that SFs from patients with OA are more prone to enhance bone formation.

  • 3.
    Belibasakis, Georgios N
    et al.
    Umeå University, Faculty of Medicine, Odontology, Oral Cell Biology. Umeå University, Faculty of Medicine, Odontology, Oral Microbiology.
    Johansson, Anders
    Umeå University, Faculty of Medicine, Odontology, Periodontology.
    Wang, Y
    Chen, C
    Kalfas, S
    Lerner, Ulf
    Umeå University, Faculty of Medicine, Odontology, Oral Cell Biology.
    The cytolethal distending toxin induces receptor activator of NF-κB ligand expression in human gingival fibroblasts and periodontal ligament cells2005In: Infection and Immunity, ISSN 0019-9567, E-ISSN 1098-5522, Vol. 73, no 1, p. 342-351Article in journal (Refereed)
    Abstract [en]

    Actinobacillus actinomycetemcomitans is associated with localized aggressive periodontitis, a disease characterized by rapid loss of the alveolar bone surrounding the teeth. Receptor activator of NF-kappaB Ligand (RANKL) and osteoprotegerin (OPG) are two molecules that regulate osteoclast formation and bone resorption. RANKL induces osteoclast differentiation and activation, whereas OPG blocks this process by acting as a decoy receptor for RANKL. The purpose of this study was to investigate the effect of A. actinomycetemcomitans on the expression of RANKL and OPG in human gingival fibroblasts and periodontal ligament cells. RANKL mRNA expression was induced in both cell types challenged by A. actinomycetemcomitans extract, whereas OPG mRNA expression remained unaffected. Cell surface RANKL protein was also induced by A. actinomycetemcomitans, whereas there was no change in OPG protein secretion. A cytolethal distending toxin (Cdt) gene-knockout strain of A. actinomycetemcomitans did not induce RANKL expression, in contrast to its wild-type strain. Purified Cdt from Haemophilus ducreyi alone, or in combination with extract from the A. actinomycetemcomitans cdt mutant strain, induced RANKL expression. Pretreatment of A. actinomycetemcomitans wild-type extract with Cdt antiserum abolished RANKL expression. In conclusion, A. actinomycetemcomitans induces RANKL expression in periodontal connective tissue cells. Cdt is crucial for this induction and may therefore be involved in the pathological bone resorption during the process of localized aggressive periodontitis.

  • 4.
    Belibasakis, Georgios N
    et al.
    Umeå University, Faculty of Medicine, Odontology, Oral Microbiology. Umeå University, Faculty of Medicine, Odontology, Oral Cell Biology.
    Johansson, Anders
    Umeå University, Faculty of Medicine, Odontology, Periodontology.
    Wang, Y
    Chen, C
    Lagergård, T
    Kalfas, S
    Lerner, Ulf
    Umeå University, Faculty of Medicine, Odontology, Oral Cell Biology.
    Cytokine responses of human gingival fibroblasts to Actinobacillus actinomycetemcomitans cytolethal distending toxin2005In: Cytokine, ISSN 1043-4666, E-ISSN 1096-0023, Vol. 30, no 2, p. 56-63Article in journal (Refereed)
    Abstract [en]

    Actinobacillus actinomycetemcomitans is implicated in the pathogenesis of localized aggressive periodontitis, and has the capacity to express a cytolethal distending toxin (Cdt). Gingival fibroblasts (GF) are resident cells of the periodontium, which can express several osteolytic cytokines. The aims of this study were a) to investigate the role of Cdt in A. actinomycetemcomitans-induced expression of osteolytic cytokines and their cognate receptors in GF and b) to determine if the previously demonstrated induction of receptor activator of NFkappaB ligand (RANKL) by A. actinomycetemcomitans is mediated by these pro-inflammatory cytokines or by prostaglandin E(2) (PGE(2)). A. actinomycetemcomitans clearly induced interleukin (IL)-6, IL-1beta, and to a minimal extent, tumor necrosis factor (TNF)-alpha mRNA expression. At the protein level, IL-6 but not IL-1beta or TNF-alpha expression was stimulated. The mRNA expression of the different receptor subtypes recognizing IL-6, IL-1beta and TNF-alpha was not affected. A cdt-knockout strain of A. actinomycetemcomitans had similar effects on cytokine and cytokine receptor mRNA expression, compared to its parental wild-type strain. Purified Cdt stimulated IL-6, but not IL-1beta or TNF-alpha protein biosynthesis. Antibodies neutralizing IL-6, IL-1 or TNF-alpha, and the PGE(2) synthesis inhibitor indomethacin, did not affect A. actinomycetemcomitans-induced RANKL expression. In conclusion, a) A. actinomycetemcomitans induces IL-6 production in GF by a mechanism largely independent of its Cdt and b) A. actinomycetemcomitans-induced RANKL expression in GF occurs independently of IL-1, IL-6, TNF-alpha, or PGE(2).

  • 5. Brage, M
    et al.
    Abrahamson, M
    Lindström, V
    Grubb, A
    Lerner, Ulf
    Umeå University, Faculty of Medicine, Odontology, Oral Cell Biology.
    Different cysteine proteinases involved in bone resorption and osteoclast formation.2005In: Calcified Tissue International, ISSN 0171-967X, E-ISSN 1432-0827, Vol. 76, no 6, p. 439-447Article in journal (Refereed)
    Abstract [en]

    Cysteine proteinases, especially cathepsin K, play an important role in osteoclastic degradation of bone matrix proteins and the process can, consequently, be significantly inhibited by cysteine proteinase inhibitors. We have recently reported that cystatin C and other cysteine proteinase inhibitors also reduce osteoclast formation. However, it is not known which cysteine proteinase(s) are involved in osteoclast differentiation. In the present study, we compared the relative potencies of cystatins C and D as inhibitors of bone resorption in cultured mouse calvariae, osteoclastogenesis in mouse bone marrow cultures, and cathepsin K activity. Inhibition of cathepsin K activity was assessed by determining equilibrium constants for inhibitor complexes in fluorogenic substrate assays. The data demonstrate that whereas human cystatins C and D are equipotent as inhibitors of bone resorption, cystatin D is 10-fold less potent as an inhibitor of osteoclastogenesis and 200-fold less potent as an inhibitor of cathepsin K activity. A recombinant human cystatin C variant with Gly substitutions for residues Arg8, Leu9, Val10, and Trp106 did not inhibit bone resorption, had 1,000-fold decreased inhibitory effect on cathepsin K activity compared to wildtype cystatin C, but was equipotent with wildtype cystatin C as an inhibitor of osteoclastogenesis. It is concluded that (i) different cysteine proteinases are likely to be involved in bone resorption and osteoclast formation, (ii) cathepsin K may not be an exclusive target enzyme in any of the two systems, and (iii) the enzyme(s) involved in osteoclastogenesis might not be a typical papain-like cysteine proteinase.

  • 6. Brage, M
    et al.
    Lie, Anita
    Umeå University, Faculty of Medicine, Odontology, Oral Cell Biology.
    Ransjö, Maria
    Umeå University, Faculty of Medicine, Odontology, Oral Cell Biology.
    Kasprzykowski, F
    Kasprzykowska, R
    Abrahamson, M
    Grubb, A
    Lerner, Ulf
    Umeå University, Faculty of Medicine, Odontology, Oral Cell Biology.
    Osteoclastogenesis is decreased by cysteine proteinase inhibitors2004In: Bone, ISSN 8756-3282, E-ISSN 1873-2763, Vol. 34, no 3, p. 412-24Article in journal (Refereed)
    Abstract [en]

    The effects of cystatin C and other cysteine proteinase inhibitors on osteoclast formation and differentiation have been investigated. Cystatin C decreased osteoclast formation stimulated by parathyroid hormone (PTH), 1,25(OH)2-vitamin D3 or interleukin-6 (IL-6) (in the presence of its soluble receptor) as assessed by the number of tartrate-resistant acid phosphatase (TRAP+) multinucleated cells in mouse bone marrow cultures. The inhibitory effect was associated with decreased mRNA expression for the calcitonin receptor as well as decreased number of specific binding sites for 125I-calcitonin, and without any effect on the mRNA expression of receptor activator of nuclear factor kappaB (NF-kappaB) ligand (RANKL). Similarly, the cysteine proteinase inhibitors leupeptin, E-64 and benzyloxycarbonyl-Phe-Ala-diazomethane (Z-FA-CHN2) decreased PTH-stimulated formation of TRAP+ multinucleated cells and binding of 125I-calcitonin. A peptidyl derivative synthesized to mimic part of the proteinase-binding site of cystatin C (benzyloxycarbonyl-Arg-Leu-Val-Gly-diazomethane, or Z-RLVG-CHN2) also decreased PTH-stimulated osteoclast formation. In a 9-day culture, addition of cystatin C during the last 5 days was sufficient to cause substantial inhibition of osteoclast formation. Cystatin C-induced decrease of osteoclast formation was associated with enhanced number of F4/80-positive macrophages and increased mRNA expression of the macrophage receptor c-fms in the bone marrow culture. Osteoclast formation in mouse bone marrow cultures as well as in mouse spleen cell cultures, stimulated by macrophage colony-stimulating factor (M-CSF) and RANKL was also decreased by different cysteine proteinase inhibitors. In addition, cystatin C inhibited M-CSF/RANKL induction of calcitonin receptor mRNA in spleen cell cultures. The inhibitory effect by cystatin C in spleen cells was associated with decreased mRNA expression of RANK and the transcription factor NFAT2. It is concluded that cysteine proteinase inhibitors decrease formation of osteoclasts by interfering at a late stage of pre-osteoclast differentiation.

