Limits...
Interaction between the immune system and bone metabolism: an emerging field of osteoimmunology.

Takayanagi H - Proc. Jpn. Acad., Ser. B, Phys. Biol. Sci. (2007)

Bottom Line: In addition, the immune cells are maintained in the bone marrow, which provides a space for mutual interaction.Thus, bone turns out to be a dynamic tissue that is constantly renewed, where the immune system participates to a hitherto unexpected extent.This emerging field of osteoimmunology will be of great importance not only to the better understanding of the two systems but also to the development of new treatment for rheumatic diseases.

View Article: PubMed Central - PubMed

Affiliation: Department of Cell Signaling, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan . ; Center of Excellence Program for Frontier Research on Molecular Destruction and Reconstruction of Tooth and Bone, Tokyo Medical and Dental University, Tokyo, Japan .

ABSTRACT
The interaction between the immune and bone systems has long been appreciated, but recent research into arthritis as well as various bone phenotypes found in immune-related knockout mice has highlighted the importance of the interplay and the interdisciplinary field called osteoimmunology. In rheumatoid arthritis, IL-17-producing helper T cells (TH17) induces receptor activator of NF-κB ligand (RANKL), which stimulates osteoclast differentiation through nuclear factor of activated T cells (NFAT)c1. Accumulating evidence suggests that the immune and skeletal systems share cytokines, signaling molecules, transcription factors and membrane receptors. In addition, the immune cells are maintained in the bone marrow, which provides a space for mutual interaction. Thus, bone turns out to be a dynamic tissue that is constantly renewed, where the immune system participates to a hitherto unexpected extent. This emerging field of osteoimmunology will be of great importance not only to the better understanding of the two systems but also to the development of new treatment for rheumatic diseases.

No MeSH data available.


Related in: MedlinePlus

Mechanism of bone destruction in autoimmune arthritis.In rheumatoid arthritis, inflammatory synovium invades and destroys bone, which is mediated by osteoclasts induced by receptor activator of nuclear factor-κB (NF-κB) ligand (RANKL). CD4+ T-cell infiltration, a hallmark of the pathogenesis of arthritis, link the abnormal immune responses to the activation of osteoclastic bone resorption. Interleukin (IL)-17-producing helper T (TH17) cells are the only osteoclastogenic TH-cell (THOc) subset characterized so far. TH17 cells do not produce interferon (IFN)-γ, which suppresses RANKL signaling, but secrete a huge amount of IL-17 that induces RANKL on synovial fibroblasts. IL-17 also stimulates the local inflammation and activates synovial macrophages to secrete proinflammatory cytokines such as tumour necrosis factor (TNF)-α, IL-1, and IL-6. These cytokines activate osteoclastogenesis by either directly acting on osteoclast precursor cells or inducing RANKL on synovial fibroblasts. TH17 cells also express RANKL on their membrane, which partly contributes to the enhanced osteoclastogenesis.
© Copyright Policy - open-access
Related In: Results  -  Collection


getmorefigures.php?uid=PMC3756876&req=5

f1-83_136: Mechanism of bone destruction in autoimmune arthritis.In rheumatoid arthritis, inflammatory synovium invades and destroys bone, which is mediated by osteoclasts induced by receptor activator of nuclear factor-κB (NF-κB) ligand (RANKL). CD4+ T-cell infiltration, a hallmark of the pathogenesis of arthritis, link the abnormal immune responses to the activation of osteoclastic bone resorption. Interleukin (IL)-17-producing helper T (TH17) cells are the only osteoclastogenic TH-cell (THOc) subset characterized so far. TH17 cells do not produce interferon (IFN)-γ, which suppresses RANKL signaling, but secrete a huge amount of IL-17 that induces RANKL on synovial fibroblasts. IL-17 also stimulates the local inflammation and activates synovial macrophages to secrete proinflammatory cytokines such as tumour necrosis factor (TNF)-α, IL-1, and IL-6. These cytokines activate osteoclastogenesis by either directly acting on osteoclast precursor cells or inducing RANKL on synovial fibroblasts. TH17 cells also express RANKL on their membrane, which partly contributes to the enhanced osteoclastogenesis.

