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  • 1. 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.

  • 2. Boström, Elisabeth A.
    et al.
    Lundberg, Pernilla
    Umeå University, Faculty of Medicine, Department of Odontology.
    The Newly Discovered Cytokine IL-34 Is Expressed in Gingival Fibroblasts, Shows Enhanced Expression by Pro-Inflammatory Cytokines, and Stimulates Osteoclast Differentiation2013In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 8, no 12, p. e81665-Article in journal (Refereed)
    Abstract [en]

    Background: Interleukin-34 (IL-34) is a recently discovered cytokine functionally overlapping macrophage colony stimulating factor (M-CSF), a mediator of inflammation and osteoclastogenesis in bone-degenerative diseases such as rheumatoid arthritis. The objective of this study was to assess the expression of IL-34 in human gingival fibroblasts and investigate if the pro-inflammatory cytokines tumor necrosis factor alpha (TNF-alpha) and Interleukin-1B (IL-1 beta) modulate its expression, and moreover if IL-34 could contribute to recruitment of bone-resorbing osteoclasts. Methods: IL-34 expression was evaluated in gingival fibroblasts by real time PCR following stimulation by TNF-alpha, IL-1 beta, and treatment with inhibitors of intracellular pathways. The formation of osteoclasts was evaluated by tartrate-resistant acid phosphatase (TRAP) staining of bone marrow macrophages treated with IL-34 or M-CSF in addition to receptor activator of nuclear factor kappa-B ligand (RANKL). Results: IL-34 was expressed in gingival fibroblasts. The expression was enhanced by TNF-alpha and IL-1 beta, regulated by the transcription factor nuclear factor kappa B (NF-kappa B) and activation of c-Jun N-terminal kinase (JNK). Further, IL-34 supports RANKL-induced osteoclastogensis of bone marrow macrophages, independently of M-CSF. Summary: In conclusion, this study shows for the first time IL-34 expression in human gingival fibroblasts, stimulated by TNF-alpha and IL-1 beta, key mediators of periodontal inflammation. Furthermore, IL-34 can be substituted for M-CSF in RANKL-induced osteoclastogenesis. IL-34 may contribute to inflammation and osteoclastogenesis in bone-degenerative diseases such as periodontitis.

  • 3.
    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.

  • 4.
    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)
  • 5.
    Granholm, Susanne
    et al.
    Umeå University, Faculty of Medicine, Odontology. Umeå University, Faculty of Medicine, Odontology, Oral Cell Biology.
    Lundberg, Pernilla
    Lerner, Ulf H
    Expression of the calcitonin receptor, calcitonin receptor-like receptor, and receptor activity modifying proteins during osteoclast differentiation.2008In: Journal of cellular biochemistry, ISSN 1097-4644, Vol. 104, no 3, p. 920-933Article in journal (Refereed)
    Abstract [en]

    The expressions of the calcitonin receptor (CTR), the calcitonin receptor-like receptor (CLR), the receptor activity-modifying proteins (RAMP) 1-3, and of the receptor component protein (RCP) have been studied in mouse bone marrow macrophages (BMM) during osteoclast differentiation, induced by treatment with M-CSF and RANKL. Analyses of mRNA showed that CLR and RAMP1-3, but not CTR, were expressed in M-CSF stimulated BMM. RANKL gradually increased CTR mRNA, transiently enhanced CLR and transiently decreased RAMP1 mRNA, but did not affect RAMP2, RAMP3, or RCP mRNA. However, RANKL did not affect protein levels of CLR or RAMP1-3 as assessed by Western blots or FACS analyses, whereas immunocytochemistry showed enhanced CTR protein. Analyses of cAMP production showed that BMM cells expressed functional receptors for calcitonin gene-related peptide (CGRP), amylin, adrenomedullin, and intermedin, but not for calcitonin and calcitonin receptor stimulating peptide (CRSP), but that RANKL induced the expression of receptors for calcitonin and CRSP as well. Calcitonin, CGRP, amylin, adrenomedullin, intermedin, and CRSP all down regulated the CTR mRNA, but none of the peptides caused any effects on the expression of CLR or any of the RAMPs. Our data show that BMM cells express receptors for CGRP, amylin, adrenomedullin, and intermedin and that RANKL induces the formation of receptors for calcitonin and CRSP in these cells. We also show, for the first time, that the CTR is not only down regulated by signaling through the CTR but also by the peptides signaling through CLR/RAMPs.