  • 7. Brand, HS
    et al.
    Lerner, Ulf
    Umeå University, Faculty of Medicine, Odontology, Oral Cell Biology.
    Grubb, A
    Beertsen, W
    Nieuw Amerongen, AV
    Everts, V
    Family 2 cystatins inhibit osteoclast-mediated bone resorption in calvarial bone explants.2004In: Bone, ISSN 8756-3282, E-ISSN 1873-2763, Vol. 35, no 3, p. 689-696Article in journal (Refereed)
    Abstract [en]

    Osteoclastic bone resorption depends on the activity of various proteolytic enzymes, in particular those belonging to the group of cysteine proteinases. Biochemical studies have shown that cystatins, naturally occurring inhibitors of these enzymes, inhibit bone matrix degradation. Since the mechanism by which cystatins exert this inhibitory effect is not completely resolved yet, we studied the effect of cystatins on bone resorption microscopically and by Ca-release measurements. Calvarial bone explants were cultured in the presence or absence of family 2 cystatins and processed for light and electron microscopic analysis, and the culture media were analyzed for calcium release. Both egg white cystatin and human cystatin C decreased calcium release into the medium significantly. Microscopic analyses of the bone explants demonstrated that in the presence of either inhibitor, a high percentage of osteoclasts was associated with demineralized non-degraded bone matrix. Following a 24-h incubation in the presence of cystatin C, 41% of the cells were adjacent to areas of demineralized non-degraded bone matrix, whereas in controls, this was only 6%. If bone explants were cultured with both PTH and cystatin C, 60% of the osteoclasts were associated with demineralized non-degraded bone matrix, compared to 27% for bones treated with PTH only (P < 0.01). Our study provides evidence that cystatins, the naturally occurring inhibitors of cysteine proteinases, reversibly inhibit bone matrix degradation in the resorption lacunae adjacent to osteoclasts. These findings suggest the involvement of cystatins in the modulation of osteoclastic bone degradation.

  • 8.
    Brechter, Anna Bernhold
    et al.
    Umeå University, Faculty of Medicine, Department of Odontology, Oral Cell Biology.
    Persson, Emma
    Umeå University, Faculty of Medicine, Department of Odontology, Oral Cell Biology.
    Lundgren, Inger
    Umeå University, Faculty of Medicine, Department of Odontology, Oral Cell Biology.
    Lerner, Ulf H
    Umeå University, Faculty of Medicine, Department of Odontology, Oral Cell Biology.
    Kinin B1 and B2 receptor expression in osteoblasts and fibroblasts is enhanced by interleukin-1 and tumour necrosis factor-alpha. Effects dependent on activation of NF-kappaB and MAP kinases.2008In: Bone, ISSN 8756-3282, E-ISSN 1873-2763, Vol. 43, no 1, p. 72-83Article in journal (Refereed)
    Abstract [en]

    Pro-inflammatory mediators formed by the kallikrein-kinin system can stimulate bone resorption and synergistically potentiate bone resorption induced by IL-1 and TNF-alpha. We have shown that the effect is associated with synergistically enhanced RANKL expression and enhanced prostaglandin biosynthesis, due to increased cyclooxygenase-2 expression. In the present study, the effects of osteotropic cytokines and different kinins on the expression of receptor subtypes for bradykinin (BK), des-Arg10-Lys-BK (DALBK), IL-1beta and TNF-alpha have been investigated. IL-1beta and TNF-alpha enhanced kinin B1 and B2 receptor binding in the human osteoblastic cell line MG-63 and the mRNA expression of B1 and B2 receptors in MG-63 cells, human gingival fibroblasts and intact mouse calvarial bones. Kinins did not affect mRNA expression of IL-1 or TNF receptors. EMSA showed that IL-1beta and TNF-alpha activated NF-kappaB and AP-1 in MG-63 cells. IL-1beta stimulated NF-kappaB via a non-canonical pathway (p52/p65) and TNF-alpha via the canonical pathway (p50/p65). Activation of AP-1 involved c-Jun in both IL-1beta and TNF-alpha stimulated cells, but c-Fos only in TNF-alpha stimulated cells. Phospho-ELISA and Western blots showed that IL-1beta activated JNK and p38, but not ERK 1/2 MAP kinase. Pharmacological inhibitors showed that NF-kappaB, p38 and JNK were important for IL-1beta induced stimulation of B1 receptors, and NF-kappaB and p38 for B2 receptors. p38 and JNK were important for TNF-alpha induced stimulation of B1 receptors, whereas NF-kappaB, p38 and JNK were involved in TNF-alpha induced expression of B2 receptors. These data show that IL-1beta and TNF-alpha upregulate B1 and B2 receptor expression by mechanisms involving activation of both NF-kappaB and MAP kinase pathways, but that signal transduction pathways are different for IL-1beta and TNF-alpha. The enhanced kinin receptor expression induced by the pro-inflammatory cytokines IL-1beta and TNF-alpha might be one important mechanism involved in the synergistic enhancement of prostaglandin formation caused by co-treatment with kinins and one of the two cytokines. These mechanisms might help to explain the enhanced bone resorption associated with inflammatory disorders, including periodontitis and rheumatoid arthritis.

  • 9.
    Brechter, Anna
    et al.
    Umeå University, Faculty of Medicine, Odontology, Oral Cell Biology.
    Lerner, Ulf
    Umeå University, Faculty of Medicine, Odontology, Oral Cell Biology.
    Bradykinin potentiates cytokine-induced prostaglandin biosynthesis in osteoblasts by enhanced expression of cyclooxygenase 2, resulting in increased RANKL expression2007In: Arthritis and Rheumatism, ISSN 0004-3591, E-ISSN 1529-0131, Vol. 56, no 3, p. 910-923Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: Bradykinin (BK) stimulates bone resorption in vitro and synergistically potentiates interleukin-1 (IL-1)-induced bone resorption and prostaglandin (PG) formation, suggesting that kinins are important in inflammation-induced bone loss. The present study was undertaken to study 1) the role of the kinin B1 and B2 receptors in the synergistic interaction with IL-1 and tumor necrosis factor alpha (TNFalpha), 2) the molecular mechanisms involved in synergistic enhancement of PG formation, and 3) the effects of kinins on cytokine-induced expression of RANKL, RANK, and osteoprotegerin (OPG) (the latter being crucial molecules in osteoclast differentiation). METHODS: Formation of PGs, expression of enzymes involved in arachidonic acid metabolism, and expression of RANKL, RANK, and OPG were assessed in the human osteoblastic cell line MG-63 and in mouse calvarial bones. The role of NF-kappaB and MAP kinases was studied using pharmacologic inhibitors. RESULTS: PGE(2) formation and cyclooxygenase 2 (COX-2) protein expression were induced by IL-1beta and potentiated by kinins with affinity for the B1 or B2 receptors, resulting in PGE(2)-dependent enhancement of RANKL. The enhancements of PGE(2) formation and COX-2 were markedly decreased by inhibition of p38 and JNK MAP kinases, whereas inhibition of NF-kappaB resulted in abolishment of the PGE(2) response with only slight inhibition of COX-2. CONCLUSION: Kinin B1 and B2 receptors synergistically potentiate IL-1- and TNFalpha-induced PG biosynthesis in osteoblasts by a mechanism involving increased levels of COX-2, resulting in increased RANKL. The synergistic stimulation is dependent on NF-kappaB and MAP kinases. These mechanisms might help to explain the enhanced bone resorption associated with inflammatory disorders, including that in rheumatoid arthritis.

  • 10. Conaway, H. Herschel
    et al.
    Henning, Petra
    Lerner, Ulf H.
    Umeå University, Faculty of Medicine, Department of Odontology.
    Vitamin A metabolism, action, and role in skeletal homeostasis2013In: Endocrine reviews, ISSN 0163-769X, E-ISSN 1945-7189, Vol. 34, no 6, p. 766-797Article in journal (Refereed)
    Abstract [en]

    Vitamin A (retinol) is ingested as either retinyl esters or carotenoids and metabolized to active compounds, such as 11-cis-retinal, which is important for vision, and all-trans-retinoic acid (ATRA), which is the primary mediator of biological actions of vitamin A. ATRA binds to retinoic acid receptors (RARs), which heterodimerize with retinoid X receptors (RXRs). RAR-RXR heterodimers function as transcription factors, binding RAR responsive elements in promoters of different genes. Numerous cellular functions, including bone cell functions, are mediated by vitamin A; however, it has long been recognized that increased levels of vitamin A can have deleterious effects on bone resulting in increased skeletal fragility. Bone mass is dependent on the balance between bone resorption and bone formation. A decrease in bone mass may be caused by either an excess of resorption or decreased bone formation. Early studies indicated that the primary skeletal effect of vitamin A was to increase bone resorption, but later studies have shown that vitamin A can not only stimulate the formation of bone resorbing osteoclasts, but inhibit their formation as well. Effects of vitamin A on bone formation have not been studied in as great a detail and are not as well characterized as effects on bone resorption. Several epidemiological studies have shown an association between vitamin A, decreased bone mass, and osteoporotic fractures, but the data are not conclusive, for other studies have found no associations, and some studies have suggested that vitamin A primarily promotes skeletal health. In this presentation, we have summarized how vitamin A is absorbed, metabolized, and functions intracellularly. Vitamin A deficiency and excess are introduced, and detailed descriptions of clinical and pre-clinical studies of the effects of vitamin A on the skeleton are presented.

