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Interferon-Gamma-Mediated Osteoimmunology

Mengjia Tang, Li Tian, Guojing Luo and 1 more

Frontiers in Immunology · 2018 · Review

doi:10.3389/fimmu.2018.01508

Abstract

Osteoimmunology is the interdiscipline that focuses on the relationship between the skeletal and immune systems. They are interconnected by shared signal pathways and cytokines. Interferon-gamma (IFN-γ) plays important roles in immune responses and bone metabolism. IFN-γ enhances macrophage activation and antigen presentation. It regulates antiviral and antibacterial immunity as well as signal transduction. IFN-γ can promote osteoblast differentiation and inhibit bone marrow adipocyte formation. IFN-γ plays dual role in osteoclasts depending on its stage. Furthermore, IFN-γ is an important pathogenetic factor in some immune-mediated bone diseases including rheumatoid arthritis, postmenopausal osteoporosis, and acquired immunodeficiency syndrome. This review will discuss the contradictory findings of IFN-γ in osteoimmunology and its clinical application potential.

Full text

From PubMed Central, U.S. National Library of Medicine, as current on Oct 24, 2026. Paragraph numbers are ours, so an answer can point at one.

Introduction

Osteoimmunology is the interdiscipline that focuses on the relationship between the skeletal and immune systems. In 2000, Arron and Choi first proposed the term “osteoimmunology”. Over the last 20 years, accumulating evidence has shown the involvement of the skeletal system in the process of hematoiesis and its influences in the immune system. Simultaneously, multiple immune cells and immune-derived cytokines are involved in bone homeostasis. The complex crossover between the skeletal and immune systems can also be found in various clinically relevant diseases such as osteoporosis, rheumatoid arthritis (RA), ankylosing spondylitis, human immunodeficiency virus (HIV), inflammatory bowel disease, and systemic lupus erythematosus. With a better understanding of osteoimmunology, there is higher possibility to prevent and treat immune-mediated bone diseases by targeting immune cells or immune-derived cytokines. Interferon-gamma (IFN-γ) is one of the immune-derived cytokines in the innate and adaptive immune responses. Recent studies have showed the active roles of IFN-γ in the differentiation of osteoclasts, osteoblasts, and bone marrow adipocytes. However, the effect of IFN-γ in osteoimmunology is less explored. This review will summarize current understanding in this field and discuss the clinical application value of IFN-γ in osteoimmunology.

Osteoimmunology: Interaction Between the Skeletal and Immune Systems

The immune system consists of immune organs, multiple immune cells, and immune factors, which participate in the process of immune defense, immune surveillance, and immune homeostasis. Bone cells including osteoclasts, osteoblasts, bone lining cells, and osteocytes are indispensable moderators for bone homeostasis. Bone provides physiological function for life by maintaining a balance between bone resorption and bone formation. The skeletal and immune systems are interconnected by shared signal pathways and intermediary cytokines (Figure 1).

Bone marrow is both a hematopoietic organ and an immune organ. In the bone marrow microenvironment, hematopoietic stem cells differentiate into erythrocytes, granulocytes, platelets, and all kinds of immune cells including monocytes, dendritic cells, T cells, B cells, and natural killer (NK) cells. Among them, the monocytes/macrophages from hematopoietic lineage are osteoclast precursors. Furthermore, osteoblasts are derived from mesenchymal stem cells (MSCs) in the bone marrow. Bone marrow is located in relatively confined bone marrow cavity. Several diversified immune cells including CD4+ T cells, CD8+ T cells, Treg cells, B cells, dendritic cells, and NK cells reside in the bone marrow. Osteoclasts and osteoblasts attach to the bone surface. Osteocytes are embed in the bone matrix. Bone cells thus share the same microenvironment with immune cells in the bone marrow (Figure 1).

Similar to immune cells, osteoclasts originate from multipotent hematopoietic stem cells. Macrophage colony stimulating factor (M-CSF) binds to c-Fms to mediate the cytoskeletal rearrangement, survival, and proliferation of osteoclasts through the Grb2/extracellular signal-regulated kinase (ERK) and Src/PI3K/Akt pathways. Furthermore, M-CSF activates PU.1 and MITF to initiate early osteoclast differentiation. After that, the RANK–RANKL pathway regulates osteoclast differentiation. RANKL binds to RANK on osteoclast precursors and recruits tumor necrosis factor receptor-associated factors 6 (TRAF6) to activate the mitogen-activated protein kinase (MAPK) family and IkB kinase. The MAPK family includes ERK, c-Jun N-terminal kinase (JNK), and p38 MAPK. The downstream signaling NF-κB and AP-1 regulate the expression of NFATc1 to promote osteoclast formation. TREM2 and OSCAR, immunoglobulin-like receptors on the surface of osteoclasts, are associated with immunoreceptor tyrosine-based activation motif (ITAM)-harboring adapters, FcRγ and DAP12, to initiate RANK–RANKL costimulatory signaling. The signaling pathways increase intracellular calcium levels and then regulate transcription of NFATc1. Another important member of bone homeostasis is the osteoblasts derived from MSCs. Bone morphogenetic protein and Wnt signaling are responsible for the differentiating of MSCs toward the osteoprogenitor lineage. Runt-related transcription factor 2 (Runx2) and osterix (Osx) play crucial roles in this process. Finally, some osteoblasts can become osteocytes (Figure 1).

As mentioned above, many signaling pathways are involved in regulating the formation of osteoblasts, osteocytes, and osteoclasts. Among them, the RANK–RANKL–OPG is the most important shared signaling pathway between the skeletal and immune systems. RANKL and RANK are expressed not only by the skeletal system but also by the immune system. In addition to osteoblasts and osteocytes, activated T cells, B cells, NK cells, fibroblasts, and thymus cells can also produce RANKL. Apart from osteoclasts and their progenitor cells, dendritic cells also express RANK. Previous studies suggested that osteoblasts were the main source of OPG. New findings show that B cells are also a source of OPG. The RANK–RANKL pathway participates in the development of lymph nodes, the self-tolerance of T cells, the survival and apoptosis of dendritic cells, and antigen presentation. As an antagonist of RANKL, OPG reduces T cell activation by antagonistic RANK–RANKL. It also directly inhibits the survival and function of dendritic cells. In addition to its role as the downstream of the costimulatory signal of RANK–RANKL, ITAM also participates in various signaling cascade in the immune process. Adapter protein DAP12 and FcRγ with ITAM exist in a variety of immune cells including NK cells, neutrophils, macrophages, dendritic cells, basophils, eosinophilic cells, and mast cells to regulate immune response. Cytotoxic T lymphocyte antigen 4 (CTLA-4) binds to CD80/CD86 on the surface of the antigen-presenting cells to inhibit the costimulatory signaling of T cells. By binding to CD80/CD86 on the surface of osteoclasts and inducing indoleamine 2,3-dioxygenase (IDO), CTLA-4 promotes osteoclast precursor apoptosis. Moreover, Eph receptor, CD100, and osteopontin have the capacity of regulating both the skeletal and immune systems (Figure 1).