  • 6.
    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)
  • 7.
    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)
  • 8.
    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)
  • 9.
    Kolan, Shrikant
    et al.
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Lejon, Kristina
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Koskinen Holm, Cecilia
    Umeå University, Faculty of Medicine, Department of Odontology.
    Sulniute, Rima
    Umeå University, Faculty of Medicine, Department of Odontology.
    Lundberg, Pernilla
    Umeå University, Faculty of Medicine, Department of Odontology.
    Matozaki, Takashi
    Department of Biochemistry and Molecular Biology, Division of Molecular and Cellular Signaling, Kobe University Graduate School of Medicine, Kobe, Japan.
    Oldenborg, Per-Arne
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
    Non-Hematopoietic and Hematopoietic SIRPα Signaling Differently Regulates Murine B Cell Maturation in Bone Marrow and Spleen2015In: PLoS One, Vol. 10, no 7, article id e0134113Article in journal (Refereed)
    Abstract [en]

    B lymphocyte development occurs in the bone marrow, while final differentiation and maturation can occur in both the bone marrow and the spleen. Here we provide evidence that signal regulatory protein α (SIRPα), an Ig-superfamily ITIM-receptor expressed by myeloid but not by lymphoid cells, is involved in regulating B cell maturation. Lack of SIRPα signaling in adult SIRPα-mutant mice resulted in a reduced maturation of B cells in the bone marrow, evident by reduced numbers of semi-mature IgD+IgMhi follicular type-II (F-II) and mature IgD+IgMlofollicular type-I (F-I) B cells, as well as reduced blood B cell numbers. In addition, lack of SIRPα signaling also impaired follicular B cell maturation in the spleen. Maturing BM or splenic B cells of SIRPα-mutant mice were found to express higher levels of the pro-apoptotic protein BIM and apoptosis was increased among these B cells. Bone marrow reconstitution experiments revealed that the B cell maturation defect in bone marrow and blood was due to lack of SIRPα signaling in non-hematopoietic cells, while hematopoietic SIRPα signaling was important for follicular B cell maturation in the spleen. Adding on to our previous findings of a stromal cell defect in SIRPα-mutant mice was the finding that gene expression of receptor activator of nuclear factor-ĸB ligand (RANKL) was significantly lower in cultured bone marrow stromal cells of SIRPα mutant mice. These data suggest a novel and opposite contribution of SIRPα signaling within non-hematopoietic and hematopoietic cells, respectively, to maintain B cell maturation and to prevent apoptosis in the bone marrow and spleen of adult mice.

  • 10.
    Koskinen, Cecilia
    et al.
    Umeå University, Faculty of Medicine, Department of Odontology.
    Engman, Sara
    Sulniute, Rima
    Umeå University, Faculty of Medicine, Department of Odontology.
    Matozaki, Takashi
    Oldenborg, Per-Arne
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Histology and Cell Biology.
    Lundberg, Pernilla
    Umeå University, Faculty of Medicine, Department of Odontology.
    Reduced SIRPα phosphorylation and concommitant SHP-2–PI3K–Akt2 signaling decrease osteoblast differentiationArticle in journal (Other academic)
    Abstract [en]

    Normal differentiation of bone forming osteoblasts is a prerequisite for maintenance of skeletal health and is dependent on an intricate cellular signaling including the essential transcription factor Runx2. The cell surface glycoprotein CD47 and its receptor signal regulatory protein alpha (SIRPα) are suggested to regulate bone cell differentiation. In the present study, we investigated osteoblastic differentiation of bone marrow stromal cells from SIRPα mutant mice lacking the cytoplasmic signaling domain of SIRPα. Moreover, we compared downstream signaling events of SIRPα in wild-type and CD47-deficient mouse bone marrow stromal cells. SIRPα-mutant stromal cells showed significantly less expression of Runx2, Sp7 (osterix), Bglap (osteocalcin), and Akp1 (alkaline phosphatase) mRNA compared to stromal cells from wild-type mice. An impaired osteoblastogenesis in SIRPα-mutant cell cultures was demonstrated by lower alkaline phosphatase activity and less mineral formation compared to wild-type cultures. Western blot analyses showed that CD47 expression was required for Src homology-2 domain containing protein tyrosine phosphatase- 2 (SHP-2) to associate with SIRPa. As a result, SHP-2 and Akt2 in stromal cells from CD47 deficient mice were less phosphorylated, as compared to that in wild-type stromal cells. In conclusion, we here show that CD47-dependent SIRPα signaling through SHP-2–PI3K–Akt2 strongly influences osteogenic differentiation of bone marrow stromal cells.