  • 11.
    Conaway, H Herschel
    et al.
    University of Arkansas for Medical Sciences.
    Lerner, Ulf H
    Umeå University, Faculty of Medicine, Department of Odontology, Molecular Periodontology.
    Retinoids and bone2011In: Contemporary aspects of endocrinology / [ed] Evanthia Diamanti-Kandarakis, InTech, 2011, p. 443-454Chapter in book (Other academic)
  • 12. Conaway, H Herschel
    et al.
    Persson, Emma
    Umeå University, Faculty of Medicine, Department of Odontology, Oral Cell Biology.
    Halén, Marie
    Umeå University, Faculty of Medicine, Department of Odontology, Oral Cell Biology.
    Granholm, Susanne
    Umeå University, Faculty of Medicine, Department of Odontology, Oral Cell Biology.
    Svensson, Olle
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Orthopaedics.
    Pettersson, Ulrika
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Pharmacology.
    Lie, Anita
    Umeå University, Faculty of Medicine, Department of Odontology, Oral Cell Biology.
    Lerner, Ulf H
    Umeå University, Faculty of Medicine, Department of Odontology, Oral Cell Biology.
    Retinoids inhibit differentiation of hematopoietic osteoclast progenitors2009In: The FASEB Journal, ISSN 0892-6638, E-ISSN 1530-6860, Vol. 23, no 10, p. 3526-3538Article in journal (Refereed)
    Abstract [en]

    Whether vitamin A promotes skeletal fragility, has no effect on fracture rate, or protects against bone loss is unclear. In the present study, effects of retinoids on osteoclast differentiation in cultured mouse bone marrow cells (BMCs), bone marrow macrophages (BMMs), spleen cells, and RAW264.7 cells were evaluated by analyzing osteoclast formation and expression of genes important in signal transduction and osteoclast function. All-trans-retinoic acid (ATRA) did not stimulate osteoclastogenesis in BMCs, but inhibited hormone and RANKL-induced gene expression and formation of osteoclasts. In BMMs, spleen cells, and RAW264.7 cells, osteoclast differentiation and formation stimulated by M-CSF/RANKL were inhibited (IC(50) = 0.3 nM) by ATRA. The effect was exerted at an early step of RANKL-induced differentiation. ATRA also abolished increases of the transcription factors c-Fos and NFAT2 stimulated by RANKL and suppressed down-regulation of the antiosteoclastogenic transcription factor MafB. By comparing effects of several compounds structurally related to ATRA, as well as by using receptor antagonists, evaluation pointed to inhibition being mediated by RARalpha, with no involvement of PPARbeta/delta. The results suggest that activation of RARalpha by retinoids in myeloid hematopoietic precursor cells decreases osteoclast formation by altering expression of the transcription factors c-Fos, NFAT2, and MafB.

  • 13.
    Conaway, H. Herschel
    et al.
    Department of Physiology and Biophysics, University of Arkansas for Medical Sciences, Little Rock, Arkansas.
    Pirhayati, Amir
    Umeå University, Faculty of Medicine, Department of Odontology, Molecular Periodontology.
    Persson, Emma
    Umeå University, Faculty of Medicine, Department of Odontology, Molecular Periodontology.
    Pettersson, Ulrika
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Pharmacology.
    Svensson, Olle
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Lindholm, Catharina
    Center for Bone and Arthritis Research at the Institute for Medicine, Sahlgrenska Academy at the University of Gothenburg.
    Henning, Petra
    Center for Bone and Arthritis Research at the Institute for Medicine, Sahlgrenska Academy at the University of Gothenburg.
    Tuckermann, Jan
    Tissue-specific Hormone Action, Leibniz Institute for Age Research, Fritz Lipmann Institute, D-07745 Jena, Germany.
    Lerner, Ulf H.
    Umeå University, Faculty of Medicine, Department of Odontology, Molecular Periodontology.
    Retinoids Stimulate Periosteal Bone Resorption by Enhancing the Protein RANKL: a Response Inhibited by Monomeric Glucocorticoid Receptor2011In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 286, p. 31425-31436Article in journal (Refereed)
    Abstract [en]

    Increased vitamin A (retinol) intake has been suggested to increase bone fragility. In the present study, we investigated effects of retinoids on bone resorption in cultured neonatal mouse calvarial bones and their interaction with glucocorticoids (GC). All-trans-retinoic acid (ATRA), retinol, retinalaldehyde, and 9-cis-retinoic acid stimulated release of (45)Ca from calvarial bones. The resorptive effect of ATRA was characterized by mRNA expression of genes associated with osteoclast differentiation, enhanced osteoclast number, and bone matrix degradation. In addition, the RANKL/OPG ratio was increased by ATRA, release of (45)Ca stimulated by ATRA was blocked by exogenous OPG, and mRNA expression of genes associated with bone formation was decreased by ATRA. All retinoid acid receptors (RAR alpha/beta/gamma) were expressed in calvarial bones. Agonists with affinity to all receptor subtypes or specifically to RAR alpha enhanced the release of (45)Ca and mRNA expression of Rankl, whereas agonists with affinity to RAR beta/gamma or RAR gamma had no effects. Stimulation of Rankl mRNA by ATRA was competitively inhibited by the RAR alpha antagonist GR110. Exposure of calvarial bones to GC inhibited the stimulatory effects of ATRA on 45Ca release and Rankl mRNA and protein expression. This inhibitory effect was reversed by the glucocorticoid receptor (GR) antagonist RU 486. Increased Rankl mRNA stimulated by ATRA was also blocked by GC in calvarial bones from mice with a GR mutation that blocks dimerization (GR(dim) mice). The data suggest that ATRA enhances periosteal bone resorption by increasing the RANKL/OPG ratio via RAR alpha receptors, a response that can be inhibited by monomeric GR.

  • 14.
    Crnalic, Sead
    et al.
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Orthopaedics.
    Hörnberg, Emma
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Wikström, Pernilla
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Lerner, Ulf H
    Umeå University, Faculty of Medicine, Department of Odontology.
    Tieva, Åse
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Svensson, Olle
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Orthopaedics.
    Widmark, Anders
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Bergh, Anders
    Umeå University, Faculty of Medicine, Department of Medical Biosciences, Pathology.
    Nuclear androgen receptor staining in bone metastases is related to a poor outcome in prostate cancer patients2010In: Endocrine-Related Cancer, ISSN 1351-0088, E-ISSN 1479-6821, Vol. 17, no 4, p. 885-895Article in journal (Refereed)
    Abstract [en]

    Androgen receptors (ARs) are probably of importance during all phases of prostate cancer (PC) growth, but their role in bone metastases is largely unexplored. Bone metastases were therefore collected from hormone-naive (n=11), short-term castrated (n=7) and castration-resistant PC (CRPC, n=44) patients by biopsy (n=4) or at surgery to alleviate symptoms from metastases complications (metastasis surgery, n=58), and immunostained for nuclear ARs, Ki67, active caspase-3, prostate-specific antigen (PSA) and chromogranin A, and results were related to serum PSA, treatments and outcome. Nuclear AR immunostaining was decreased and apoptosis was increased, but cell proliferation remained largely unaffected in metastases within a few days after surgical castration. In CRPC patients, nuclear AR staining of metastases was increased when compared to short-term castrated patients. The nuclear AR staining score was related to tumour cell proliferation, but it was not associated with other downstream effects of AR activation such as apoptosis and PSA staining, and it was only marginally related to the presence of neuroendocrine tumour cells. Serum PSA at metastasis surgery, although related to outcome, was not associated with AR staining, markers of metastasis growth or PSA staining in metastases. High nuclear AR immunostaining was associated with a particularly poor prognosis after metastasis surgery in CRPC patients, suggesting that such men may benefit from the potent AR blockers now tested in clinical trials.

  • 15. Engvall, Inga-Lill
    et al.
    Svensson, Björn
    Boonen, Annelies
    van der Heijde, Désirée
    Lerner, Ulf H
    Umeå University, Faculty of Medicine, Department of Odontology.
    Hafström, Ingiäld
    Low-dose prednisolone in early rheumatoid arthritis inhibits collagen type I degradation by matrix metalloproteinases as assessed by serum 1CTP--a possible mechanism for specific inhibition of radiological destruction2013In: Rheumatology, ISSN 1462-0324, E-ISSN 1462-0332, Vol. 52, no 4, p. 733-742Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: To study the effects of low-dose prednisolone on the osteoclast-regulating proteins osteoprotegerin (OPG) and RANK ligand (RANKL) and on markers of bone resorption, 1CTP generated by MMPs and CTX-1 generated by cathepsin K, in patients with early RA in relation to inflammation and joint destruction.

    METHODS: In 225 patients, who at the start of the first DMARD had been randomized to 7.5 mg prednisolone daily for 2 years, the P-group, or no prednisolone, the NoP-group, OPG and RANKL were analysed at 0-24 months and 1CTP and CTX-1 at 0-12 months. Radiographs of hands and feet were assessed at 0, 1 and 2 years using the modified Sharp-van der Heijde score and radiological progression defined as increase in total Sharp score above 5.8. Data were analysed with a mixed linear model and by the GENMOD procedure.

    RESULTS: In the P-group, RANKL and the ratio OPG/RANKL were stable between baseline and 24 months, whereas in the NoP-group, RANKL increased and the ratio OPG/RANKL decreased. CTX-1 decreased significantly more in the P-group. 1CTP decreased over time in both groups, but more in the P-group, P < 0.001, a difference also present in the subgroups of patients in remission. The decrease in 1CTP was associated with less radiological progression after 2 years and displayed a significant interaction with treatment. CONCLUSION: Low-dose prednisolone may inhibit progression of joint destruction by interfering with MMP activity, seen as a marked decrease in 1CTP, as well as by impairing osteoclast activation, shown by a stable OPG/RANKL ratio.