A variety of immune cells including T cells, B cells, NK cells, and dendritic cells produce various kinds of cytokines to regulate bone metabolism. Activated CD4+T cells and CD8+ T cells secrete RANKL, TNF-α, IL-1, IL-6, and IL-17 to promote osteoclast formation. Th17 cells secrete IL-17, RANKL, TNF-α, IL-1, and IL-6 to induce osteoclast formation. γδT cells secrete IL-23 to promote osteoclast formation. Treg cells inhibit osteoclast formation directly through CTLA-4 and indirectly through TGF-β, IL-4, and IL-10. FoxP3+ CD8 T-cells produce IFN-γ and CTLA-4 to inhibit osteoclastogenesis while RANKL to promote osteoclastogenesis. Both Th1 and Th2 cells secrete IFN-γ and IL-4 to inhibit osteoclast formation. Furthermore, IL-23 and IL-6 could inhibit osteoclast formation. B cells produce TNF-α and TNF-β to promote osteoclast formation, while producing OPG, IFN-γ, and TGF-β to inhibit osteoclast formation. NK cells play an active role in osteoclast formation by producing RANKL and M-CSF. Apart from regulating osteoclasts, some immune cells produce cytokines to regulate osteoblast formation. CD8+ T cells produce Wnt10b to activate Wnt signaling while γδ T cells secrete IL-17A to promote bone formation. Furthermore, multiple bone cells are capable of influencing the immune system. Osteoblasts regulate B cell development by expressing CXCL12 and IL-7 to influence the common lymphoid progenitors. DLL4 derived from osteoblasts promotes T-linage competent cell function. Osteocytes are involved in lymphopoiesis by maintaining primary lymphoid organ microenvironment (Figure 1).

The interaction between bone cells and immune cells is acknowledged in osteoimmunology. However, the importance of bone marrow adipocytes in osteoimmunology seems to be ignored. Bone marrow adipocytes and osteoblasts share the same origin. Adipogenic transcription factors, PPARγ, and C/EBPs promote MSCs to differentiate into adipocytes in the bone marrow. As an important component of bone marrow, bone marrow adipocytes share a common microenvironment with bone cells and immune cells. Bone marrow adipocytes produce OPG and RANKL to regulate the RANK–RANKL–OPG pathway and osteoimmunology. In puberty, bone marrow adipocytes seem to be beneficial to the skeletal system, whereas the increase of bone marrow adipocytes is associated with bone loss in aging, starvation, osteoporosis, unloading, and type 1 diabetes. In these pathological states, bone marrow adipocytes produce several factors including M-CSF, IL-6, IL-1 β, TNF-α, CXCL1, and CXCL2 to disturb the balance between the skeletal and immune systems. The exact mechanism remains unknown, however, this imbalance is hypothesized to increase osteoclastogenesis and reduce osteogenesis. Furthermore, CXCL1 and CXCL2 can activate osteoclasts. Further studies are needed to address the physiopathological roles among bone cells, immune cells, and bone marrow adipocytes in osteoimmunology (Figure 1).

Osteoimmunology is involved in immune-mediated bone diseases. Menopause and aging are pathogenesis factors for osteoporosis. An increasing number of studies have shown that immune activation and bone loss concomitantly initiate during aging and menopause. Glucocorticoids have inhibitory effects on a broad range of immune responses. Their clinical application may cause osteoporosis. The immunosuppression and bone loss may be correlated. In RA, activated immune cells (T cells and B cells) and upregulation of some immune factors, e.g., TNF-α and RANKL result in bone destruction and bone loss. Local bone erosion and hyperplasia coexist in ankylosing spondylitis. Th17, TNF-α, IL-23, and IL-17 are involved in the pathological process of ankylosing spondylitis. In addition, immune deficiency also has detrimental effects on bone health. Patients with acquired immunodeficiency syndrome have lower bone mineral density and a higher fracture risk. Activated B cells and T cells as well as various immune factors may be the reason behind this. The imbalance of bone resorption and bone formation caused by immune dysfunction provides a clue to seek therapeutic targets through osteoimmunology.

Osteoimmunology emphasizes the interaction between the skeletal and the immune systems. The source of IFN-γ is not as widespread as TNF-α, IL-6 and more limited to the immune system. Several studies also showed that IFN-γ was involved in bone homeostasis. The involvement of IFN-γ in cancer, atherosclerosis, and hematopoiesis has already been summarized. However, the role of IFN-γ in osteoimmunology has not been reviewed in detail.

Signaling Pathway and Function of IFN-γ

Components of the interferon family include type I IFN, type II IFN, and type III IFN. Type I IFN and type III IFN contain several sub-types whereas IFN-γ is the only type II interferon. IFN-γ is produced by multiple types of lymphocyte cells including CD4+ and CD8+ T cells, Treg cells, FoxP3+ CD8 T-cells, γδ T cells, B cells, and NK cells. Apart from lymphocyte cells, other immune cells are also capable of producing IFN-γ including monocyte/macrophage, dendritic cells, and neutrophile granulocytes. Abundant evidence suggests that T cells and NK cells are the major sources of IFN-γ. MSCs secrete low-level IFN-γ to regulate hematopoiesis. Early studies demonstrated that the monocyte/macrophage and dendritic cells produced IL-12 and IL-18 to upregulate IFN-γ in the monocyte/macrophage, dendritic cells, NK cells, and Th1 cells. IFN-γ also upregulates its own expression in the macrophages by autocrine. Through cell–cell contact and factors existing in the co-culture medium, MSCs facilitate IL-12/IL-18-stimulated NK cells to secrete IFN-γ. Furthermore, IL-4 and IL-10 negatively regulate its expression. In a word, a variety of immune cells produce IFN-γ and the activity and quantity of IFN-γ are dependent on certain inflammatory and immune states.

Interferon-gamma interacts with its receptors to trigger the cellular responses. IFN-γ receptors are ubiquitously expressed on the cellular surface of nearly all types of cells except for erythrocytes. The functional receptors consist of receptor α chain (IFNGR1) and β chain (IFNGR2), both of which are vital for activating IFN-γ signaling. The expression of IFNGR1 seems to be constitutive. On the other hand, the expression of IFNGR2 is inducible because of its extremely low level at typical states. IFNGR1 is required for ligand binding with IFN-γ binding sets in the extracellular domain. Furthermore, IFNGR1 is critical for the downstream signal transduction with the tyrosine kinase JAK1 binding sets and STAT1 binding sets. IFNGR2 contains the tyrosine kinase JAK2 binding sets. The JAK–STAT1 pathway is the canonical signaling pathway of IFN-γ and commonly exists in many intracellular responses. By binding to receptors, IFN-γ activates JAK2 and JAK1. The formation of STAT1 binding sets leads to STAT1 recruitment, activation, and homodimer formation. STAT1 homodimers translocate to the nucleus and bind to the gamma-interferon activation site, the promoter regions of interferon-stimulated genes (ISGs), to initiate or turn off its expression. ISGs play a vital role in the subsequent biological process. Apart from the canonical JAK–STAT1 pathway, IFN-γ also initiates the MAP kinase pathway, PI3K pathway, and NF-κB pathway. Meanwhile, IFN-γ could activate transcription factors STAT3, STAT5, and AP-1. The canonical and non-canonical signaling pathways form its complex signal network (Figure 2).

