Immune complexes regulate bone metabolism through FcRγ signalling

Negishi-Koga, Takako; Gober, Hans Jürgen; Sumiya, Eriko; Komatsu, Noriko; Okamoto, Kazuo; Sawa, Shinichiro; Suematsu, Ayako; Suda, Tomomi; Sato, Kojiro; Takai, Toshiyuki; Takayanagi, Hiroshi

doi:10.1038/ncomms7637

Cited by 110 publications

(122 citation statements)

References 51 publications

(84 reference statements)

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“…Previous studies show that ligation of activating Fcγ receptors by immune complexes can generate either negative or positive effects on osteoclastogenesis (Grevers et al, 2013; Negishi-Koga et al, 2015; Seeling et al, 2013). Although the contribution of Fcγ receptors to bone erosion during inflammatory arthritis varies among different models of arthritis (Negishi-Koga et al, 2015; Seeling et al, 2013; van Lent et al, 2006), it has been shown that serum of arthritic mice containing pathological immune complexes directly promotes in vitro osteoclastogenesis (Negishi-Koga et al, 2015), suggesting the diverse function of IgGs in bone metabolism.…”

Section: Discussionmentioning

confidence: 99%

Intravenous Immunoglobulin (IVIG) Attenuates TNF‐Induced Pathologic Bone Resorption and Suppresses Osteoclastogenesis by Inducing A20 Expression

Lee

Lim

Mun

et al. 2015

Journal Cellular Physiology

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Investigations on the therapeutic effects of intravenous immunoglobulin (IVIG) have focused on the suppression of autoantibody- and immune complex-mediated inflammatory pathogenesis. Inflammatory diseases such as rheumatoid arthritis are often accompanied by excessive bone erosion but the effect of IVIG on osteoclasts, bone-resorbing cells, has not been studied. Here, we investigate whether IVIG directly regulates osteoclast differentiation and has therapeutic potential for suppressing osteoclast-mediated pathologic bone resorption. IVIG or cross-linking of Fcγ receptors with plate-bound IgG suppressed receptor activator of nuclear factor-kappa B ligand (RANKL)-induced osteoclastogenesis and expression of osteoclast-related genes such as integrin β3 and cathepsin K in a dose-dependent manner. Mechanistically, IVIG or plate-bound IgG suppressed osteoclastogenesis by downregulating RANKL-induced expression of NFATC1, the master regulator of osteoclastogenesis. IVIG suppressed NFATC1 expression by attenuating RANKL-induced NF-κB signaling, explained in part by induction of the inflammatory signaling inhibitor A20. IVIG administration attenuated in vivo osteoclastogenesis and suppressed bone resorption in the tumor necrosis factor (TNF)-induced calvarial osteolysis model. Our findings show that, in addition to suppressing inflammation, IVIG directly inhibits osteoclastogenesis through a mechanism involving suppression of RANK signaling. Direct suppression of osteoclast differentiation may provide beneficial effects on preserving bone mass when IVIG is used to treat rheumatic disorders.

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Section: Discussionmentioning

confidence: 99%

Intravenous Immunoglobulin (IVIG) Attenuates TNF‐Induced Pathologic Bone Resorption and Suppresses Osteoclastogenesis by Inducing A20 Expression

Lee

Lim

Mun

et al. 2015

Journal Cellular Physiology

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“…Establishment and maintenance of inflammation is driven by neutrophils via activating Fc-receptors through activated complement components C3a and C5a (Figure 9). More recently, several studies have documented a critical role for Fc-receptors in the process of bone destruction (440–443). Consistent with the essential role of neutrophils and activating FcγRs in disease pathology, Syk or PLCg-deficient mice or animals with a neutrophil-specific deletion of Syk were protected from arthritis development (444, 445).…”

Section: Autoantibody-induced Inflammationmentioning

confidence: 99%

Mechanisms of Autoantibody-Induced Pathology

et al. 2017

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Autoantibodies are frequently observed in healthy individuals. In a minority of these individuals, they lead to manifestation of autoimmune diseases, such as rheumatoid arthritis or Graves' disease. Overall, more than 2.5% of the population is affected by autoantibody-driven autoimmune disease. Pathways leading to autoantibody-induced pathology greatly differ among different diseases, and autoantibodies directed against the same antigen, depending on the targeted epitope, can have diverse effects. To foster knowledge in autoantibody-induced pathology and to encourage development of urgently needed novel therapeutic strategies, we here categorized autoantibodies according to their effects. According to our algorithm, autoantibodies can be classified into the following categories: (1) mimic receptor stimulation, (2) blocking of neural transmission, (3) induction of altered signaling, triggering uncontrolled (4) microthrombosis, (5) cell lysis, (6) neutrophil activation, and (7) induction of inflammation. These mechanisms in relation to disease, as well as principles of autoantibody generation and detection, are reviewed herein.

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“…Under basal conditions, osteoclast precursors express FcγRIIB and FcγRIII (64). FcγRIII is well known to respond to immune complexes during infections.…”

Section: Fcgamma Associated Receptorsmentioning

confidence: 99%

A Comprehensive Review of Immunoreceptor Regulation of Osteoclasts

Humphrey

Nakamura

2015

Clinic Rev Allerg Immunol

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Osteoclasts require coordinated co-stimulation by several signaling pathways to initiate and regulate their cellular differentiation. RANKL (Receptor Activator for NFkB ligand or TNFSF25), a TNF (tumor necrosis factor) superfamily member, is the master cytokine required for osteoclastogenesis with essential co-stimulatory signals mediated by ITAM (immunoreceptor tyrosine-based activation motif)-signaling adaptors, DAP12 (DNAX associated protein 12kD size) and FcRγ (FcεR1 gamma chain). The ITAM-signaling adaptors do not have an extracellular ligand-binding domain, and therefore must pair with ligand-binding immunoreceptors to interact with their extracellular environment. DAP12 pairs with a number of different immunoreceptors including TREM-2 (Triggering Receptor Expressed on Myeloid Cells 2), MDL-1 (Myeloid Dap-12 associated Lectin) and Siglec-15 (Sialic acid-binding immunoglobulin-type lectin15), while FcRγ pairs with a different set of receptors including OSCAR (Osteoclast Specific Activating Receptor), PIR-A (Paired Immunoglobulin Receptor A), and Fc Receptors. The ligands for many of these receptor in the bone microenvironment remain unknown. Here we will review immunoreceptors known to pair with either DAP12 or FcRγ that have been shown to regulate osteoclastogenesis, However, co-stimulation and the effects of ITAM-signaling have turned out to be complex including paradoxical findings that ITAM-signaling adaptor-associated receptors can inhibit osteoclastogenesis and ITIM (immunoreceptor tyrosine-based inhibitory motif) receptors can promote osteoclastogenesis. Thus, co-stimulation of osteoclastogenesis continues to reveal additional complexities that are important in the regulatory mechanisms that seek to maintain bone homeostasis.

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Immune complexes regulate bone metabolism through FcRγ signalling

Cited by 110 publications

References 51 publications

Intravenous Immunoglobulin (IVIG) Attenuates TNF‐Induced Pathologic Bone Resorption and Suppresses Osteoclastogenesis by Inducing A20 Expression

Intravenous Immunoglobulin (IVIG) Attenuates TNF‐Induced Pathologic Bone Resorption and Suppresses Osteoclastogenesis by Inducing A20 Expression

Mechanisms of Autoantibody-Induced Pathology

A Comprehensive Review of Immunoreceptor Regulation of Osteoclasts

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