  • 16.
    Granholm, Susanne
    et al.
    Umeå University, Faculty of Medicine, Department of Odontology, Molecular Periodontology.
    Henning, Petra
    Göteborgs universitet.
    Lerner, Ulf H
    Umeå University, Faculty of Medicine, Department of Odontology, Molecular Periodontology.
    Comparisons between the effects of calcitonin receptor-stimulating peptide and intermedin and other peptides in the calcitonin family on bone resorption and osteoclastogenesis2011In: Journal of Cellular Biochemistry, ISSN 0730-2312, E-ISSN 1097-4644, Vol. 112, no 11, p. 3300-3312Article in journal (Refereed)
    Abstract [en]

    Calcitonin receptor-stimulating peptide (CRSP) and intermedin (IMD) are two recently discovered peptides in the calcitonin (CT) family of peptides. CRSP and IMD, similar to CT, calcitonin gene-related peptide (CGRP) and amylin (AMY), but in contrast to adrenomedullin (ADM), inhibited bone resorption in mouse calvarial bones. CRSP and IMD, similar to CT, CGRP, AMY, but in contrast to ADM, decreased formation of osteoclasts and number of pits in bone marrow macrophage cultures stimulated by M-CSF and RANKL, with no effect on the expression of a number of genes associated with osteoclast progenitor cell differentiation. CRSP and IMD inhibited osteoclastogenesis at a late stage but had no effect on DC-STAMP mRNA. IMD, similar to CGRP, AMY and ADM stimulated cyclic AMP formation in M-CSF expanded osteoclast progenitor cells lacking CT receptors. RANKL induced CT receptors and a cyclic AMP response also to CT and CRSP, and increased the cyclic AMP response to CGRP, AMY and IMD but decreased the response to ADM. Our data demonstrate that CRSP and IMD share several functional properties of peptides in the CT family of peptides, including inhibition of bone resorption and osteoclast formation. The data also show that the reason why ADM does not inhibit osteoclast activity or formation is related to the fact that RANKL decreases ADM receptor signalling through the adenylate cyclase-cyclic AMP pathway. Finally, the findings indicate that activation by CGRP, AMY and IMD may include activation of both CT and CT receptor-like receptors. J. Cell. Biochem. © 2011 Wiley-Liss, Inc.

  • 17.
    Granholm, Susanne
    et al.
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Henning, Petra
    Lindholm, Catharina
    Lerner, Ulf H.
    Umeå University, Faculty of Medicine, Department of Odontology, School of Dentistry.
    Osteoclast progenitor cells present in significant amounts in mouse calvarial osteoblast isolations and osteoclastogenesis increased by BMP-22013In: Bone, ISSN 8756-3282, E-ISSN 1873-2763, Vol. 52, no 1, p. 83-92Article in journal (Refereed)
    Abstract [en]

    Enzymatically released cells from neonatal mouse calvarial bones are frequently used as primary mouse osteoblasts for in vitro studies. We, here, report that although these cells lack mRNA expression of the osteoclastic genes Calcr, Acp5 and Mmp-9 at early time points after their isolation, these transcripts are gradually upregulated when the calvarial osteoblast cultures are differentiated to more mature osteoblasts in long term cultures. Similarly, Calcr, Acp5, Mmp-9, as well as Rank and Nfatc1 mRNA expressions are robustly increased when the osteoblast cultures were induced to differentiate by treatment with bone morphogenetic protein (BMP-2). The increased Calcr mRNA resulted in functionally active calcitonin receptors. Enhanced osteoblastic differentiation was associated with increased Rankl mRNA expression and decreased Opg and Cfs1 mRNA expression. Treatment of the osteoblastic cells with BMP-2 or RANKL, either on plastic dishes or bone slices, resulted in the formation of multinucleated tartrate-resistant acid phosphatase positive cells, which were able to excavate resorption pits and release CTX from the bones. In contrast, increased osteoblastic differentiation induced by BMP-2 in the mouse calvarial osteoblastic cell line MC3T3-E1 was not associated with increased mRNA expression of Calcr, Acp5, Rank, c-Fms or Oscar. Interestingly, Ctsk mRNA was increased during osteoblastic differentiation in both mouse calvarial osteoblast cultures and in MC3T3-E1 cultures. Also osteoblasts isolated from mouse long bones by outgrowth from explant cultures were contaminated with osteoclast progenitors able to differentiate into bone resorbing osteoclasts. These data indicate that mouse calvarial osteoblast cultures contain osteoclast progenitor cells, which will be differentiated along the osteoclastic lineage during osteoblastic differentiation. Moreover, the data show that BMP-2 not only stimulates osteoblastic differentiation but can also induce osteoclastogenesis through increased RANKL.

  • 18.
    Granholm, Susanne
    et al.
    Umeå University, Faculty of Medicine, Odontology, Oral Cell Biology.
    Lundberg, Pernilla
    Umeå University, Faculty of Medicine, Odontology, Oral Cell Biology.
    Lerner, Ulf
    Umeå University, Faculty of Medicine, Odontology, Oral Cell Biology.
    Calcitonin inhibits osteoclast formation in mouse haematopoetic cells independently of transcriptional regulation by receptor activator of NF-{kappa}B and c-Fms2007In: The Journal of Endocrinology, ISSN 1479-6805, Vol. 195, no 3, p. 415-427Article in journal (Refereed)
    Abstract [en]

    The effects of calcitonin (CT) on osteoclast formation and gene expression have been studied in cultured mouse spleen cells and mouse bone marrow macrophages (BMMs). CT inhibited the formation of multinucleated osteoclasts and resorption pits in spleen cell cultures and BMM as well as in CD115(+) CD3(-) CD45R(-)sorted BMM cultures, incubated in the presence of macrophage colony-stimulating factor and receptor activator of NF-kappaB ligand (RANKL). No effect on apoptosis by CT was observed. CT did not affect the mRNA expressions of RANK and c-Fms, or the mRNA expressions of a wide variety of transcription factors and genes important for osteoclast differentiation and activity. CT induced inhibition of tartrate-resistant acid phosphatase (TRAP), positive multinucleated osteoclast formation was not associated with any decrease of total TRAP activity, resulting in a large number of TRAP(+) mononucleated cells in CT-treated cultures. CT did not affect the mRNA expression of dendritic cell-specific transmembrane protein, d2 isoform of vacuolar (H(+)) ATPase v(o) domain, a disintegrin and metalloproteinase domain 8 (ADAM8), ADAM12, DNAX-activating protein or Fc receptor common gamma chain suggested to be involved in fusion of mononucleated osteoclast progenitor cells. The inhibitory effect by CT was mimicked not only by compounds activating cAMP and protein kinase A (PKA) but also by a cAMP analogue activating the exchange protein directly activated by cAMP (Epac) pathway. It is concluded that CT, through cAMP/PKA/Epac cascades, inhibits osteoclast formation and that this effect is not associated with decreased transcription of genes known to be important for osteoclast progenitor cell differentiation, fusion or function.

  • 19.
    Granholm, Susanne
    et al.
    Umeå University, Faculty of Medicine, Odontology.
    Lundberg, Pernilla
    Lerner, Ulf H
    Calcitonin inhibits osteoclast formation in mouse hematopoetic cells independently of transcriptional regulation by RANK and c-Fms2007In: Journal of endocrinology, ISSN 0022–0795/07/0195–415, Vol. 195, no 3, p. 415-427Article in journal (Refereed)
  • 20. Henning, P.
    et al.
    Kindlund, B.
    Pettersson, Ulrika
    Umeå University, Faculty of Medicine, Department of Pharmacology and Clinical Neuroscience, Clinical Pharmacology.
    Conaway, H. H.
    Lerner, Ulf H
    Umeå University, Faculty of Medicine, Department of Odontology, Molecular Periodontology.
    Inhibition of osteoclast formation in human peripheral CD14+cells by vitamin A2012In: Bone, ISSN 8756-3282, E-ISSN 1873-2763, Vol. 50, no Supplement 1, p. S92-S92Article in journal (Refereed)
  • 21. Henningsson, Louise
    et al.
    Jirholt, Pernilla
    Bogestal, Yalda Rahpeymai
    Eneljung, Tove
    Adiels, Martin
    Lindholm, Catharina
    McInnes, Iain
    Bulfone-Paus, Silvia
    Lerner, Ulf H
    Umeå University, Faculty of Medicine, Department of Odontology, Molecular Periodontology.
    Gjertsson, Inger
    Interleukin 15 mediates joint destruction in staphylococcus aureus arthritis2012In: Journal of Infectious Diseases, ISSN 0022-1899, E-ISSN 1537-6613, Vol. 206, no 5, p. 687-696Article in journal (Refereed)
    Abstract [en]

    Background. Staphylococcus aureus arthritis causes severe and rapid joint damage despite antibiotics. Thus, there is a need to identify new treatment targets in addition to antibiotics. Lately, interleukin 15 (IL-15) has been implicated both in osteoclastogenesis and in bacterial clearance-2 important issues in S. aureus-induced joint destruction. This has prompted us to investigate the importance of IL-15 in S. aureus-induced arthritis.

    Methods.Toxic shock syndrome toxin-1 producing S. aureus was intravenously inoculated in IL-15 knockout and wildtype mice and in wildtype mice treated with anti-IL-15 antibodies (aIL-15ab) or isotype control antibody.

    Results. Absence of IL-15, either in knockout mice or after treatment with aIL-15ab, significantly reduced weight loss compared with controls during the infection. The severity of synovitis and joint destruction was significantly decreased in IL-15 knockout and aIL-15ab treated mice compared with controls. In IL-15 knockout mice there was a reduced number of osteoclasts in the joints. The host's ability to clear bacteria was not influenced in the IL-15 knockout mice, but significantly increased after treatment with aIL-15ab.

    Conclusions. IL-15 is a mediator of joint destruction in S. aureus-induced arthritis and contributes to general morbidity, which makes this cytokine an interesting treatment target in addition to conventional antibiotics.