Interferon-gamma participates in many immunological functions (innate and adaptive immune responses) and inflammation. IFN-γ enhances macrophage activation and antigen presentation. It is broadly involved in antiviral and antibacterial immunity as well as signal transduction. Due to the complex role of IFN-γ in physiological and pathological conditions, it is difficult to label its effect as pro-inflammatory or anti-inflammatory. Many studies aim to explore the possibility of IFN-γ as a drug to treat certain types of cancer, idiopathic pulmonary fibrosis, invasive fungal infection, hepatic fibrosis, RA, and mycosis fungoides. The US Food and Drug Administration has approved IFN-γ-1b (marketed as Actimmune) to decrease the number and severity of infections in patients with chronic granulomatous disease and to delay the progression of severe, malignant osteopetrosis.

Effects of IFN-γ on Osteoblasts

Ruiz et al. reported that human osteoblast-like cells express a slight level of IFN-γ. Early studies showed that IFN-γ increases alkaline phosphatase (ALP) activity in osteoblast-like cells derived from human femur. Meanwhile, IFN-γ promotes calvarial osteoblast formation by upregulating osteogenic factors including Runx2, osterix, Alp, and osteocalcin. Activated CD4+ T cells can promote human MSCs to differentiate into osteoblasts in the co-culture system. After blocking IFN-γ with antibodies, osteogenic activity is downregulated. Human MSCs also produce IFN-γ to promote its own osteogenic differentiation. The upregulated osteogenic transcription factors Runx2 is responsible for osteoblast formation. MSCs are able to differentiate into bone marrow adipocytes as well as osteoblasts. IFN-γ inhibits MSCs to differentiate into adipocytes through the downregulation of adipogenic transcription factor PPARγ and the upregulation of osteogenic transcription factor Runx2. MSCs from IFN-γR−/− mice show a lower osteogenic differentiation due to lower Runx2 expression. Furthermore, IFN-γ siRNA inhibits osteoblast differentiation from MSCs. However, the signaling pathway of IFN-γ in osteoblast differentiation is not clear yet.

Effects of IFN-γ on Osteoclasts

Previous studies demonstrated an inhibitory effect of IFN-γ on osteoclast differentiation (Figure 3). Various immune cells including B cells, pro-inflammatory M1 macrophages, dendritic cells, and NK cells produce IFN-γ to inhibit osteoclastogenesis. Furthermore, both activated and resting T cells secrete IFN-γ to inhibit osteoclast formation. The activated T-cell supernatant inhibits osteoclast differentiation from bone marrow macrophages. Anti-IFN-γ antibodies can block its effect in the culture system. The resting T cells also produce IFN-γ to reduce osteoclast formation when co-cultured with peripheral blood monocytes. IFN-γ downregulates c-Fms in monocyte-derived osteoclast precursors to reduce RANK. The M-CSF/c-Fms is critical for early osteoclast proliferation and differentiation. The decrease of RANK+ osteoclast precursors influences subsequent RANKL-dependent osteoclastogenesis. The recognized mechanism of IFN-γ in osteoclastogenesis is to promote TRAF6 degradation in RANKL-induced osteoclast differentiation. IFN-γ activates the classical JAK–STAT1 pathway to initiate the ubiquitin-proteasome to increase the degradation of ubiquitin ligase TRAF6. Due to the downregulation of TRAF6, the downstream transcription factors of TRAF6 including NF-κB and JNK are inhibited, therefore, osteoclast formation is reduced. However, two reports indicated that IFN-γ did not target on TRAF6. IFN-γ inhibits osteoclasts via downregulating NFATc1. IFN-γ inhibits osteoclast formation when IFN-γ and RANKL are simultaneously used in bone marrow macrophages or RAW264.7 cells. However, the inhibitory effect is almost completely neutralized after being pretreated with RANKL during a certain period of time. RANKL treatment with a short time did not resist the inhibitory effect of IFN-γ on osteoclastogenesis. Furthermore, high concentration RANKL might overly activate both the RANK–RANKL pathway and the RANK intracellular domain (ivvy535–538) to counteract the inhibitory effect. Apart from inhibiting osteoclast differentiation, IFN-γ also reduces osteoclast formation by promoting osteoclast apoptosis. IFN-γ inhibits TNF-α-induced osteoclastogenesis by inducing FasL expression in bone marrow cells. IFN-γ promotes osteoclast precursor apoptosis by Fas–FasL interaction. IFN-γ might increase FasL expression on osteoblasts by activating the NF-κB pathway to regulate osteoclast apoptosis. Furthermore, IFN-γ stimulates osteoblasts to produce NO to promote osteoclast apoptosis.

On the other hand, some studies showed that IFN-γ promotes osteoclast formation (Figure 3). IFN-γ promotes osteoclast maturation in the late stage of osteoclast formation. When monocytes/macrophages are differentiated into functional osteoclasts, they need to be matured into functional osteoclasts by fusion. A seven-transmembrane DC-STAMP protein is involved in osteoclast fusion. Miyamoto et al. reported that NFATc1 and c-fos regulated the expression of DC-STAMP. IFN-γ upregulates c-fos and NFATc1 to ultimately increase DC-STAMP expression. Thus, the fusion of osteoclast is enhanced. IFN-γ induces osteoclasts to express IDO to inhibit T cells proliferation. However, IFN-γ increases MHC class II expression in the antigen-presenting cells to enhance T cells activation. T cells produce more TNF-α and RANKL to promote osteoclast formation. Furthermore, IFN-γ promotes multiple immune cells including monocytes and macrophages to secrete CXCL10. CXCL10 induces CD4+ T cells to secrete RANKL and TNF-α to promote the differentiation of osteoclasts.

