Immune complex-induced inhibition of osteoclastogenesis is mediated via activating but not inhibitory Fcγ receptors on myeloid precursor cells

Grevers, Lilyanne C.; Vries, Teun J. de; Everts, Vincent; Verbeek, J. Sjef; Berg, Wim B. van den; Lent, P.L.E.M. van

doi:10.1136/annrheumdis-2012-201568

Cited by 37 publications

(33 citation statements)

References 52 publications

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“…This may occur because lower level Fcγ receptor activation may not reach a threshold required to generate an inhibitory signal (for example, a minimal level of A20 required to suppress signaling), or because occupancy of different Fcγ receptors may generate a qualitatively different signal. Because the inhibitory effect of IVIG on osteoclastogenesis, in part, comes from immune-complexes, our findings help to explain the discrepancy between previous studies showing that ligation of activating Fcγ receptors by immune complexes can generate either negative or positive effects on osteoclastogenesis (Grevers et al, 2013; Seeling et al, 2013). However, in the TNF-induced osteolysis model IVIG attenuated in vivo osteoclastogenesis regardless of timing of the treatment, suggesting that in this model the response to IVIG of OCPs prior to their arrival at target sites where they are exposed to RANKL plays an important role in suppression of in vivo bone destruction.…”

Section: Discussionmentioning

confidence: 65%

“…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%

“…However, the effect of immune complexes on osteoclastogenesis in inflammatory bone diseases remains controversial. While immune complexes are one of the key inducers in promoting bone resorption during inflammatory responses, immune complexes are capable of suppressing osteoclast differentiation in mouse bone marrow cells (Grevers et al, 2013; Seeling et al, 2013). Fcγ receptors play an important role in immune-complex mediated diseases, especially murine activating receptor FcγRIV, which has a prominent role in the pathogenesis of autoantibody-induced arthritis (Ji et al, 2002; Mancardi et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

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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: 65%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

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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“…multiple positive and negative receptors, the effect of IgGs varies among the different subtypes and the effect of monomeric and polymeric IgG also differs, it has been difficult to elucidate the molecular basis of IgG regulation of osteoclastogenesis despite the wealth of in vitro and in vivo observations of the involvement of FcgRs in bone metabolism 6,7,14,[6][7][8][9][10][11][12][13][14][15][16][17][18]28,29 . This study affords a detailed picture of the regulation of osteoclastogenesis by the IgG-FcgR system, in which both ligands and receptors are differentially regulated under physiological and pathological conditions, providing clear evidence for the IC-mediated regulation of bone metabolism.…”

Section: Discussionmentioning

confidence: 99%

Immune complexes regulate bone metabolism through FcRγ signalling

et al. 2015

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Autoantibody production and immune complex (IC) formation are frequently observed in autoimmune diseases associated with bone loss. However, it has been poorly understood whether ICs regulate bone metabolism directly. Here we show that the level of osteoclastogenesis is determined by the strength of FcRg signalling, which is dependent on the relative expression of positive and negative FcgRs (FcgRI/III/IV and IIB, respectively) as well as the availability of their ligands, ICs. Under physiological conditions, unexpectedly, FcgRIII inhibits osteoclastogenesis by depriving other osteoclastogenic Ig-like receptors of FcRg. Fcgr2b À / À mice lose bone upon the onset of a hypergammaglobulinemia or the administration of IgG1 ICs, which act mainly through FcgRIII. The IgG2 IC activates osteoclastogenesis by binding to FcgRI and FcgRIV, which is induced under inflammatory conditions. These results demonstrate a link between the adaptive immunity and bone, suggesting a regulatory role for ICs in bone resorption in general, and not only in inflammatory diseases.

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“…The expression level of immune activating receptors (FcγRI, FcγRIII, and FcγRIV) is lower on osteoclasts than other innate immune cells, however the expression lever of immune inhibitory receptors (FcγRII) is similar with other innate immune cells [46,47]. Most immune complex, except anti-citrullinated peptide antibodies (ACPA), inhibits osteoclast differentiation [48].…”

Section: Osteoclasts As An Immune Cellmentioning

confidence: 99%

Osteoclasts: Crucial in Rheumatoid Arthritis

Jeong

Kim

2016

J Rheum Dis

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Osteoclasts are a major component of bone metabolism in physiologic condition and in rheumatoid arthritis (RA). RA is a chronic, autoimmune, inflammatory disease primarily affecting the joints. Joint inflammation leads to cartilage and bone destruction by osteoclast activation. This osteoclast activation leads to typical RA symptoms and is the therapeutic target. Several kinds of drugs are used for preventing bone loss by osteoclasts in RA patients. However, the bone destructive action of osteoclasts is not the only mechanism in RA pathogenesis. Recent research suggests that the osteoclasts regulate hematopoietic stem cell niches and invoke immune responses in bone. Osteoclasts are derived from bone marrow hematopoietic stem cells, and maintain the hematopoietic stem cell niches contract with osteoblasts. Osteoclasts secret several cytokines to regulate inflammation and T cell differentiation, and present antigen to T cells via major histocompatibility complex class I and class II molecules. Osteoclast concepts in both origins and functions are under major reconsideration and research. In this review, we will discuss these new insights. (J Rheum Dis 2016;23:141-147)

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Immune complex-induced inhibition of osteoclastogenesis is mediated via activating but not inhibitory Fcγ receptors on myeloid precursor cells

Cited by 37 publications

References 52 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

Immune complexes regulate bone metabolism through FcRγ signalling

Osteoclasts: Crucial in Rheumatoid Arthritis

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