  • 22. Holmberg, Anders R
    et al.
    Lerner, Ulf H
    Umeå University, Faculty of Medicine, Department of Odontology, Oral Cell Biology.
    Alayia, Ayodele A
    Al-Mohanna, Mai
    Adra, Chaker
    Marquez, Marcela
    Meurling, Lennart
    Nilsson, Sten
    Development of a novel poly bisphosphonate conjugate for treatment of skeletal metastasis and osteoporosis2010In: International Journal of Oncology, ISSN 1019-6439, Vol. 37, no 3, p. 563-567Article in journal (Refereed)
    Abstract [en]

    Advanced stage prostate and breast cancer frequently metastasize to the skeleton (approximately 75%). An additional complication in these patients, that further affects the bones, is that their hormonal treatment, induces osteoporosis. Bisphosphonates (bpns) are standard drugs against osteoporosis and have been shown to have clinically significant anti-tumor effects. This study describes the development of a new polybisphosphonate conjugate (ODX) with enhanced dual efficacy i.e. with anti-bone resorption and anti-tumor properties. Zoledronic acid (Zometa) was used as a positive control (at equimolar concentrations). Alendronic acid and aminoguanidine were conjugated to oxidized dextran with subsequent reductive amination (on average approximately 8 alendronate and approximately 50 guanidine moieties per conjugate). ODX was tested in a bone resorption assay for its capacity to inhibit bone resorbing osteoclasts (bone organ culture from neonatal mice, 45Ca labelled bone mineral). Tumor cell toxicity was studied on prostate (PC3) and breast cancer (MDA231, MDA453) cell cultures. Two methods were employed, a fluorescent cytotoxicity assay (FMCA) and an apoptosis assay (Annexin V assay). In the bone resorption assay, Zometa and ODX showed very similar potency with 50% osteoclast inhibition at approximately 20 nM and 100% at 0.2 microM. In the FMCA, IC50 for ODX was at approximately 2 microM and 25 microM for Zometa (PC3). In the apoptosis assay, ODX induced approximately 85-97% apoptosis at 10 microM in both cell lines, while Zometa failed to induce any significant apoptosis in any of the cell lines at the tested concentration range (10 nM-10 microM). ODX appears to be a promising drug candidate with high dual efficacy for the treatment of bone metastasis and osteoporosis. It has both potent osteoclast inhibiting properties and enhanced anti-tumor efficacy.

  • 23. Holmlund, A
    et al.
    Hänström, L
    Lerner, Ulf
    Umeå University, Faculty of Medicine, Odontology, Oral Cell Biology.
    Bone resorbing activity and cytokine levels in gingival crevicular fluid before and after treatment of periodontal disease.2004In: Journal of Clinical Periodontology, ISSN 0303-6979, E-ISSN 1600-051X, Vol. 31, no 6, p. 475-482Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: The aim of the present study was to investigate bone resorption activity (BRA), interleukin-1 alpha (IL-1 alpha), IL-1 beta and interleukin-1 receptor antagonist (IL-1ra) in gingival crevicular fluid (GCF) in sites with no signs of periodontal disease and in sites with horizontal or angular loss of periodontal bone. These assessments were performed before and after periodontal treatment. METHODS: GCFs were collected from 10 individuals with filter strips from two healthy sites and four sites with deep pathological periodontal pockets, two of which showed horizontal bone loss and two with angular bone loss. All diseased pockets were treated with flap surgery and systemic Doxyferm. Twelve months later GCF was collected again and treatment outcome evaluated. BRA in GCFs was assessed in a bone organ culture system by following the release of (45)Ca from neonatal mouse calvariae. The amounts of IL-1 alpha, IL-1 beta and IL-1ra in GCFs were quantified by enzyme-linked immunosorbent assay (ELISA). RESULTS: Treatment resulted in reduction of pocket depths with 3.5+/-0.5 mm in sites with angular bone loss and 2.8+/-0.3 mm in sites with horizontal bone loss. Initially, BRA, IL-1 alpha, IL-1 beta and IL-1ra were significantly higher in GCFs from diseased sites compared with healthy sites. No differences in BRA and cytokine levels were seen between GCFs from pockets with horizontal and angular bone losses. The levels of IL-1 alpha, IL-1 beta and IL-1ra were significantly reduced after treatment of diseased pockets. Pocket depths were significantly correlated to BRA only in pre-treatment sites with angular bone loss. BRA was correlated to Il-1 alpha, IL-1 beta, but not to IL-1ra, in diseased sites with angular bone loss, before and after treatment. The reductions of BRA in the individual sites, seen after treatment, were not correlated to the reductions of Il-1 alpha, IL-1 beta or IL-1ra. CONCLUSIONS: These data show that BRA and cytokine levels are increased in GCFs from sites with periodontal disease and that periodontal treatment results in reduction of the cytokines. Our findings further indicate that IL-1 alpha and IL-1 beta play important roles for the BRA present in GCFs, but that other factors also contribute to this activity.

  • 24. Holmlund, Anders
    et al.
    Hedin, Måns
    Pussinen, Pirkko J
    Lerner, Ulf H
    Umeå University, Faculty of Medicine, Department of Odontology, Oral Cell Biology.
    Lind, Lars
    Porphyromonas gingivalis (Pg) a possible link between impaired oral health and acute myocardial infarction2011In: International Journal of Cardiology, ISSN 0167-5273, E-ISSN 1874-1754, Vol. 148, no 2, p. 148-153Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: To investigate if oral health parameters were impaired in patients with myocardial infarction (MI) and if there was an association with serum antibody levels against the periodontal pathogens Porphyromonas gingivalis (Pg) and Aggregatibacter actinomycetemcomitans (Aa).

    METHODS: A case-control study consisting of 100 patients with MI and 100 age- and sex-matched controls from the same geographic area was investigated regarding oral health.

    RESULTS: The MI group had significantly more periodontal bone loss (PBL), number of deepened pockets (NDP), and bleeding on probing (BOP), and lower number of teeth (NT) than the controls. After adjustment for known cardiovascular risk factors NT, BOP, and NDP still remained significantly related to MI (p=0.014, p=0.02, and p=0.0069, respectively). IgG antibody levels against Pg were higher in subjects with MI (p=0.043), as well as in those with >4 deepened pockets (p=0.05), BOP>20% (p=0.001) and PBL (p=0.0003). However, indicating a causal pathway, the relationship between MI and Pg IgG disappeared when the oral parameters were included in the logistic regression model (p=0.69). No correlation was seen between MI and Aa in the present study.

    CONCLUSION: Patients with MI had an impaired oral health compared to controls. Furthermore, IgG levels against Pg were related to both MI and oral health, suggesting this pathogen as a possible link between oral health and CVD.

  • 25. Johansson, H.
    et al.
    Oden, A.
    Lerner, Ulf H.
    Umeå University, Faculty of Medicine, Department of Odontology, Molecular Periodontology.
    Jutberger, H.
    Lorentzon, M.
    Barrett-Connor, E.
    Karlsson, M. K.
    Ljunggren, O.
    Smith, U.
    McCloskey, E.
    Kanis, J. A.
    Ohlsson, C.
    Mellstrom, D.
    High serum adiponectin predicts incident fractures in elderly men: mr os sweden2012In: Osteoporosis International, ISSN 0937-941X, E-ISSN 1433-2965, Vol. 23, no Suppl 2, p. S306-S307Article in journal (Other academic)
  • 26. Johansson, Helena
    et al.
    Oden, Anders
    Lerner, Ulf H
    Umeå University, Faculty of Medicine, Department of Odontology, Molecular Periodontology.
    Jutberger, Hans
    Lorentzon, Mattias
    Barrett-Connor, Elizabeth
    Karlsson, Magnus K
    Ljunggren, Östen
    Smith, Ulf
    McCloskey, Eugene
    Kanis, John A
    Ohlsson, Claes
    Mellström, Dan
    High serum adiponectin predicts incident fractures in elderly men: osteoporotic fractures in men (MrOS) Sweden2012In: Journal of Bone and Mineral Research, ISSN 0884-0431, E-ISSN 1523-4681, Vol. 27, no 6, p. 1390-1396Article in journal (Refereed)
    Abstract [en]

    Adipocytes and osteoblasts share a common progenitor, and there is, therefore, potential for both autocrine and endocrine effects of adiponectin on skeletal metabolism. The aim of the present study was to determine whether high serum adiponectin was associated with an increased risk of fracture in elderly men. We studied the relationship between serum adiponectin and the risk of fracture in 999 elderly men drawn from the general population and recruited to the Osteoporotic Fractures in Men (MrOS) study in Gothenburg, Sweden. Baseline data included general health questionnaires, lifestyle questionnaires, body mass index (BMI), bone mineral density (BMD), serum adiponectin, osteocalcin, and leptin. Men were followed for up to 7.4 years (average, 5.2 years). Poisson regression was used to investigate the relationship between serum adiponectin, other risk variables and the time-to-event hazard function of fracture. Median levels of serum adiponectin at baseline were 10.4 mu g/mL (interquartile range, 7.714.3). During follow-up, 150 men sustained one or more fractures. The risk of fracture increased in parallel with increasing serum adiponectin (hazard ratio [HR]/SD, 1.46; 95% confidence interval [CI], 1.231.72) and persisted after multivariate-adjusted analysis (HR/SD, 1.30; 95% CI, 1.091.55). Serum adiponectin shows graded stepwise association with a significant excess risk of fracture in elderly men that was independent of several other risk factors for fracture. Its measurement holds promise as a risk factor for fracture in men. (C) 2012 American Society for Bone and Mineral Research.