  • 11.
    Koskinen, Cecilia
    et al.
    Umeå University, Faculty of Medicine, Department of Odontology.
    Persson, Emelie
    Umeå University, Faculty of Medicine, Department of Odontology.
    Baldock, Paul
    Stenberg, Åsa
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Histology and Cell Biology.
    Boström, Ingrid
    Umeå University, Faculty of Medicine, Department of Odontology.
    Matozaki, Takashi
    Oldenborg, Per-Arne
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Histology and Cell Biology.
    Lundberg, Pernilla
    Umeå University, Faculty of Medicine, Department of Odontology.
    Lack of CD47 impairs bone cell differentiation and results in an osteopenic phenotype in vivo due to impaired signal regulatory protein α (SIRPα) signaling2013In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 288, no 41, p. 29333-29344Article in journal (Refereed)
    Abstract [en]

    Here, we investigated whether the cell surface glycoprotein CD47 was required for normal formation of osteoblasts and osteoclasts and to maintain normal bone formation activity in vitro and in vivo. In parathyroid hormone or 1α,25(OH)2-vitamin D3 (D3)-stimulated bone marrow cultures (BMC) from CD47(-/-) mice, we found a strongly reduced formation of multinuclear tartrate-resistant acid phosphatase (TRAP)(+) osteoclasts, associated with reduced expression of osteoclastogenic genes (nfatc1, Oscar, Trap/Acp, ctr, catK, and dc-stamp). The production of M-CSF and RANKL (receptor activator of nuclear factor κβ ligand) was reduced in CD47(-/-) BMC, as compared with CD47(+/+) BMC. The stromal cell phenotype in CD47(-/-) BMC involved a blunted expression of the osteoblast-associated genes osterix, Alp/Akp1, and α-1-collagen, and reduced mineral deposition, as compared with that in CD47(+/+) BMC. CD47 is a ligand for SIRPα (signal regulatory protein α), which showed strongly reduced tyrosine phosphorylation in CD47(-/-) bone marrow stromal cells. In addition, stromal cells lacking the signaling SIRPα cytoplasmic domain also had a defect in osteogenic differentiation, and both CD47(-/-) and non-signaling SIRPα mutant stromal cells showed a markedly reduced ability to support osteoclastogenesis in wild-type bone marrow macrophages, demonstrating that CD47-induced SIRPα signaling is critical for stromal cell support of osteoclast formation. In vivo, femoral bones of 18- or 28-week-old CD47(-/-) mice showed significantly reduced osteoclast and osteoblast numbers and exhibited an osteopenic bone phenotype. In conclusion, lack of CD47 strongly impairs SIRPα-dependent osteoblast differentiation, deteriorate bone formation, and cause reduced formation of osteoclasts.

  • 12.
    Koskinen, Cecilia
    et al.
    Umeå University, Faculty of Medicine, Department of Odontology, Molecular Periodontology.
    Persson, Emma
    Umeå University, Faculty of Medicine, Department of Radiation Sciences, Oncology.
    Baldock, P.
    Garvan Institute of Medical Research, Darlinghurst, New South Wales.
    Oldenborg, Per-Arne
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Histology and Cell Biology.
    Lundberg, Pernilla
    Umeå University, Faculty of Medicine, Department of Odontology, Molecular Periodontology.
    Lack of CD47 leads to impaired bone cell differentiation and results in an osteopenic bone phenotype2012In: Bone, ISSN 8756-3282, E-ISSN 1873-2763, Vol. 50, no Supplement 1, p. S42-S43Article in journal (Refereed)
  • 13.
    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.