Mentions: What is the pathologically important TH cell subset responsible for abnormal bone resorption? We defined this subset as osteoclastogenic TH (THOc) cells and have long worked on the identification of this population.1), 6), 35) Our previous investigations showed the osteoclastogenic T cells (i.e., THOc cells) in RA joints fulfill the characteristics as described below. First, THOc cells do not produce a large amount of IFNγ. Second, THOc cells trigger local inflammation and production of inflammatory cytokines, including TNFα, that induce RANKL expression on synovial fibroblasts. Third, THOc cells express RANKL and might directly participate in accelerated osteoclastogenesis. Because THOc cells have such osteoclastogenic characteristics, they can tip the balance in favour of osteoclastogenesis in various aspects. Although autoimmune arthritis has been traditionally categorized as a TH1-type disease, TH1 cells do not have such characteristics, indicating that the THOc cells might belong to an as-yet unknown subset. We explored the effects of various CD4+ T cell subsets on osteoclast differentiation, and identified IL-17-producing T cells (TH17 cells) as the exclusive osteoclastogenic T cell subset (THOc) among the known CD4+ T cell lineages, whereas TH1 or TH2 cells have marked antiosteoclastogenic effects.38) It has been already reported that IL-17 expression is increased in RA joints.39) IL-17 is well known to induce local inflammation in autoimmune diseases through inflammatory cytokine production.40) In addition, IL-17 induces RANKL on mesenchymal cells.39) We also showed that TH17 cells express RANKL stronger than TH1 or TH2 subsets.38) Therefore, TH17 cells represent the long-sought THOc subset fulfilling all the criteria mentioned above and link the abnormal T-cell response to bone damage in arthritis (Fig. 1). Since osteoclast-mediated bone destruction in the LPS-induced bone loss model is abolished in mice deficient in IL-17 or IL-23, it is strongly suggested that TH17 cells function as the THOc subset in bone destruction associated with inflammation.38) It will be an important issue in the near future to determine the subset of T cells in the RA joints. TH17 cells are essential for the onset phase of autoimmune arthritis,41) but these results show that they are also critical for bone destruction phase. Thus, pathogenesis of autoimmune arthritis should be reconsidered in the context of a TH17-type disease. Clearly, this subset will be an auspicious target of future therapy.


Interaction between the immune system and bone metabolism: an emerging field of osteoimmunology.

Takayanagi H - Proc. Jpn. Acad., Ser. B, Phys. Biol. Sci. (2007)

Mechanism of bone destruction in autoimmune arthritis.In rheumatoid arthritis, inflammatory synovium invades and destroys bone, which is mediated by osteoclasts induced by receptor activator of nuclear factor-κB (NF-κB) ligand (RANKL). CD4+ T-cell infiltration, a hallmark of the pathogenesis of arthritis, link the abnormal immune responses to the activation of osteoclastic bone resorption. Interleukin (IL)-17-producing helper T (TH17) cells are the only osteoclastogenic TH-cell (THOc) subset characterized so far. TH17 cells do not produce interferon (IFN)-γ, which suppresses RANKL signaling, but secrete a huge amount of IL-17 that induces RANKL on synovial fibroblasts. IL-17 also stimulates the local inflammation and activates synovial macrophages to secrete proinflammatory cytokines such as tumour necrosis factor (TNF)-α, IL-1, and IL-6. These cytokines activate osteoclastogenesis by either directly acting on osteoclast precursor cells or inducing RANKL on synovial fibroblasts. TH17 cells also express RANKL on their membrane, which partly contributes to the enhanced osteoclastogenesis.
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3756876&req=5