These contradictory results may result from the differences in the concentrations of IFN-γ, RANKL, and M-CSF, as well as the exposure time and the stage of osteoclast differentiation. IFN-γ inhibits osteoclast differentiation in a dose-dependent manner. However, low level of IFN-γ does not exert the inhibitory effect in osteoclast and treatment with high level of RANKL antagonizes its inhibitory effect in osteoclast differentiation. Also IFN-γ might potentially lose its inhibitory effect during a certain stage of osteoclasts. The inhibitory effect of IFN-γ seems to be limited to the early stage of osteoclast differentiation. The M-CSF/c-Fms signaling is important for early osteoclast proliferation and differentiation. The RANK–RANKL pathway is also vital for early osteoclast differentiation. IFN-γ downregulates c-Fms and RANK to inhibit osteoclastogenesis in the early stage of proliferation and differentiation. IFN-γ also increases the degradation of TRAF6 or downregulates the NFATc1 in the downstream of RANK–RANKL pathway to inhibit osteoclastogenesis in the early stage of osteoclast differentiation. However, IFN-γ promotes osteoclast maturation by increasing fusion in the late stage of osteoclast formation. Interestingly, there is an overlapped transcription factor. IFN-γ downregulates NFATc1 to inhibit osteoclastogenesis in the early stage of differentiation but upregulates NFATc1 to increase the fusion of osteoclast in the late stage of differentiation. In addition to its direct effect, IFN-γ also indirectly increases osteoclastic factors to promote osteoclast formation by activating T cells. However, IFN-γ may reduce T cells proliferation by inducing the IDO in osteoclasts. IFN-γ activates immune response to promote osteoclast formation in the early stage whereas multinucleated osteoclasts inhibit the activation T cells in turn. In summary, the dual effect of IFN-γ in osteoclastogenesis may result from the different role of IFN-γ during different stages of osteoclast differentiation. Furthermore, the differences between direct and indirect actions also lead to the conflicting results.

Effects of IFN-γ on Bone Mass

IFN-γ−/− mice do not produce IFN-γ. IFN-γR−/− mice produce IFN-γ but lack the receptors. Both mice show lower bone mass. Human T cell lymphotropic virus type 1-Tax transgenic mice (Tax+) have the potential to develop osteolytic bone tumors. Due to the absence of IFN-γ, Tax+IFN-γ−/− mice show more severe tumor-associated osteolytic destruction and lower bone mass with increased osteoclastogenesis. Administration of IFN-γ recused cancer-induced bone loss in Tax+IFN-γ−/− mice. Dcir−/− mice are easier to develop ankylosing enthesitis with slightly higher bone mass, while the knockout of IFN-γ counteracts the effect in Dcir−/− mice. Duque et al. found IFN-γ increased bone mass in wide-type mice.

However, some other studies demonstrated that systematic administration of IFN-γ can reduce bone mass. The clinic trial with recombinant human IFN-γ-1b revealed that IFN-γ promotes bone resorption by functional improvement of osteoclasts. Mann et al. found that systemic application of IFN-γ for 8 days led to cancellous bone loss in Sprague-Dawley rats. Gao et al. reported that IFN-γ treatment decreased spinal bone mass and increased serum level of C-terminal telopeptides in T cell–replete nude mice and wide-type mice, but not in T cell–nude mice, implicating the importance of T cells.

The knockout of IFN-γ or its receptors in animal models induces bone loss. It seems that IFN-γ is necessary to maintain normal bone mass. However, the administration of IFN-γ showed contradictory results. Under a certain medication schedule such as 2,000 or 10,000 IU three times a week for 6 weeks, IFN-γ may increase bone mass. However, IFN-γ may cause bone loss in some other schedule such as 1 × 106 IU/kg body weight twice a week for 3 weeks or 1 × 106 IU/kg body weight once a day for 8 days. Long-term use of IFN-γ at a low dosage seems to promote bone formation and inhibit osteoclast differentiation at its early stage. However, short-term use of IFN-γ at a high dosage seems to act on the late stage of differentiation to promote osteoclast formation. Furthermore, short-term use of IFN-γ in a high dosage may activate immune responses especially T cell-mediated immune responses to promote osteoclastogenesis. In summary, IFN-γ may be vital to maintain normal bone mass but its dosage, frequency, usage, and course may be important factors. The balance of osteoblasts and osteoclasts, the predominant effect on osteoclasts differentiation, and the activation of immune cells may be the reason behind these contradictory results. Further studies are required to disclose its complex roles in different pathophysiological conditions.

Rheumatoid Arthritis

Rheumatoid arthritis is defined as inflammatory arthritis with periarticular and systemic bone loss. The etiology of RA is not completely clear but it is known that various adaptive immune responses and innate immune responses are involved in. Immune cells including B cells, T cells, NK cells, dendritic cells, macrophages, and immune factors play important roles in RA inflammatory and bone loss. Osteoclast activation and osteoblast inhibition lead to bone destruction and bone loss. Synovial fibroblasts, activated B cells, and T cells produce RANKL to influence the RANK–RANKL–OPG pathway and regulate osteoclast formation. Furthermore, synovial fibroblasts produce DKK-1 to block the Wnt signaling pathway and inhibit osteoblast formation. Inflammatory cytokines including TNF-α, IL-1, IL-6, IL-17, IL-18, and IL-23 also activate osteoclasts.

Interferon-gamma also plays an important role in the development and progression of RA. NK-like T cells, monocytes, T cells, and B cells secret higher levels of IFN-γ in RA. The high levels of IFN-γ are found in RA plasma, synovial tissue, and synovial fluid. With the progression of disease, IFN-γ levels show an upward trend in plasma. Cacciapaglia et al. found that the IFN-γ level in mononuclear cells from the peripheral blood was consistent with the serous of RA.

Several studies have reported a negative role of IFN-γ in RA. IFN-γ antibodies are a promising advantage to RA patients. Anti-IFN-γ and anti-TNF-α show similar efficacy in alleviating the synovial membrane thickness and clinical indices in RA. In animal experiment, IFN-γ antibodies could reduce synovial proliferation, cell infiltration, bone erosion, and cartilage destruction in the joints of onset RA. Meanwhile, systemic administration of IFN-γ increases arthritic scores in the early stage of RA. IFN-γ seems to accelerate the onset and development of RA in the early stage. IFN-γ might initiate disease by activating inflammation and immune responses. IFN-γ mobilizes lymphocytes by activating the classic transcription factor STAT1 to promote RA inflammatory. Treg cells limit excessive immune responses, whereas IFN-γ derived from B cells inhibits the differentiation of Treg cells thus activating immune response in RA. Furthermore, T cells and macrophages activated by IFN-γ produce more RANKL and TNF-α to promote bone erosion. CXCL10 induced by IFN-γ promotes bone resorption by attracting immune cells such as T cells to be involved in RA.

Apart from promoting RA progression, some studies highlight a protective role of IFN-γ in RA. Some trials from 1980 to 1995 provided evidence of improvement and benefit. After the administration of IFN-γ, RA clinical symptoms were relieved. In animal experiment, IFN-γ−/− mice and IFN-γR−/− mice are easier to induce to be a model of RA. IFN-γ inhibited anti-CII antibody responses to inhibit type II collagen-induced arthritis. By contrast, IFN-γ antibody exacerbated the severity in the late stage of RA. IFN-γ inhibits CII-induced T cell proliferation by limiting IgG1 and IgG2b antibody to the autoantigen in RA. The high temperature requirement A1 (HTRA1) is a protease and marker for the incidence and severity of RA. IFN-γ initiates p38 MAPK/STAT1 pathway to inhibit HTRA1 in RA joint tissues. As a destructive factor in the progression of RA, IL-17 produced by Th17 cells is involved in the RA pathogenesis. IFN-γ inhibits IL-17 production to alleviate RA.