  • 14.
    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)
  • 15.
    Lundberg, Pernilla
    et al.
    Umeå University, Faculty of Medicine, Odontology, Oral Cell Biology.
    Allison, SJ
    Lee, NJ
    Baldock, PA
    Brouard, N
    Rost, S
    Enriquez, RF
    Sainsbury, A
    Lamghari, M
    Simmons, P
    Eisman, JA
    Gardiner, EM
    Herzog, H
    Greater bone formation of Y2 knockout mice is associated with increased osteoprogenitor numbers and altered Y1 receptor expression.2007In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 282, no 26, p. 19082-19091Article in journal (Refereed)
    Abstract [en]

    Germ line or hypothalamus-specific deletion of Y2 receptors in mice results in a doubling of trabecular bone volume. However, the specific mechanism by which deletion of Y2 receptors increases bone mass has not yet been identified. Here we show that cultured adherent bone marrow stromal cells from Y2(-/-) mice also demonstrate increased mineralization in vitro. Isolation of two populations of progenitor cell types, an immature mesenchymal stem cell population and a more highly differentiated population of progenitor cells, revealed a greater number of the progenitor cells within the bone of Y2(-/-) mice. Analysis of Y receptor transcripts in cultured stromal cells from wild-type mice revealed high levels of Y1 but not Y2, Y4, Y5, or y6 receptor mRNA. Interestingly, germ line Y2 receptor deletion causes Y1 receptor down-regulation in stromal cells and bone tissue possibly due to the lack of feedback inhibition of NPY release and subsequent overstimulation of Y1 receptors. Furthermore, deletion of Y1 receptors resulted in increased bone mineral density in mice. Together, these findings indicate that the greater number of mesenchymal progenitors and the altered Y1 receptor expression within bone cells in the absence of Y2 receptors are a likely mechanism for the greater bone mineralization in vivo and in vitro, opening up potential new treatment avenues for osteoporosis.

  • 16.
    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.

  • 17.
    Lundberg, Pernilla
    et al.
    Umeå University, Faculty of Medicine, Odontology, Oral Cell Biology.
    Morhed-Hultvall, ML
    Twetman, Svante
    Mutans streptococci colonization and longitudinal caries detection with laser fluorescence in fissures of newly erupted 1st permanent molars.2007In: Acta Odontologica Scandinavica, ISSN 0001-6357, E-ISSN 1502-3850, Vol. 65, no 4, p. 189-193Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: To longitudinally apply a laser fluorescence (LF) device (DIAGNOdent) in newly erupted 1st permanent molars over a 3-year period and to relate the findings to mutans streptococci (MS) colonization, fissure morphology, and caries development. MATERIAL AND METHODS: The material consisted of 101 consecutive 5 to 6-year-old children attending a Public Dental Clinic and who volunteered after ethical approval and informed consent had been given. Only fully erupted molars with clinically sound fissures were included. At baseline, the fissures were subjectively categorized as "shallow" or "deep", and, prior to the LF readings, a plaque sample was collected and cultivated for MS using a chair-side kit. The registrations were repeated annually and the microbial samplings after 2 years. The total drop-out rate was 12%. RESULTS: The mean LF values increased significantly (p<0.05) with increasing age from 8.2 to 12.4 in the teeth that remained sound. Thirty-five teeth were decayed or filled during the follow-up and their mean LF values increased from 13.4 to 40.7. The LF readings were significantly higher in molars with "deep" fissures (p<0.05) at all visits. MS colonization at baseline was associated with an increased risk for caries (OR = 11.6, p<0.05) and significantly elevated LF readings. Baseline LF readings > or =12 were not diagnostic for dentin caries or fillings over the study period (sensitivity 0.57; specificity 0.86). CONCLUSION: LF readings could be used to some extent to monitor fissure morphology and caries development in fissures of newly permanent molars over time, but elevated initial values were not predictive for caries development.

  • 18.
    Palmqvist, Py
    et al.
    Umeå University, Faculty of Medicine, Odontology, Oral Cell Biology.
    Lundberg, Pernilla
    Umeå University, Faculty of Medicine, Odontology, Oral Cell Biology.
    Lundgren, Inger
    Umeå University, Faculty of Medicine, Odontology, Oral Cell Biology.
    Hänström, Lennart
    Umeå University, Faculty of Medicine, Odontology, Periodontology.
    Lerner, Ulf
    Umeå University, Faculty of Medicine, Odontology, Oral Cell Biology.
    IL-1beta and TNF-alpha regulate IL-6-type cytokines in gingival fibroblasts.2008In: Journal of Dental Research, ISSN 0022-0345, E-ISSN 1544-0591, Vol. 87, no 6, p. 558-563Article in journal (Refereed)
    Abstract [en]