  • 27.
    Kassem, Ali
    et al.
    Umeå University, Faculty of Medicine, Department of Odontology, Molecular Periodontology.
    Lunberg, Pernilla
    Umeå University, Faculty of Medicine, Department of Odontology, Molecular Periodontology.
    Lindholm, C.
    Souza, P.
    Lerner, Ulf
    Umeå University, Faculty of Medicine, Department of Odontology, Molecular Periodontology.
    Regulation of osteoclast formation by toll-like receptors 2 and 52012In: Bone, ISSN 8756-3282, E-ISSN 1873-2763, Vol. 50, no Supplement 1, p. S86-S87Article in journal (Refereed)
  • 28.
    Kassem, Ali
    et al.
    Umeå University, Faculty of Medicine, Department of Odontology, Molecular Periodontology.
    Lunberg, Pernilla
    Umeå University, Faculty of Medicine, Department of Odontology, Molecular Periodontology.
    Lindholm, C.
    Souza, P.
    Lerner, Ulf
    Umeå University, Faculty of Medicine, Department of Odontology, Molecular Periodontology.
    Regulation of osteoclast formation by toll-like receptors 2 and 52012In: Bone, ISSN 8756-3282, E-ISSN 1873-2763, Vol. 50, no Supplement 1, p. S67-S67Article in journal (Refereed)
  • 29.
    Kassem, Ali
    et al.
    Umeå University, Faculty of Medicine, Department of Odontology, Molecular Periodontology.
    Souza, Pedro C. C.
    Umeå University, Faculty of Medicine, Department of Odontology, Molecular Periodontology.
    Lundberg, Pernilla
    Umeå University, Faculty of Medicine, Department of Odontology, Molecular Periodontology.
    Lindholm, Catharina
    Lerner, Ulf H.
    Umeå University, Faculty of Medicine, Department of Odontology, Molecular Periodontology.
    Stimulation of bone resorption in calvarial bones by toll-like2 receptor through enhanced rankl2012In: Annals of the Rheumatic Diseases, ISSN 0003-4967, E-ISSN 1468-2060, Vol. 71, p. A68-A68Article in journal (Other academic)
  • 30.
    Kelk, Peyman
    et al.
    Umeå University, Faculty of Medicine, Department of Odontology, Periodontology.
    Claesson, Rolf
    Umeå University, Faculty of Medicine, Department of Odontology, Oral Microbiology.
    Hänström, L
    Umeå University, Faculty of Medicine, Department of Odontology, Periodontology.
    Lerner, Ulf
    Umeå University, Faculty of Medicine, Department of Odontology, Oral Cell Biology.
    Kalfas, S
    Johansson, Anders
    Umeå University, Faculty of Medicine, Department of Odontology, Periodontology.
    Abundant secretion of bioactive interleukin-1beta by human macrophages induced by Actinobacillus actinomycetemcomitans leukotoxin2005In: Infection and Immunity, ISSN 0019-9567, E-ISSN 1098-5522, Vol. 73, no 1, p. 453-458Article in journal (Refereed)
    Abstract [en]

    Actinobacillus actinomycetemcomitans produces a leukotoxin that selectively kills human leukocytes. Recently, we reported that macrophages are highly sensitive to leukotoxin and that their lysis involves activation of caspase 1. In this study, we show that leukotoxin also induces the production and release of proinflammatory cytokines from human macrophages. The macrophages were challenged with leukotoxin or lipopolysaccharide (LPS) from A. actinomycetemcomitans or LPS from Escherichia coli, and the production and secretion of interleukin-1beta (IL-1beta), IL-6, and tumor necrosis factor alpha (TNF-alpha) were determined at the mRNA and protein levels by reverse transcription-PCR and enzyme-linked immunosorbent assay, respectively. Leukotoxin (1 to 30 ng/ml) induced abundant production and secretion of IL-1beta, while the effects on IL-6 and TNF-alpha production were limited. Leukotoxin (1 ng/ml) caused a 10-times-higher release of IL-1beta than did LPS (100 ng/ml). The secreted IL-1beta was mainly the bioactive 17-kDa protein. At higher concentrations (>30 ng/ml), leukotoxin caused secretion of mainly inactive cytokine, the 31-kDa pro-IL-1beta. The presence of specific antibodies to IL-1beta or of a caspase 1 inhibitor blocked the secretion and production of the cytokine. Supernatants of leukotoxin-challenged macrophages stimulated bone resorption when tested in a mouse calvarial model. The activity could be blocked by an IL-1 receptor antagonist or specific antibodies to IL-1beta. We concluded that A. actinomycetemcomitans leukotoxin can trigger abundant production and secretion of bioactive IL-1beta by human macrophages, which is mediated by activation of caspase 1.

  • 31.
    Lerner, Ulf
    Umeå University, Faculty of Medicine, Odontology, Oral Cell Biology.
    Bone Remodeling in Post-menopausal Osteoporosis.2006In: Journal of Dental Research, ISSN 0022-0345, E-ISSN 1544-0591, Vol. 85, no 7, p. 584-595Article in journal (Refereed)
    Abstract [en]

    Bone mass in the skeleton is dependent on the coordinated activities of bone-forming osteoblasts and bone-resorbing osteoclasts in discrete bone multi-cellular units. Remodeling of bone in these units is important not only for maintaining bone mass, but also to repair microdamage, to prevent accumulation of too much old bone, and for mineral homeostasis. The activities of osteoblasts and osteoclasts are controlled by a variety of hormones and cytokines, as well as by mechanical loading. Most importantly, sex hormones are very crucial for keeping bone mass in balance, and the lack of either estrogen or testosterone leads to decreased bone mass and increased risk for osteoporosis. The prevalence of osteoporotic fractures is increasing dramatically in the Western part of the world and is a major health problem in many countries. In the present review, the cellular and molecular mechanisms controlling bone remodeling and the influence of sex hormones on these processes are summarized. In a separate paper in this issue, the pathogenesis of post-menopausal osteoporosis will be compared with that of inflammation-induced bone remodeling, including the evidence for and against the hypothesis that concomitant post-menopausal osteoporotic disease influences the progression of periodontal disease.

  • 32.
    Lerner, Ulf
    Umeå University, Faculty of Medicine, Odontology, Oral Cell Biology.
    Deletions of genes encoding calcitonin/alpha-CGRP, amylin and calcitonin receptor have given new and unexpected insights into the function of calcitonin receptors and calcitonin receptor-like receptors in bone.2006In: Journal of Musculoskeletal & Neuronal Interactions, Vol. 6, no 1, p. 87-95Article in journal (Refereed)
    Abstract [en]

    It has been suggested that skeletal nerves fibers may play important roles in neuro-osteogenic interactions. This view is partly based upon information obtained from immunohistochemical studies, chemical and surgical denervation experiments and clinical observations in patients with stroke and spinal cord injury, indicating the presence of a network of nerve fibers in the skeleton and that defective signalling in skeletal nerve fibers affects remodelling of bone. This view is also supported by data showing that functional receptors for signalling molecules in skeletal nerve fibers are expressed in bone cells and that activation of these receptors leads to profound effects on bone forming osteoblasts and bone resorbing osteoclasts. Convincing evidence for a role of neuronal signalling in bone metabolism has been provided by gene deletion approaches in which it has been shown that leptin-sensitive and neuropeptide Y-sensitive receptors in hypothalamus are important for bone remodelling in mice. Recently, gene deletion experiments have shown that calcitonin gene-related peptide (CGRP), one of the neuropeptides present in skeletal nerve fibers, is an important physiological regulator of bone formation at the level of osteoblast activity. CGRP belongs to the calcitonin (CT) family of peptides also including CT, amylin and adrenomedullin, as well as the recently described intermedin and calcitonin receptor-stimulating peptide. These peptides utilize two seven transmembrane G protein-coupled receptors - the calcitonin receptor (CTR) and the calcitonin receptor- like receptor (CRLR) - which can dimerize with three different single transmembrane proteins, making up the RAMP family. Associations between RAMPs and either CTR or CRLR give rise to seven distinct, molecularly characterized, receptors for CT, CGRP, amylin and adrenomedullin. Deletions of the genes for ligands in the CT family of peptides and for one of the receptors have revealed unexpected findings that have changed our view on the role of these peptides in bone remodelling. It was anticipated that deletions of the CT/alpha-CGRP and CTR genes would lead to bone loss, since CT has been shown to inhibit bone resorption in vitro and in vivo and has been used to treat patients with excessive bone resorption. Surprisingly, it was found that CT/alpha-CGRP-/- and CTR+/- mice have increased bone mass due to increased bone formation. Mice with deletion of the amylin gene, however, exhibited bone loss due to enhanced bone resorption. Selective deletion of the alpha-CGRP gene also leads to bone loss, but due to decreased bone formation. Thus, our understanding of the role of the CT family of peptides has been changed dramatically and much more data have to be gained before we fully understand the roles these peptides have in bone biology.

  • 33.
    Lerner, Ulf
    Umeå University, Faculty of Medicine, Department of Odontology.
    Endokrin reglering av benförlust och benregeneration2012In: BestPractice Reumatologi, no 13, p. 14-18Article in journal (Other academic)
  • 34.
    Lerner, Ulf
    Umeå University, Faculty of Medicine, Odontology, Oral Cell Biology.
    Inflammation-induced Bone Remodeling in Periodontal Disease and the Influence of Post-menopausal Osteoporosis.2006In: Journal of Dental Research, ISSN 0022-0345, E-ISSN 1544-0591, Vol. 85, no 7, p. 596-607Article in journal (Refereed)
    Abstract [en]

    During physiological conditions, the skeleton is remodeled in so-called bone multi-cellular units. Such units have been estimated to exist at 1-2 x 10(6) sites in the adult skeleton. The number and activities of these units are regulated by a variety of hormones and cytokines. In post-menopausal osteoporosis, lack of estrogen leads to increased numbers of bone multi-cellular units and to uncoupling of bone formation and bone resorption, resulting in too little bone laid down by osteoblasts compared with the amount of bone resorbed by osteoclasts. Inflammatory processes in the vicinity of the skeleton, e.g., marginal and apical periodontitis, will affect the remodeling of the nearby bone tissue in such a way that, in most patients, the amount of bone resorbed exceeds that being formed, resulting in net bone loss (inflammation-induced osteolysis). In some patients, however, inflammation-induced bone formation exceeds resorption, and a sclerotic lesion will develop. The cellular and molecular pathogenetic mechanisms in inflammation-induced osteolysis and sclerosis are discussed in the present review. The cytokines believed to be involved in inflammation-induced remodeling are very similar to those suggested to play crucial roles in post-menopausal osteoporosis. In patients with periodontal disease and concomitant post-menopausal osteoporosis, the possibility exists that the lack of estrogen influences the activities of bone cells and immune cells in such a way that the progression of alveolar bone loss will be enhanced. In the present paper, the evidence for and against this hypothesis is presented.