Interferon-gamma seems to exert different effects in different stages of RA. In animal experiment, IFN-γ accelerates the onset and development of RA in the early stage. IFN-γ may promote autoimmunity and activate immune response, increasing the level of osteoclastic factors and leading to the development of RA and bone destruction. The indirect stimulating effect of IFN-γ on osteoclasts may be predominant in the early stage of RA. However, IFN-γ seems to have a protective role in RA in the effector phase. The activation of immune systems in the onset of RA can attract more monocytes and macrophages from blood and peripheral tissue into joints to cause massive amplification of osteoclast formation. IFN-γ reduces c-Fms and RANK to inhibit osteoclast formation. IFN-γ also induces TRAF6 degradation or downregulates NFATc1 to inhibit the RANK–RANKL pathway to prevent osteoclast differentiation. In patients with RA, most of studies show administration of IFN-γ is an effective therapy, but some patients fail to display an adequate response. The difference in the genetic and epigenetic factors, the duel effect of IFN-γ in osteoclastogenesis, disease severity, and rate of progression may be the reason for these contradictory results.

Postmenopausal Osteoporosis

Menopause is a common factor of osteoporosis. Recent researches show that osteoimmunology is involved in the pathogenesis of postmenopausal osteoporosis. T-cell activity is increased but B-cells activity is decreased in postmenopausal women. Immune cells produce some factors like IL-6, IL-7, IFN-γ, TNF-α, and RANKL to influence the skeletal and immune systems. The multiple cytokines like IL-6, IL-7, and TNF-α enhance the formation or activity of osteoclasts in estrogen deficiency. T cells and B cells produce RANKL to promote osteoclast formation. Furthermore, IL-27 has a protective role on bone loss in estrogen deficiency. A clinical research showed CD4+ T cells secreted a significant lower IFN-γ in women with postmenopausal osteoporosis. Whereas two other studies showed no different in IFN-γ in patients with postmenopausal osteoporosis. In animal experiment, IFN-γ level in bone marrow was increased after ovariectomy. The bone mass in the IFN-γ−/− mice did not significantly reduce after ovariectomy. Under estrogen deficiency, IFN-γ promoted the expression of class II transactivator in immune cells to enhance the antigen presentation between macrophages and T cells, which could upregulate TNF-α and RANKL and promote bone resorption. It seems at least in animal studies IFN-γ might enhance bone loss in estrogen deficiency through regulating osteoclastogenesis. Further study is definitely needed to clarify its pathogenesis.

Human Immunodeficiency Virus

Acquired immune deficiency syndrome (AIDS) is an acquired defect in cellular immunity associated with infection with the HIV. This syndrome leads to a large destruction of CD4+ T cells and immunodeficiency. The patients with AIDS are particularly vulnerable to bone loss and at higher risk for fracture due to HIV infection, antiretroviral therapy, hypogonadism, lower nutritional status, etc.. B cells produce more RANKL and less OPG to promote osteoclast formation in AIDS. After antiretroviral therapy, immune cells including T cells, B cells, and macrophages produce high levels of RANKL and TNF-α to activate osteoclasts. The serum level of IFN-γ is lower in exposed-uninfected individuals than that in HIV-unexposed individuals, but there is no data about the main source of IFN-γ. The lower level of IFN-γ might reduce antigen presentation and HLA class II expression to defend HIV infection. Some studies have shown IFN-γ inhibits HIV infection but the mechanism remains unknown. Another study showed that IFN-γ reduced the expression of CXCR-4 and CCR-5 in monocyte surfaces to inhibit HIV replication. IFN-γ inhibits HIV-1 replication stimulated by RANKL. The gp120-stimulated T cells secrete RANKL to enhance osteoclast formation, which is an important reason for HIV-related bone loss. IFN-γ might inhibit RANKL-mediated osteoclast formation by promoting TRAF6 degradation in AIDS. The positive effect of IFN-γ on HIV infection and HIV-related bone loss make it a promising agent for clinical application.

Conclusion and Prospect

Over the past decade, osteoimmunology has been proposed as a new interdiscipline to understand the relationship between the skeletal and the immune systems. The effects of various immune factors on bone metabolism have led to the investigations of their clinical application. IFN-γ plays an important role in bone homeostasis via activation of complex signaling pathways. IFN-γ potentially promotes osteoblastogenesis but inhibits bone marrow adipocyte formation. However, IFN-γ plays conflicting roles in osteoclastogenesis. Its functions are dependent on the balance of direct or indirect effect, as well as the stage of osteoclast differentiation. IFN-γ inhibits the early differentiation of osteoclasts by targeting the RANK–RANKL pathway, whereas it promotes the fusion of mononucleated osteoclasts in the late stage of osteoclast formation. IFN-γ indirectly increases osteoclastic factors by activating immune responses. Under a condition of complete loss of IFN-γ signaling, normal bone mass cannot be maintained. However, the administration of IFN-γ may cause bone loss or inverse. It depends on the dosage, frequency, usage, and course. Furthermore, the pathogenesis, the disease severity, and rate of progression influence the effect of IFN-γ on immune-mediated bone diseases.

Future research should focus on the molecular pathways and conditions related to the different functions of IFN-γ in osteoimmunology. IFN-γ plays dual effect in osteoclastogenesis. Most studies showed that IFN-γ acts on multiple sites of RANK–RANKL pathway including RANK, TRAF6, and NFATc1. It is urgent to find out the key initial site. NFATc1 is an overlapped transcription factor. It is worth to investigate its role in the dual effect of IFN-γ in osteoclast formation. Second, we need to determine the appropriate dosage, frequency, usage, and course to apply IFN-γ in immune-mediated bone diseases. It is important to explore the effect of IFN-γ according to the pathological mechanisms of the disease. Regarding to RA, IFN-γ seems to exert different effects in different stages. Therefore, it may be important to find a suit appropriate time to use and explore the role of IFN-γ in the skeletal and immune systems in RA.

Author Contributions

XY provided the conception of the manuscript. MT and LT were contributed to writing of the manuscript. MT and GL provided the figure.

Conflict of Interest Statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

References 201

  1. 1.

    Arron JR Choi Y Bone versus immune system. Nature (2000 ) 408(6812):535–6.

    Not in our library10.1038/35046196

  2. 2.

    Horvathova M Ilavska S Stefikova K Szabova M Krivosikova Z Jahnova E The cell surface markers expression in postmenopausal women and relation to obesity and bone status. Int J Environ Res Public Health (2017 ) 14(7):751.

    Not in our library10.3390/ijerph14070751

  3. 3.