    Interleukin-6 (IL-6)-type cytokines are pleiotropic molecules capable of stimulating bone resorption and expressed by numerous cell types. In the present study, we tested the hypothesis that gingival fibroblasts may exert local osteotropic effects through production of IL-6 and related cytokines. IL-6-type cytokine expression and regulation by IL-1beta and tumor necrosis factor-alpha (TNF-alpha) were studied in fibroblasts from the non-inflamed gingiva of healthy individuals. Constitutive mRNA expression of IL-6, IL-11, and leukemia inhibitory factor (LIF), but not of oncostatin M (OSM), was demonstrated, as was concentration-dependent stimulation of IL-6 and LIF mRNA and of protein by IL-1beta and TNF-alpha. IL-11 mRNA and protein were concentration-dependently stimulated by IL-1beta. The signaling pathway involved in IL-6 and LIF mRNA stimulation involved MAP kinases, but not NF-kappaB. The findings support the view that resident cells may influence the pathogenesis of periodontal disease through osteotropic IL-6-type cytokine production mediated by activation of MAP kinases. Abbreviations: IL-1alpha (interleukin-1alpha); IL-1beta (interleukin-1beta); IL-6 (interleukin-6); IL-11 (interleukin-11); LIF (leukemia inhibitory factor); OSM (oncostatin M); alpha(1)-coll. I (alpha(1)-collagen I); ALP (alkaline phosphatase); BMP-2 (bone morphogenetic protein-2); OC (osteocalcin); BSP (bone sialoprotein); TNFR I (tumor necrosis factor receptor I); TNFR II (tumor necrosis factor receptor II); IL-1R1 (interleukin-1 receptor 1); GAPDH (glyceraldehyde-3-phosphate dehydrogenase); RPL13A (ribosomal protein L13A); mRNA (messenger ribonucleic acid); cDNA (complementary deoxyribonucleic acid); PCR (polymerase chain-reaction); BCA (bicinchoninic acid); ELISA (enzyme-linked immunosorbent assay); alpha-MEM (alpha modification of Minimum Essential Medium); and FCS (fetal calf serum).

  • 19.
    Shungin, Dmitry
    et al.
    Umeå University, Faculty of Medicine, Department of Odontology. Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine. Genetic and Molecular Epidemiology Unit, Department of Clinical Sciences, Skåne University Hospital, Lund University.
    Cornelis, Marilyn C.
    Divaris, Kimon
    Holtfreter, Birte
    Shaffer, John R.
    Yu, Yau-Hua
    Barros, Silvana P.
    Beck, James D.
    Biffar, Reiner
    Boerwinkle, Eric A.
    Crout, Richard J.
    Ganna, Andrea
    Hallmans, Göran
    Umeå University, Faculty of Medicine, Department of Biobank Research. Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Nutritional Research.
    Hindy, George
    Hu, Frank B.
    Kraft, Peter
    McNeil, Daniel W.
    Melander, Olle
    Moss, Kevin L.
    North, Kari E.
    Orho-Melander, Marju
    Pedersen, Nancy L.
    Ridker, Paul M.
    Rimm, Eric B.
    Rose, Lynda M.
    Rukh, Gull
    Teumer, Alexander
    Weyant, Robert J.
    Chasman, Daniel I.
    Joshipura, Kaumudi
    Kocher, Thomas
    Magnusson, Patrik K. E.
    Marazita, Mary L.
    Nilsson, Peter
    Offenbacher, Steve
    Smith, George Davey
    Lundberg, Pernilla
    Umeå University, Faculty of Medicine, Department of Odontology.
    Palmer, Tom M.
    Timpson, Nicholas J.
    Johansson, Ingegerd
    Umeå University, Faculty of Medicine, Department of Odontology. Umeå University, Faculty of Medicine, Department of Biobank Research.
    Franks, Paul W.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine. Genetic and Molecular Epidemiology Unit, Department of Clinical Sciences, Skåne University Hospital, Lund University; Department of Nutrition, Harvard School of Public Health, Boston, MA, USA.
    Using genetics to test the causal relationship of total adiposity and periodontitis: Mendelian randomization analyses in the Gene-Lifestyle Interactions and Dental Endpoints (GLIDE) Consortium2015In: International Journal of Epidemiology, ISSN 0300-5771, E-ISSN 1464-3685, Vol. 44, no 2, p. 638-650Article in journal (Refereed)
    Abstract [en]