  • 35.
    Lerner, Ulf
    Umeå University, Faculty of Medicine, Odontology, Oral Cell Biology.
    Skelettet i käkar och annorstädes – en benhård vävnad fylld av liv och rörelse både vid hälsa och sjukdom. III. Obalancerad benremodellering orsakar osteoporossjukdom.2006In: Tandläkartidningen, ISSN 0039-6982, no 98, p. 50-61Article in journal (Other academic)
  • 36.
    Lerner, Ulf H
    Umeå University, Faculty of Medicine, Department of Odontology, School of Dentistry.
    Osteoblasts, Osteoclasts, and Osteocytes: Unveiling Their Intimate-Associated Responses to Applied Orthodontic Forces2012In: Seminars in orthodontics, ISSN 1073-8746, Vol. 18, no 4, p. 237-248Article in journal (Refereed)
    Abstract [en]

    Bone is remodeled and modeled by the concerted activities of 3 cell types — osteoblasts, osteocytes, and osteoclasts. Osteoblasts are the cells that produce bone extracellular matrix and are responsible for its mineralization. Osteoblasts also have endocrine activity through secretion of osteocalcin, which regulates fat and energy metabolism. These cells also control the differentiation and activity of osteoclasts. Osteocytes are osteoblasts that have been incorporated into bone matrix and are cells with extensive dendritic processes through which the cells communicate with other osteocytes and with osteoblasts. Mechanical loading is sensitized by the dendritic processes and transferred to biochemical responses involved in control of osteoblast and osteoclast function. Osteocytes also have endocrine activity by releasing fibroblast growth factor 23, which is involved in phosphate secretion in kidneys. Differentiation of osteoclast mononuclear progenitors to mature multinucleated osteoclasts is regulated by macrophage colony-stimulating factor and receptor activator of NF-κB ligand, expressed by stromal cells in bone marrow or osteoblasts in bone, as well as by osteocytes. The integrated endo- and paracrine control of osteoblasts, osteocytes, and osteoclasts is important for maintaining bone mass and for control of remodeling and modeling processes in bone, including during orthodontic-induced tooth movement.

  • 37.
    Lerner, Ulf H
    Umeå University, Faculty of Medicine, Department of Odontology, Molecular Periodontology. Centrum för ben- och artritforskning, Institutionen för medicin, Sahlgrenska akademin, Göteborgs universitet, Göteborg.
    Skelettet i käkar och annorstädes: 4. Skelettet som ett hormonproducerande organ med betydelse för energimetabolism och fosfatutsöndring2012In: Tandläkartidningen, ISSN 0039-6982, Vol. 104, no 8, p. 60-68Article in journal (Refereed)
    Abstract [sv]

    Ny forskning visar att skelettet inte bara regleras av hormoner utan också producerar hormoner. Dessa hormoner påverkar fettceller, insulinproducerande celler i bukspottkörteln och njurens fosfatreglering.

  • 38.
    Lerner, Ulf H
    Umeå University, Faculty of Medicine, Department of Odontology.
    The biology of bone remodelling in jaw bones with and without teeth2012In: Textbook of removable prosthodontics: the Scandinavian approach / [ed] Margareta Molin Thorén och Johan Gunne, Munksgaard Forlag, 2012, 1, p. 51-60Chapter in book (Refereed)
    Abstract [en]

    Bone tissues, together with enamel, dentin and cementum, are unique tissues in the human body because of the presence of large amounts of mineral crystals in the extracellular matrix. It is a common misconception that mineralized tissues of the body are dead tissues with the only task of forming the skeleton and the teeth. However, bone tissue is a living organ with different cell types that have important functions for mineral homeostasis and for remodelling as well as modelling of the skeleton in order to renew it and to adapt to functional demands. Two morphologically distinct bone tissues make up all bones; the cortical bones in the periphery and the network of trabecular bone in the inner part of the bones. Some bones have only small amounts of trabecular bone, whereas others are filled up more densely. It is not known why some osteoblasts are producing cortical bone and others trabecular bone. Interestingly, trabecular bone is more frequently remodelled. This is the reason why metabolic bone diseases, such as osteoporosis, affect bone with large amounts of trabecular bone more severely. Much remains to be understood about the different processes of bone formation, how it is controlled and why we have two types of bone. Although the general view is that all osteoblasts and osteoclasts in the body are very similar, it has become clearer during recent years that a substantial heterogeneity exists in osteoblasts and osteoclasts present in different bones. Most studies are performed on bone cells isolated from calvarial bones and long bones and very few from jaw bones. This is important, since the biology of osteoblasts and osteoclasts in maxilla and mandible is not necessarily similar in all aspects to the one observed in cells from other areas. This chapter presents a brief summary of bone cell biology, bone remodelling and modelling including the effects by inflammatory processes on bone cell activities and, finally, summarizes the relatively spare information available on bone remodelling in the vicinity of removable prosthetic dentures.

  • 39.
    Lerner, Ulf H
    Umeå University, Faculty of Medicine, Department of Odontology, Molecular Periodontology.
    Vad gör A-vitaminen med skelettet?2010In: Osteoporos-nytt, ISSN 1404-6199, no 4, p. 10-11Article in journal (Other academic)
  • 40.
    Lerner, Ulf H
    et al.
    Umeå University, Faculty of Medicine, Department of Odontology, Molecular Periodontology.
    Lundberg, Pernilla
    Umeå University, Faculty of Medicine, Department of Odontology, Molecular Periodontology.
    Brechter, Anna
    Palmqvist, Py
    Umeå University, Faculty of Medicine, Department of Odontology.
    Persson, Emma
    Umeå University, Faculty of Medicine, Department of Odontology.
    Skelettet vid hälsa och sjukdom2008In: Tandläkartidningen, ISSN 0039-6982, Vol. 100, no 5, p. 84-90Article in journal (Other academic)
    Abstract [sv]

    Hur ombyggnaden av benvävnaden i käkar och skelett fungerar och hur processen påverkas vid sjukdomstillstånd som parodontit, benskörhet, tumörer med mera är föremål för omfattande forskning i Umeå.

  • 41.
    Lerner, Ulf H
    et al.
    Umeå University, Faculty of Medicine, Department of Odontology, Molecular Periodontology. Centrum för ben- och artritforskning, Institutionen för medicin, Sahlgrenska akademin, Göteborgs universitet, Göteborg.
    Mellström, Dan
    Centrum för ben- och artritforskning, Institutionen för medicin, Sahlgrenska akademin, Göteborgs universitet, Göteborg.
    Behandlingsprinciper för olika läkemedel vid osteoporos: skelettet i käkar och annorstädes, del 52012In: Tandläkartidningen, ISSN 0039-6982, Vol. 104, no 11, p. 64-79Article in journal (Refereed)
    Abstract [sv]

    Osteoporos drabbar många individer i hela världen. Från att ha varit en sjukdom utan farmakologisk behandling har ett flertal läkemedel nu utvecklats och fler är på väg. Här beskrivs behandlingsprinciperna för de läkemedel som i dag används vid osteoporos.

  • 42.
    Lerner, Ulf H
    et al.
    Umeå University, Faculty of Medicine, Department of Odontology. Centre for Bone and Arthritis Research, Institute for Medicine, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden.
    Ohlsson, C
    Centre for Bone and Arthritis Research, Institute for Medicine, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden.
    The WNT system: background and its role in bone2015In: Journal of Internal Medicine, ISSN 0954-6820, E-ISSN 1365-2796, Vol. 277, no 6, p. 630-649Article in journal (Refereed)
    Abstract [en]

    WNTs are extracellular proteins that activate different cell surface receptors linked to canonical and noncanonical WNT signalling pathways. The Wnt genes were originally discovered as important for embryonic development of fruit flies and malignant transformation of mouse mammary cancers. More recently, WNTs have been implicated in a wide spectrum of biological phenomena and diseases. During the last decade, several lines of clinical and preclinical evidence have indicated that WNT signalling is critical for trabecular and cortical bone mass, and this pathway is currently an attractive target for drug development. Based on detailed knowledge of the different WNT signalling pathways, it appears that it might be possible to develop drugs that specifically target cortical and trabecular bone. Neutralization of a bone-specific WNT inhibitor is now being evaluated as a promising anabolic treatment for patients with osteoporosis. Here, we provide the historical background to the discoveries of WNTs, describe the different WNT signalling pathways and summarize the current understanding of how these proteins regulate bone mass by affecting bone formation and resorption.

  • 43.
    Lerner, Ulf H
    et al.
    Umeå University, Faculty of Medicine, Department of Odontology, Molecular Periodontology.
    Ohlsson, Claes
    Ahlman, Håkan
    Mellström, Dan
    Serotonin: budbärare mellan hjärna/tunntarm och skelett. Djurmodeller styrker hypotes om serotoninets roll för bildning av benmassa2011In: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 108, no 11, p. 600-605Article in journal (Refereed)
    Abstract [en]

    Recent studies by Karsenty and co-workers at Columbia University, New York, have demonstrated the importance in skeletal remodeling in mice of serotonin in the brain and in the periphery. Leptin activates receptors in the brain stem which inhibit tryptophane hydroxylase 2 (Tph2), decreasing serotonin biosynthesis. As a consequence, fewer hypothalamic serotonin receptors are activated, sympathetic outflow increases, and there is enhanced activation of ?-adrenergic receptors on osteoblasts. This leads to decreased bone formation, and increased expression of RANKL, which stimulates bone resorption. In contrast, peripheral serotonin is produced in enterochromaffine cells in the dudenum by the enzyme Tph1. Activation of osteoblastic receptors by peripheral serotonin decreases bone formation without affecting RANKL or resorption. Interstingly, pharmacological inhibition of Tph1 in the duodenum can prevent bone loss after ovariectomy in both mice and rats. These preclinical data need to be confirmed in humans and the feedback loops between the skeleton and serontonin releasing cells in brain and gut to be elucidated.