    Titanji K. Beyond antibodies: B cells and the OPG/RANK-RANKL pathway in health, non-HIV disease and HIV-induced bone loss. Front Immunol (2017 ) 8:1851.

    Not in our library10.3389/fimmu.2017.01851

  4. 4.

    Iseme RA McEvoy M Kelly B Agnew L Walker FR Attia J. Is osteoporosis an autoimmune mediated disorder? Bone Rep (2017 ) 7:121–31.

    Not in our library10.1016/j.bonr.2017.10.003

  5. 5.

    Sylvester FA. Inflammatory bowel disease: effects on bone and mechanisms. Adv Exp Med Biol (2017 ) 1033:133–50.

    Not in our library10.1007/978-3-319-66653-2_7

  6. 6.

    Gallagher JC. Advances in bone biology and new treatments for bone loss. Maturitas (2008 ) 60(1):65–9.

    Not in our library10.1016/j.maturitas.2008.04.005

  7. 7.

    Costa MHG de Soure AM Cabral JMS Ferreira FC da Silva CL Hematopoietic niche – exploring biomimetic cues to improve the functionality of hematopoietic stem/progenitor cells. Biotechnol J (2018 ) 13(2).

    Not in our library10.1002/biot.201700088

  8. 8.

    Bar-Shavit Z. The osteoclast: a multinucleated, hematopoietic-origin, bone-resorbing osteoimmune cell. J Cell Biochem (2007 ) 102(5):1130–9.

    Not in our library10.1002/jcb.21553

  9. 9.

    Quinn JM Neale S Fujikawa Y McGee JO Athanasou NA. Human osteoclast formation from blood monocytes, peritoneal macrophages, and bone marrow cells. Calcif Tissue Int (1998 ) 62(6):527–31.

    Not in our library10.1007/s002239900473

  10. 10.

    Garg P Mazur MM Buck AC Wandtke ME Liu J Ebraheim NA. Prospective review of mesenchymal stem cells differentiation into osteoblasts. Orthop Surg (2017 ) 9(1):13–9.

    Not in our library10.1111/os.12304

  11. 11.

    Chenery AL Antignano F Hughes MR Burrows K McNagny KM Zaph C Chronic Trichuris muris infection alters hematopoiesis and causes IFN-gamma-expressing T-cell accumulation in the mouse bone marrow. Eur J Immunol (2016 ) 46(11):2587–96.

    Not in our library10.1002/eji.201646326

  12. 12.

    Fu Y Wang T Xiu L Shi X Bian Z Zhang Y Levamisole promotes murine bone marrow derived dendritic cell activation and drives Th1 immune response in vitro and in vivo. Int Immunopharmacol (2016 ) 31:57–65.

    Not in our library10.1016/j.intimp.2015.12.015

  13. 13.

    Siracusa F Alp OS Maschmeyer P McGrath M Mashreghi MF Hojyo S Maintenance of CD8(+) memory T lymphocytes in the spleen but not in the bone marrow is dependent on proliferation. Eur J Immunol (2017 ) 47(11):1900–5.

    Not in our library10.1002/eji.201747063

  14. 14.

    Tokoyoda K Zehentmeier S Hegazy AN Albrecht I Grun JR Lohning M Professional memory CD4+ T lymphocytes preferentially reside and rest in the bone marrow. Immunity (2009 ) 30(5):721–30.

    Not in our library10.1016/j.immuni.2009.03.015

  15. 15.

    Glatman Zaretsky A Konradt C Depis F Wing JB Goenka R Atria DG T regulatory cells support plasma cell populations in the bone marrow. Cell Rep (2017 ) 18(8):1906–16.

    Not in our library10.1016/j.celrep.2017.01.067

  16. 16.

    Manko VM. B lymphocyte regulation of proliferation and differentiation of hematopoietic stem cells. Russ J Immunol (1996 ) 1(1):9–16.

    Not in our library

  17. 17.

    Zhang XH Wang GX Zhu HH Liu YR Xu LP Han W Recruitment of CD8(+) T cells into bone marrow might explain the suppression of megakaryocyte apoptosis through high expression of CX3CR1(+) in prolonged isolated thrombocytopenia after allogeneic hematopoietic stem cell transplantation. Ann Hematol (2015 ) 94(10):1689–98.

    Not in our library10.1007/s00277-015-2436-6

  18. 18.

    Okhrimenko A Grun JR Westendorf K Fang Z Reinke S von Roth P Human memory T cells from the bone marrow are resting and maintain long-lasting systemic memory. Proc Natl Acad Sci U S A (2014 ) 111(25):9229–34.

    Not in our library10.1073/pnas.1318731111

  19. 19.

    Fujisaki J Wu J Carlson AL Silberstein L Putheti P Larocca R In vivo imaging of Treg cells providing immune privilege to the haematopoietic stem-cell niche. Nature (2011 ) 474(7350):216–9.

    Not in our library10.1038/nature10160

  20. 20.

    Wang YX Xu CG Ran JL Wu XC Sun JH Wang JD [In vitro activation of bone marrow natural killer T cells of aplastic anemia patients]. Zhonghua Xue Ye Xue Za Zhi (2010 ) 31(8):536–9.

    Not in our library10.3760/cma.j.issn.0253-2727.2010.08.009

  21. 21.

    Carlsten M Baumann BC Simonsson M Jadersten M Forsblom AM Hammarstedt C Reduced DNAM-1 expression on bone marrow NK cells associated with impaired killing of CD34+ blasts in myelodysplastic syndrome. Leukemia (2010 ) 24(9):1607–16.

    Not in our library10.1038/leu.2010.149

  22. 22.

    Ross FP. M-CSF, c-Fms, and signaling in osteoclasts and their precursors. Ann N Y Acad Sci (2006 ) 1068:110–6.

    Not in our library10.1196/annals.1346.014

  23. 23.

    Sharma SM Bronisz A Hu R Patel K Mansky KC Sif S MITF and PU.1 recruit p38 MAPK and NFATc1 to target genes during osteoclast differentiation. J Biol Chem (2007 ) 282(21):15921–9.

    Not in our library10.1074/jbc.m609723200

  24. 24.

    Kim K Kim JH Lee J Jin HM Lee SH Fisher DE Nuclear factor of activated T cells c1 induces osteoclast-associated receptor gene expression during tumor necrosis factor-related activation-induced cytokine-mediated osteoclastogenesis. J Biol Chem (2005 ) 280(42):35209–16.

    Not in our library10.1074/jbc.m505815200

  25. 25.

    Matsumoto M Kogawa M Wada S Takayanagi H Tsujimoto M Katayama S Essential role of p38 mitogen-activated protein kinase in cathepsin K gene expression during osteoclastogenesis through association of NFATc1 and PU.1. J Biol Chem (2004 ) 279(44):45969–79.

    Not in our library10.1074/jbc.m408795200

  26. 26.

    Amarasekara DS Yun H Kim S Lee N Kim H Rho J. Regulation of osteoclast differentiation by cytokine networks. Immune Netw (2018 ) 18(1):e8.