    Background: The observational relationship between obesity and periodontitis is widely known, yet causal evidence is lacking. Our objective was to investigate causal associations between periodontitis and body mass index (BMI). Methods: We performed Mendelian randomization analyses with BMI-associated loci combined in a genetic risk score (GRS) as the instrument for BMI. All analyses were conducted within the Gene-Lifestyle Interactions and Dental Endpoints (GLIDE) Consortium in 13 studies from Europe and the USA, including 49 066 participants with clinically assessed (seven studies, 42.1% of participants) and self-reported (six studies, 57.9% of participants) periodontitis and genotype data (17 672/31 394 with/without periodontitis); 68 761 participants with BMI and genotype data; and 57 871 participants (18 881/38 990 with/without periodontitis) with data on BMI and periodontitis. Results: In the observational meta-analysis of all participants, the pooled crude observational odds ratio (OR) for periodontitis was 1.13 [95% confidence interval (CI): 1.03, 1.24] per standard deviation increase of BMI. Controlling for potential confounders attenuated this estimate (OR = 1.08; 95% CI: 1.03, 1.12). For clinically assessed periodontitis, corresponding ORs were 1.25 (95% CI: 1.10, 1.42) and 1.13 (95% CI: 1.10, 1.17), respectively. In the genetic association meta-analysis, the OR for periodontitis was 1.01 (95% CI: 0.99, 1.03) per GRS unit (per one effect allele) in all participants and 1.00 (95% CI: 0.97, 1.03) in participants with clinically assessed periodontitis. The instrumental variable meta-analysis of all participants yielded an OR of 1.05 (95% CI: 0.80, 1.38) per BMI standard deviation, and 0.90 (95% CI: 0.56, 1.46) in participants with clinical data. Conclusions: Our study does not support total adiposity as a causal risk factor for periodontitis, as the point estimate is very close to the null in the causal inference analysis, with wide confidence intervals.

  • 20.
    Souza, P. P. C.
    et al.
    Umeå University, Faculty of Medicine, Department of Odontology.
    Brechter, A. B.
    Reis, R. I.
    Costa, C. A. S.
    Lundberg, Pernilla
    Umeå University, Faculty of Medicine, Department of Odontology.
    Lerner, U. H.
    Umeå University, Faculty of Medicine, Department of Odontology.
    IL-4 and IL-13 inhibit IL-1 beta and TNF-alpha induced kinin B-1 and B-2 receptors through a STAT6-dependent mechanism2013In: British Journal of Pharmacology, ISSN 0007-1188, E-ISSN 1476-5381, Vol. 169, no 2, p. 400-412Article in journal (Refereed)
    Abstract [en]

    Background and Purpose Bone resorption induced by interleukin-1 (IL-1) and tumour necrosis factor (TNF-) is synergistically potentiated by kinins, partially due to enhanced kinin receptor expression. Inflammation-induced bone resorption can be impaired by IL-4 and IL-13. The aim was to investigate if expression of B1 and B2 kinin receptors can be affected by IL-4 and IL-13. Experimental Approach We examined effects in a human osteoblastic cell line (MG-63), primary human gingival fibroblasts and mouse bones by IL-4 and IL-13 on mRNA and protein expression of the B1 and B2 kinin receptors. We also examined the role of STAT6 by RNA interference and using Stat6-/- mice. Key Results IL-4 and IL-13 decreased the mRNA expression of B1 and B2 kinin receptors induced by either IL-1 or TNF- in MG-63 cells, intact mouse calvarial bones or primary human gingival fibroblasts. The burst of intracellular calcium induced by either bradykinin (B2 agonist) or des-Arg10-Lys-bradykinin (B1 agonist) in gingival fibroblasts pretreated with IL-1 was impaired by IL-4. Similarly, the increased binding of B1 and B2 ligands induced by IL-1 was decreased by IL-4. In calvarial bones from Stat6-deficient mice, and in fibroblasts in which STAT6 was knocked down by siRNA, the effect of IL-4 was decreased. Conclusions and Implications These data show, for the first time, that IL-4 and IL-13 decrease kinin receptors in a STAT6-dependent mechanism, which can be one important mechanism by which these cytokines exert their anti-inflammatory effects and impair bone resorption.

