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      RANTES and fibroblast growth factor 2 in jawbone cavitations: triggers for systemic disease?

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          Abstract

          Background

          Jawbone cavitations (JC) are hollow dead spaces in jawbones with dying or dead bone marrow. These areas are defined as fatty degenerative osteonecrosis of the jawbone or neuralgia-inducing cavitational osteonecrosis and may produce facial pain. These afflictions have been linked to the immune system and chronic illnesses. Surgical debridement of JC is reported to lead to an improvement in immunological complaints, such as rheumatic, allergic, and other inflammatory diseases (ID). Little is known about the underlying cause/effect relationship.

          Objectives

          JC bone samples were analyzed to assess the expression and quantification of immune modulators that can play a role in the pathogenesis of IDs. The study supports a potential mechanism where JC is a mediating link in IDs.

          Materials and methods

          Samples of fatty softened bone taken from JCs were extracted from 31 patients. The specimens were analyzed by bead-based multiplex technology and tested for seven immune messengers.

          Results

          Regulated upon activation, normal T-cell expressed, and secreted (RANTES) and fibroblast growth factor (FGF)-2 were found at high levels in the JCs tested. Other cytokines could not be detected at excessive levels.

          Discussion

          The study confirms that JC is able to produce inflammatory messengers, primarily RANTES, and, secondarily, FGF-2. Both are implicated in many serious illnesses. The excessive levels of RANTES/FGF-2 in JC patients with amyotrophic lateral sclerosis, multiple sclerosis, rheumatoid arthritis, and breast cancer are compared to levels published in medical journals. Levels detected in JCs are higher than in the serum and cerebrospinal fluid of amyotrophic lateral sclerosis and multiple sclerosis patients and four-fold higher than in breast cancer tissue.

          Conclusion

          This study suggests that JC might serve as a fundamental cause of IDs, through RANTES/FGF-2 production. Thus, JC and implicated immune messengers represent an integrative aspect of IDs and serve as a possible cause. Removing JCs may be a key to reversing IDs. There is a need to raise awareness about JC throughout medicine and dentistry.

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          Most cited references54

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          T-lymphocyte infiltration in visceral adipose tissue: a primary event in adipose tissue inflammation and the development of obesity-mediated insulin resistance.

          Adipose tissue inflammation may play a critical role in the pathogenesis of insulin resistance (IR). The present study examined the role of lymphocytes in adipose tissue inflammation and IR. In a mouse model of obesity-mediated IR, high-fat diet (HFD) induced IR already after 5 weeks, which was associated with a marked T-lymphocyte infiltration in visceral adipose tissue. In contrast, recruitment of macrophages was delayed with an increase of MAC3-positive staining and F4/80 mRNA expression after 10 weeks of HFD, suggesting a dissociation of macrophage invasion into adipose tissue and IR initiation. In patients with type 2 diabetes, lymphocyte content in adipose tissue biopsies significantly correlated with waist circumference, a marker of IR. Immunohistochemical staining of human adipose tissue revealed the presence of mainly CD4-positive lymphocytes as well as macrophage infiltration. Most macrophages were HLA-DR-positive, reflecting activation through IFNgamma, a cytokine released from CD4-positive lymphocytes. Proinflammatory T-lymphocytes are present in visceral adipose tissue and may contribute to local inflammatory cell activation before the appearance of macrophages, suggesting that these cells could play an important role in the initiation and perpetuation of adipose tissue inflammation as well as the development of IR.
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            CC chemokine and CC chemokine receptor profiles in visceral and subcutaneous adipose tissue are altered in human obesity.

            Obesity is associated with a low-grade inflammation, insulin resistance, and macrophage infiltration of adipose tissue. The role of CC chemokines and their respective receptors in human adipose tissue inflammation remains to be determined. sc and visceral adipose tissue of obese patients (body mass index 53.1 +/- 11.3 kg/m(2)) compared with lean controls (body mass index 25.9 +/- 3.8 kg/m(2)) was analyzed for alterations in inflammatory gene expression. Macrophage infiltration was increased in sc and visceral adipose tissue of obese patients as determined by increased mRNA expression of a macrophage-specific marker (CD68) and by elevated macrophage infiltration. Gene expression of CC chemokines involved in monocyte chemotaxis (CCL2, CCL3, CCL5, CCL7, CCL8, and CCL11) and their receptors (CCR1, CCR2, CCR3, and CCR5) was higher in sc and visceral adipose tissue of obese patients. Serum concentrations of the inflammatory marker IL-6 and C-reactive protein were elevated in obese patients compared with lean controls. Obese patients revealed increased insulin resistance as assessed by the homeostasis model assessment of insulin resistance index and reduced plasma adiponectin concentrations. Adipose tissue expression of many CC chemokines and their receptors in the obese group positively correlated with CD68 expression. Up-regulation of the CC chemokines and their respective receptors in adipose tissue occurs in human obesity and is associated with increased systemic inflammation.
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              The balance between IL-1 and IL-1Ra in disease.

              IL-1 is an important mediator of inflammation and tissue damage in multiple organs, both in experimental animal models of disease and in human diseases. The IL-1 family consists of two agonists, IL-1alpha and IL-1beta, two receptors, biologically active IL-1RI and inert IL-1RII, and a specific receptor antagonist, IL-1Ra. The balance between IL-1 and IL-1Ra in local tissues plays an important role in the susceptibility to and severity of many diseases. An allelic polymorphism in the IL-1Ra gene has been associated with a variety of human diseases primarily of epithelial and endothelial cell origin. This association may be secondary to an imbalance in the IL-1 system with enhanced production of IL-1beta and reduced production of the major intracellular isoform of IL-1Ra. Treatment of RA with daily subcutaneous injections of recombinant IL-1Ra protein has been shown to be efficacious. Gene therapy approaches with IL-1Ra are being evaluated for the treatment of RA and other human diseases.
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                Author and article information

                Journal
                Int J Gen Med
                Int J Gen Med
                International Journal of General Medicine
                Dove Medical Press
                1178-7074
                2013
                22 April 2013
                : 6
                : 277-290
                Affiliations
                [1 ]Clinic for Integrative Dentistry, Munich, Germany
                [2 ]Compartment of Immunology and Allergology on Institute for Medical Diagnostics in MVZ GbR, Berlin, Germany
                Author notes
                Correspondence: Johann Lechner, Clinic for Integrative Dentistry, Gruenwalder Str 10A, 81547 Munich, Germany Tel +49 89 697 00 55 Fax +49 89 692 58 30 Email drlechner@ 123456aol.com
                Article
                ijgm-6-277
                10.2147/IJGM.S43852
                3636973
                23637551
                9a23ae09-4de0-4b46-b43f-13b5e4840522
                © 2013 Lechner and von Baehr, publisher and licensee Dove Medical Press Ltd

                This is an Open Access article which permits unrestricted noncommercial use, provided the original work is properly cited.

                History
                Categories
                Original Research

                Medicine
                rantes,ccl5,fibroblast growth factor,fgf-2,bead-based luminex analysis,osteolytic degenerated jaw bone,nico,systemic signaling pathways

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