    Not in our library10.4110/in.2018.18.e8

  27. 27.

    Nakagawa N Kinosaki M Yamaguchi K Shima N Yasuda H Yano K RANK is the essential signaling receptor for osteoclast differentiation factor in osteoclastogenesis. Biochem Biophys Res Commun (1998 ) 253(2):395–400.

    Not in our library10.1006/bbrc.1998.9788

  28. 28.

    Matsumoto M Sudo T Saito T Osada H Tsujimoto M. Involvement of p38 mitogen-activated protein kinase signaling pathway in osteoclastogenesis mediated by receptor activator of NF-kappa B ligand (RANKL). J Biol Chem (2000 ) 275(40):31155–61.

    Not in our library10.1074/jbc.m001229200

  29. 29.

    Lee SE Woo KM Kim SY Kim HM Kwack K Lee ZH The phosphatidylinositol 3-kinase, p38, and extracellular signal-regulated kinase pathways are involved in osteoclast differentiation. Bone (2002 ) 30(1):71–7.

    Not in our library10.1016/s8756-3282(01)00657-3

  30. 30.

    Inoue J Ishida T Tsukamoto N Kobayashi N Naito A Azuma S Tumor necrosis factor receptor-associated factor (TRAF) family: adapter proteins that mediate cytokine signaling. Exp Cell Res (2000 ) 254(1):14–24.

    Not in our library10.1006/excr.1999.4733

  31. 31.

    Wong BR Josien R Lee SY Vologodskaia M Steinman RM Choi Y. The TRAF family of signal transducers mediates NF-kappaB activation by the TRANCE receptor. J Biol Chem (1998 ) 273(43):28355–9.

    Not in our library10.1074/jbc.273.43.28355

  32. 32.

    Grigoriadis AE Wang ZQ Cecchini MG Hofstetter W Felix R Fleisch HA c-Fos: a key regulator of osteoclast-macrophage lineage determination and bone remodeling. Science (1994 ) 266(5184):443–8.

    Not in our library10.1126/science.7939685

  33. 33.

    Ikeda F Nishimura R Matsubara T Tanaka S Inoue J Reddy SV Critical roles of c-Jun signaling in regulation of NFAT family and RANKL-regulated osteoclast differentiation. J Clin Invest (2004 ) 114(4):475–84.

    Not in our library10.1172/jci200419657

  34. 34.

    Fodor S Jakus Z Mocsai A. ITAM-based signaling beyond the adaptive immune response. Immunol Lett (2006 ) 104(1–2):29–37.

    Not in our library10.1016/j.imlet.2005.11.001

  35. 35.

    Negishi-Koga T Takayanagi H. Ca2+-NFATc1 signaling is an essential axis of osteoclast differentiation. Immunol Rev (2009 ) 231(1):241–56.

    Not in our library10.1111/j.1600-065x.2009.00821.x

  36. 36.

    Zhao Q Wang X Liu Y He A Jia R. NFATc1: functions in osteoclasts. Int J Biochem Cell Biol (2010 ) 42(5):576–9.

    Not in our library10.1016/j.biocel.2009.12.018

  37. 37.

    Karner CM Long F. Wnt signaling and cellular metabolism in osteoblasts. Cell Mol Life Sci (2017 ) 74(9):1649–57.

    Not in our library10.1007/s00018-016-2425-5

  38. 38.

    Sanchez-Duffhues G Hiepen C Knaus P Ten Dijke P. Bone morphogenetic protein signaling in bone homeostasis. Bone (2015 ) 80:43–59.

    Not in our library10.1016/j.bone.2015.05.025

  39. 39.

    Komori T. Signaling networks in RUNX2-dependent bone development. J Cell Biochem (2011 ) 112(3):750–5.

    Not in our library10.1002/jcb.22994

  40. 40.

    Sinha KM Zhou X. Genetic and molecular control of osterix in skeletal formation. J Cell Biochem (2013 ) 114(5):975–84.

    Not in our library10.1002/jcb.24439

  41. 41.

    Liu ZJ Zhuge Y Velazquez OC. Trafficking and differentiation of mesenchymal stem cells. J Cell Biochem (2009 ) 106(6):984–91.

    Not in our library10.1002/jcb.22091

  42. 42.

    Horwood NJ. Immune cells and bone: coupling goes both ways. Immunol Invest (2013 ) 42(7):532–43.

    Not in our library10.3109/08820139.2013.822762

  43. 43.

    Boyce AM. Denosumab: an emerging therapy in pediatric bone disorders. Curr Osteoporos Rep (2017 ) 15(4):283–92.

    Not in our library10.1007/s11914-017-0380-1

  44. 44.

    Li Y Toraldo G Li A Yang X Zhang H Qian WP B cells and T cells are critical for the preservation of bone homeostasis and attainment of peak bone mass in vivo. Blood (2007 ) 109(9):3839–48.

    Not in our library10.1182/blood-2006-07-037994

  45. 45.

    Theill LE Boyle WJ Penninger JM. RANK-L and RANK: T cells, bone loss, and mammalian evolution. Annu Rev Immunol (2002 ) 20:795–823.

    Not in our library10.1146/annurev.immunol.20.100301.064753

  46. 46.

    Seshasayee D Wang H Lee WP Gribling P Ross J Van Bruggen N A novel in vivo role for osteoprotegerin ligand in activation of monocyte effector function and inflammatory response. J Biol Chem (2004 ) 279(29):30202–9.

    Not in our library10.1074/jbc.m403968200

  47. 47.

    Criscitiello C Viale G Gelao L Esposito A De Laurentiis M De Placido S Crosstalk between bone niche and immune system: osteoimmunology signaling as a potential target for cancer treatment. Cancer Treat Rev (2015 ) 41(2):61–8.

    Not in our library10.1016/j.ctrv.2014.12.001

  48. 48.

    Hamerman JA Ni M Killebrew JR Chu CL Lowell CA. The expanding roles of ITAM adapters FcRgamma and DAP12 in myeloid cells. Immunol Rev (2009 ) 232(1):42–58.

    Not in our library10.1111/j.1600-065x.2009.00841.x

  49. 49.

    Takayanagi H. Osteoimmunology in 2014: two-faced immunology-from osteogenesis to bone resorption. Nat Rev Rheumatol (2015 ) 11(2):74–6.

    Not in our library10.1038/nrrheum.2014.219

  50. 50.

    Liu XL Song J Liu KJ Wang WP Xu C Zhang YZ Role of inhibition of osteogenesis function by Sema4D/Plexin-B1 signaling pathway in skeletal fluorosis in vitro. J Huazhong Univ Sci Technolog Med Sci (2015 ) 35(5):712–5.

    Not in our library10.1007/s11596-015-1495-1

  51. 51.