  • 44.
    Lerner, Ulf H
    et al.
    Umeå University, Faculty of Medicine, Department of Odontology, Oral Cell Biology.
    Persson, Emma
    Umeå University, Faculty of Medicine, Department of Odontology, Oral Cell Biology.
    Osteotropic effects by the neuropeptides calcitonin gene-related peptide, substance P and vasoactive intestinal peptide2008In: Journal of Musculoskeletal and Neuronal Interactions - JMNI, ISSN 1108-7161, Vol. 8, no 2, p. 154-165Article in journal (Refereed)
    Abstract [en]

    Immunohistochemical phenotypic characterization of skeletal nerve fibers has demonstrated the expression of a restricted number of neuropeptides, including calcitonin gene-related peptide (CGRP), substance P (SP) and vasoactive intestinal peptide (VIP). According to the neuro-osteological hypothesis, such neuropeptides can be released and exert paracrine biological effects on bone cells present close to the nerve endings expressing these signaling molecules. The existence of such interplay is most convincingly shown by the hypothalamic control of bone formation, in the case of leptin stimulation of hypothalamic nuclei mediated by the sympathetic nervous system and inhibitory beta-adrenergic receptors on osteoblasts. In addition to these receptors, osteoblasts and osteoclasts express functional receptors for CGRP, SP and VIP, which can regulate both bone formation and bone resorption. The evidence for these observations is summarized in the present paper.

  • 45.
    Lerner, Ulf H
    et al.
    Umeå University, Faculty of Medicine, Department of Odontology, Oral Cell Biology.
    Persson, Emma
    Umeå University, Faculty of Medicine, Department of Odontology, Oral Cell Biology.
    Lundberg, Pernilla
    Umeå University, Faculty of Medicine, Department of Odontology, Oral Cell Biology.
    Kinins and Neuro-osteogenic Factors2008In: Principles of Bone Biology 3rd Edition / [ed] John P. Bilezikian, Lawrence G. Raisz and T. John Martin, Amsterdam: Elsevier, 2008, p. 1025-1057Chapter in book (Other academic)
  • 46.
    Lerner, Ulf
    et al.
    Umeå University, Faculty of Medicine, Odontology, Oral Cell Biology.
    Ljunggren, O
    Benvävnadens omsättning. Mekanismer som förklarar uppkomsten av benskörhet och som möjliggör farmakologisk behandling.2006In: Läkartidningen, ISSN 0023-7205, E-ISSN 1652-7518, Vol. 103, no 40, p. 2972-2975Article in journal (Other academic)
  • 47. Lewerin, C.
    et al.
    Johansson, H.
    Lerner, Ulf H.
    Umeå University, Faculty of Medicine, Department of Odontology. Center for Bone and Arthritis Research (CBAR) and Geriatric Medicine, Sahlgrenska Academy, Institute of Medicine, University of Gothenburg, Gothenburg, Sweden.
    Karlsson, M. K.
    Lorentzon, M.
    Barrett-Connor, E.
    Smith, U.
    Ohlsson, C.
    Mellstrom, D.
    High serum adiponectin is associated with low blood haemoglobin in elderly men: the Swedish MrOS study2015In: Journal of Internal Medicine, ISSN 0954-6820, E-ISSN 1365-2796, Vol. 278, no 1, p. 68-76Article in journal (Refereed)
    Abstract [en]

    Objectives: Blood haemoglobin (Hb) concentration declines in elderly men, whilst the level of the adipocyte-derived protein adiponectin increases with age. The association between erythropoiesis and adiponectin in elderly men is unclear. The aim of this study was to determine whether adipokines such as adiponectin and leptin are associated with anaemia and Hb concentration in elderly community-dwelling men.

    Design and setting: The Gothenburg part of the population-based Swedish Osteoporotic Fractures in Men (MrOS) cohort (n=1010; median age 75.3years, range 69-81).

    Main outcome measures: We investigated the associations between levels of adiponectin and Hb before and after adjusting for potential confounders [i.e. age, body composition, erythropoietin (EPO), total oestradiol, leptin, cystatin C and iron and B vitamin status].

    Results: In these elderly men, age was negatively associated with Hb (r=-0.12, P<0.001) and positively associated with adiponectin level (r=0.13, P<0.001). In age-adjusted partial correlations, Hb and adiponectin levels were negatively correlated (r=-0.20, P<0.001); this association remained significant after multivariable adjustment for age, body composition, EPO, fasting insulin, sex hormones, leptin and ferritin. Age-adjusted mean adiponectin concentrations were significantly higher in anaemic men (66/1005; Hb <130gL(-1)) compared to nonanaemic men (14.0 vs. 11.7 gmL(-1), P<0.05). In multivariate analysis, adiponectin together with EPO, total oestradiol, insulin, albumin, transferrin saturation, HDL cholesterol, cystatin C, total body fat mass and free thyroxine, but not leptin, explained 35% of the variation in Hb level. These results remained essentially unchanged after exclusion of men with diabetes.

    Conclusions: Serum adiponectin, but not leptin, was negatively and independently associated with Hb. This finding suggests a possible role of adiponectin in the age-related decline in Hb level observed in apparently healthy elderly men.

  • 48. Lewerin, C.
    et al.
    Nilsson-Ehle, H.
    Jacobsson, S.
    Johansson, H.
    Sundh, V.
    Karlsson, M. K.
    Ljunggren, O.
    Lorentzon, M.
    Kanis, J. A.
    Lerner, Ulf H.
    Umeå University, Faculty of Medicine, Department of Odontology. Göteborgs universitet.
    Cummings, S. R.
    Ohlsson, C.
    Mellström, D.
    Low holotranscobalamin and cobalamins predict incident fractures in elderly men: the MrOS Sweden2014In: Osteoporosis International, ISSN 0937-941X, E-ISSN 1433-2965, Vol. 25, no 1, p. 131-140Article in journal (Refereed)
    Abstract [en]

    In a population-based study on cobalamin status and incident fractures in elderly men (n = 790) with an average follow-up of 5.9 years, we found that low levels of metabolically active and total cobalamins predict incident fractures, independently of body mass index (BMI), bone mineral density (BMD), plasma total homocysteine (tHcy), and cystatin C.

    INTRODUCTION: Cobalamin deficiency in elderlies may affect bone metabolism. This study aims to determine whether serum cobalamins or holotranscobalamin (holoTC; the metabolic active cobalamin) predict incident fractures in old men.

    METHODS: Men participating in the Gothenburg part of the population-based Osteoporotic Fractures in Men (MrOS) Sweden cohort and without ongoing vitamin B medication were included in the present study (n = 790; age range, 70-81 years).

    RESULTS: During an average follow-up of 5.9 years, 110 men sustained X-ray-verified fractures including 45 men with clinical vertebral fractures. The risk of fracture (adjusted for age, smoking, BMI, BMD, falls, prevalent fracture, tHcy, cystatin C, 25-OH-vitamin D, intake of calcium, and physical activity (fully adjusted)), increased per each standard deviation decrease in cobalamins (hazard ratio (HR), 1.38; 95 % confidence intervals (CI), 1.11-1.72) and holoTC (HR, 1.26; 95 % CI, 1.03-1.54), respectively. Men in the lowest quartile of cobalamins and holoTC (fully adjusted) had an increased risk of all fracture (cobalamins, HR = 1.67 (95 % CI, 1.06-2.62); holoTC, HR = 1.74 (95 % CI, 1.12-2.69)) compared with quartiles 2-4. No associations between folate or tHcy and incident fractures were seen.

    CONCLUSIONS: We present novel data showing that low levels of holoTC and cobalamins predicting incident fracture in elderly men. This association remained after adjustment for BMI, BMD, tHcy, and cystatin C. However, any causal relationship between low cobalamin status and fractures should be explored in a prospective treatment study.

  • 49. Liu, Yen-Chun G
    et al.
    Lerner, Ulf H
    Umeå University, Faculty of Medicine, Department of Odontology, Oral Cell Biology.
    Teng, Yen-Tung A
    Cytokine responses against periodontal infection: protective and destructive roles2010In: Periodontology 2000, ISSN 0906-6713, E-ISSN 1600-0757, Vol. 52, no 1, p. 163-206Article in journal (Refereed)
  • 50.
    Lundberg, Pernilla
    et al.
    Umeå University, Faculty of Medicine, Department of Odontology, Oral Cell Biology.
    Koskinen, Cecilia
    Umeå University, Faculty of Medicine, Department of Odontology.
    Baldock, Paul A
    Löthgren, Hanna
    Stenberg, Åsa
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Histology and Cell Biology.
    Lerner, Ulf
    Umeå University, Faculty of Medicine, Department of Odontology.
    Oldenborg, Per-Arne
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Histology and Cell Biology.
    Osteoclast formation is strongly reduced both in vivo and in vitro in the absence of CD47/SIRPalpha-interaction2007In: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, E-ISSN 1090-2104, Vol. 352, no 2, p. 444-448Article in journal (Refereed)
    Abstract [en]

    Physical interaction between the cell surface receptors CD47 and signal regulatory protein alpha (SIRPalpha) was reported to regulate cell migration, phagocytosis, cytokine production, and macrophage fusion. However, it is unclear if the CD47/SIRPalpha-interaction can also regulate macrophage colony-stimulating factor (M-CSF) and receptor activator of nuclear factor (NF)-kappaB ligand (RANKL)-stimulated formation of osteoclasts. Here, we show that functional blocking antibodies to either CD47 or SIRPalpha strongly reduced formation of multinucleated tartrate-resistant acid phosphatase (TRAP)+ osteoclasts in cultures of murine hematopoietic cells, stimulated in vitro by M-CSF and RANKL. In addition, the numbers of osteoclasts formed in M-CSF/RANKL-stimulated bone marrow macrophage cultures from CD47-/- mice were strongly reduced, and bones of CD47-/- mice exhibited significantly reduced osteoclast numbers, as compared with wild-type controls. We conclude that the CD47/SIRPalpha interaction is important for M-CSF/RANKL-stimulated osteoclast formation both in vivo and in vitro, and that absence of CD47 results in decreased numbers of osteoclasts in CD47-/- mice.

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