  • 21.
    Souza, Pedro P. C.
    et al.
    Department of Physiology and Pathology, Araraquara School of Dentistry, Sao Paulo State University, Araraquara, Brazil.
    Palmqvist, Py
    Umeå University, Faculty of Medicine, Department of Odontology, Molecular Periodontology.
    Lundberg, Pernilla
    Umeå University, Faculty of Medicine, Department of Odontology, Molecular Periodontology.
    Lundgren, Inger
    Umeå University, Faculty of Medicine, Department of Odontology, Molecular Periodontology.
    Hänström, Lennart
    Umeå University, Faculty of Medicine, Department of Odontology, Molecular Periodontology.
    Souza, Joao A. C.
    Umeå University, Faculty of Medicine, Department of Odontology, Molecular Periodontology.
    Conaway, H. Herschel
    Department of Physiology and Biophysics, University of Arkansas for Medical Sciences, Little Rock, AR 72205, United States.
    Lerner, Ulf H.
    Umeå University, Faculty of Medicine, Department of Odontology, Molecular Periodontology.
    Interleukin-4 and interleukin-13 inhibit the expression of leukemia inhibitory factor and interleukin-11 in fibroblasts2012In: Molecular Immunology, ISSN 0161-5890, E-ISSN 1872-9142, Vol. 49, no 4, p. 601-610Article in journal (Refereed)
    Abstract [en]

    Cytokines produced by inflammatory or resident mesenchymal cells play important modulatory roles in the pathogenesis of inflammation induced bone loss. In the present study, the effects of IL-4 and IL-13 on the expression of three osteotropic cytokines in the IL-6 family expressed in human gingival fibroblasts were studied. IL-4R alpha and IL-13R alpha 1 mRNA were constitutively expressed in human gingival fibroblasts. The inflammatory cytokines IL-1 beta and TNF-alpha increased expression of IL-5, LIF, and IL-11 mRNA and protein in the gingival fibroblasts. Addition of IL-4 or IL-13 had no effect on IL-6 expression, but significantly inhibited LIF and IL-11 mRNA and protein stimulated by IL-1 beta and TNF-alpha. No involvement of NF-kappa B or STAT1 was observed in the inhibition. STAT6 was phosphorylated at Y641 by treatment with IL-4 and knockdown of STAT6 with siRNA decreased the inhibition of IL-11 and LIF expression by IL-4 in IL-1 beta and TNF-alpha stimulated cells. This study suggests that activation of STAT6 by IL-4 and IL-13, through type 2 IL-4 receptors, inhibits production of IL-11 and LIF stimulated by IL-1 beta and TNF-alpha in human gingival fibroblasts. A negative modulatory role of IL-4 and IL-13 in osteotropic cytokine production could be a mechanism playing an important inhibitory role in inflammation induced periodontitis. (C) 2011 Elsevier Ltd. All rights reserved.

  • 22.
    Souza, PPC
    et al.
    University of Sao Paulo.
    Palmqvist, Py
    Umeå University, Faculty of Medicine, Department of Odontology, Oral Cell Biology.
    Lundgren, Inger
    Umeå University, Faculty of Medicine, Department of Odontology, Oral Cell Biology.
    Lie, Anita
    Umeå University, Faculty of Medicine, Department of Odontology, Oral Cell Biology.
    Costa-Neto, CM
    Lundberg, Pernilla
    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.
    Stimulation of IL-6 cytokines in fibroblasts by toll-like receptors 22010In: Journal of Dental Research, ISSN 0022-0345, E-ISSN 1544-0591, Vol. 89, no 8, p. 802-807Article in journal (Refereed)
    Abstract [en]

    The osteotropic interleukin-6 (IL-6) types of cytokines IL-6, IL-11, and leukemia inhibitory factor (LIF), but not oncostatin M, are expressed by human gingival fibroblasts, and their expressions are regulated by IL-1 and tumor necrosis factor-alpha (TNF-alpha). In the present study, we investigated whether signaling through Toll-like receptor 2 (TLR2) can affect the expression of these cytokines in human gingival fibroblasts. Lipopolysac-charide (LPS) from P. gingivalis was found to stimulate IL-6 and LIF mRNA and protein, but not IL-11 or OSM mRNA. Using two synthetic ligands acting specifically at TLR2 and siRNA knockdown of TLR2, we demonstrated the important role of TLR2 in the stimulation of IL-6 and LIF in gingival fibroblasts. Analysis of these data suggests that signaling through the innate immune system controls the expression of osteotropic cytokines in human gingival fibroblasts.

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