f1-83_136: Mechanism of bone destruction in autoimmune arthritis.In rheumatoid arthritis, inflammatory synovium invades and destroys bone, which is mediated by osteoclasts induced by receptor activator of nuclear factor-κB (NF-κB) ligand (RANKL). CD4+ T-cell infiltration, a hallmark of the pathogenesis of arthritis, link the abnormal immune responses to the activation of osteoclastic bone resorption. Interleukin (IL)-17-producing helper T (TH17) cells are the only osteoclastogenic TH-cell (THOc) subset characterized so far. TH17 cells do not produce interferon (IFN)-γ, which suppresses RANKL signaling, but secrete a huge amount of IL-17 that induces RANKL on synovial fibroblasts. IL-17 also stimulates the local inflammation and activates synovial macrophages to secrete proinflammatory cytokines such as tumour necrosis factor (TNF)-α, IL-1, and IL-6. These cytokines activate osteoclastogenesis by either directly acting on osteoclast precursor cells or inducing RANKL on synovial fibroblasts. TH17 cells also express RANKL on their membrane, which partly contributes to the enhanced osteoclastogenesis.
Mentions: What is the pathologically important TH cell subset responsible for abnormal bone resorption? We defined this subset as osteoclastogenic TH (THOc) cells and have long worked on the identification of this population.1), 6), 35) Our previous investigations showed the osteoclastogenic T cells (i.e., THOc cells) in RA joints fulfill the characteristics as described below. First, THOc cells do not produce a large amount of IFNγ. Second, THOc cells trigger local inflammation and production of inflammatory cytokines, including TNFα, that induce RANKL expression on synovial fibroblasts. Third, THOc cells express RANKL and might directly participate in accelerated osteoclastogenesis. Because THOc cells have such osteoclastogenic characteristics, they can tip the balance in favour of osteoclastogenesis in various aspects. Although autoimmune arthritis has been traditionally categorized as a TH1-type disease, TH1 cells do not have such characteristics, indicating that the THOc cells might belong to an as-yet unknown subset. We explored the effects of various CD4+ T cell subsets on osteoclast differentiation, and identified IL-17-producing T cells (TH17 cells) as the exclusive osteoclastogenic T cell subset (THOc) among the known CD4+ T cell lineages, whereas TH1 or TH2 cells have marked antiosteoclastogenic effects.38) It has been already reported that IL-17 expression is increased in RA joints.39) IL-17 is well known to induce local inflammation in autoimmune diseases through inflammatory cytokine production.40) In addition, IL-17 induces RANKL on mesenchymal cells.39) We also showed that TH17 cells express RANKL stronger than TH1 or TH2 subsets.38) Therefore, TH17 cells represent the long-sought THOc subset fulfilling all the criteria mentioned above and link the abnormal T-cell response to bone damage in arthritis (Fig. 1). Since osteoclast-mediated bone destruction in the LPS-induced bone loss model is abolished in mice deficient in IL-17 or IL-23, it is strongly suggested that TH17 cells function as the THOc subset in bone destruction associated with inflammation.38) It will be an important issue in the near future to determine the subset of T cells in the RA joints. TH17 cells are essential for the onset phase of autoimmune arthritis,41) but these results show that they are also critical for bone destruction phase. Thus, pathogenesis of autoimmune arthritis should be reconsidered in the context of a TH17-type disease. Clearly, this subset will be an auspicious target of future therapy.

Bottom Line: In addition, the immune cells are maintained in the bone marrow, which provides a space for mutual interaction.Thus, bone turns out to be a dynamic tissue that is constantly renewed, where the immune system participates to a hitherto unexpected extent.This emerging field of osteoimmunology will be of great importance not only to the better understanding of the two systems but also to the development of new treatment for rheumatic diseases.

View Article: PubMed Central - PubMed

Affiliation: Department of Cell Signaling, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan . ; Center of Excellence Program for Frontier Research on Molecular Destruction and Reconstruction of Tooth and Bone, Tokyo Medical and Dental University, Tokyo, Japan .

ABSTRACT
The interaction between the immune and bone systems has long been appreciated, but recent research into arthritis as well as various bone phenotypes found in immune-related knockout mice has highlighted the importance of the interplay and the interdisciplinary field called osteoimmunology. In rheumatoid arthritis, IL-17-producing helper T cells (TH17) induces receptor activator of NF-κB ligand (RANKL), which stimulates osteoclast differentiation through nuclear factor of activated T cells (NFAT)c1. Accumulating evidence suggests that the immune and skeletal systems share cytokines, signaling molecules, transcription factors and membrane receptors. In addition, the immune cells are maintained in the bone marrow, which provides a space for mutual interaction. Thus, bone turns out to be a dynamic tissue that is constantly renewed, where the immune system participates to a hitherto unexpected extent. This emerging field of osteoimmunology will be of great importance not only to the better understanding of the two systems but also to the development of new treatment for rheumatic diseases.

No MeSH data available.


Related in: MedlinePlus