    Ishida I Kumanogoh A Suzuki K Akahani S Noda K Kikutani H. Involvement of CD100, a lymphocyte semaphorin, in the activation of the human immune system via CD72: implications for the regulation of immune and inflammatory responses. Int Immunol (2003 ) 15(8):1027–34.

    Not in our library10.1093/intimm/dxg098

  52. 52.

    Ginaldi L De Martinis M. Osteoimmunology and beyond. Curr Med Chem (2016 ) 23(33):3754–74.

    Not in our library10.2174/0929867323666160907162546

  53. 53.

    Bryson JL Bhandoola A Editorial: ephs, ephrins, and early T cell development. J Leukoc Biol (2015 ) 98(6):877–9.

    Not in our library10.1189/jlb.1ce0315-132r

  54. 54.

    Shen LL Zhang LX Wang LM Zhou RJ Yang CZ Zhang J Disturbed expression of EphB4, but not EphrinB2, inhibited bone regeneration in an in vivo inflammatory microenvironment. Mediators Inflamm (2016 ) 2016:6430407.

    Not in our library10.1155/2016/6430407

  55. 55.

    Santamaria MH Corral RS. Osteopontin-dependent regulation of Th1 and Th17 cytokine responses in Trypanosoma cruzi-infected C57BL/6 mice. Cytokine (2013 ) 61(2):491–8.

    Not in our library10.1016/j.cyto.2012.10.027

  56. 56.

    Qi Y Li X Ma X Xu L Zhang X Jiang X The role of osteopontin in the induction of the CD40 ligand in Graves’ disease. Clin Endocrinol (2014 ) 80(1):128–34.

    Not in our library10.1111/cen.12229

  57. 57.

    Pacifici R. T cells, osteoblasts, and osteocytes: interacting lineages key for the bone anabolic and catabolic activities of parathyroid hormone. Ann N Y Acad Sci (2016 ) 1364:11–24.

    Not in our library10.1111/nyas.12969

  58. 58.

    Hofbauer LC Lacey DL Dunstan CR Spelsberg TC Riggs BL Khosla S Interleukin-1beta and tumor necrosis factor-alpha, but not interleukin-6, stimulate osteoprotegerin ligand gene expression in human osteoblastic cells. Bone (1999 ) 25(3):255–9.

    Not in our library10.1016/s8756-3282(99)00162-3

  59. 59.
    IL-17-producing γδ T cells enhance bone regeneration · 2016
    No notice
  60. 60.

    Quinn JM Sims NA Saleh H Mirosa D Thompson K Bouralexis S IL-23 inhibits osteoclastogenesis indirectly through lymphocytes and is required for the maintenance of bone mass in mice. J Immunol (2008 ) 181(8):5720–9.

    Not in our library10.4049/jimmunol.181.8.5720

  61. 61.

    Buchwald ZS Kiesel JR DiPaolo R Pagadala MS Aurora R. Osteoclast activated FoxP3+ CD8+ T-cells suppress bone resorption in vitro. PLoS One (2012 ) 7(6):e38199.

    Not in our library10.1371/journal.pone.0038199

  62. 62.

    Horwood NJ Elliott J Martin TJ Gillespie MT. IL-12 alone and in synergy with IL-18 inhibits osteoclast formation in vitro. J Immunol (2001 ) 166(8):4915–21.

    Not in our library10.4049/jimmunol.166.8.4915

  63. 63.

    Hong MH Williams H Jin CH Pike JW. The inhibitory effect of interleukin-10 on mouse osteoclast formation involves novel tyrosine-phosphorylated proteins. J Bone Miner Res (2000 ) 15(5):911–8.

    Not in our library10.1359/jbmr.2000.15.5.911

  64. 64.

    Sato K Suematsu A Okamoto K Yamaguchi A Morishita Y Kadono Y Th17 functions as an osteoclastogenic helper T cell subset that links T cell activation and bone destruction. J Exp Med (2006 ) 203(12):2673–82.

    Not in our library10.1084/jem.20061775

  65. 65.

    Honda K. Interleukin-6 and soluble interleukin-6 receptor suppress osteoclastic differentiation by inducing PGE(2) production in chondrocytes. J Oral Sci (2011 ) 53(1):87–96.

    Not in our library10.2334/josnusd.53.87

  66. 66.

    Kamiya S Nakamura C Fukawa T Ono K Ohwaki T Yoshimoto T Effects of IL-23 and IL-27 on osteoblasts and osteoclasts: inhibitory effects on osteoclast differentiation. J Bone Miner Metab (2007 ) 25(5):277–85.

    Not in our library10.1007/s00774-007-0766-8

  67. 67.

    Kozuka Y Ozaki Y Ukai T Kaneko T Hara Y. B cells play an important role in lipopolysaccharide-induced bone resorption. Calcif Tissue Int (2006 ) 78(3):125–32.

    Not in our library10.1007/s00223-005-0149-x

  68. 68.

    Choi Y Kim JJ. B cells activated in the presence of Th1 cytokines inhibit osteoclastogenesis. Exp Mol Med (2003 ) 35(5):385–92.

    Not in our library10.1038/emm.2003.51

  69. 69.

    Weitzmann MN Cenci S Haug J Brown C DiPersio J Pacifici R. B lymphocytes inhibit human osteoclastogenesis by secretion of TGFbeta. J Cell Biochem (2000 ) 78(2):318–24.

    Not in our library10.1002/(sici)1097-4644(20000801)78:2<318::aid-jcb13>3.0.co;2-n

  70. 70.

    Soderstrom K Stein E Colmenero P Purath U Muller-Ladner U de Matos CT Natural killer cells trigger osteoclastogenesis and bone destruction in arthritis. Proc Natl Acad Sci U S A (2010 ) 107(29):13028–33.

    Not in our library10.1073/pnas.1000546107

  71. 71.

    Terauchi M Li JY Bedi B Baek KH Tawfeek H Galley S T lymphocytes amplify the anabolic activity of parathyroid hormone through Wnt10b signaling. Cell Metab (2009 ) 10(3):229–40.

    Not in our library10.1016/j.cmet.2009.07.010

  72. 72.

    Okamoto K Nakashima T Shinohara M Negishi-Koga T Komatsu N Terashima A Osteoimmunology: the conceptual framework unifying the immune and skeletal systems. Physiol Rev (2017 ) 97(4):1295–349.

    Not in our library10.1152/physrev.00036.2016

  73. 73.

    Yu VW Saez B Cook C Lotinun S Pardo-Saganta A Wang YH Specific bone cells produce DLL4 to generate thymus-seeding progenitors from bone marrow. J Exp Med (2015 ) 212(5):759–74.

    Not in our library10.1084/jem.20141843

  74. 74.

    Sato M Asada N Kawano Y Wakahashi K Minagawa K Kawano H Osteocytes regulate primary lymphoid organs and fat metabolism. Cell Metab (2013 ) 18(5):749–58.

    Not in our library10.1016/j.cmet.2013.09.014

  75. 75.

    Lecka-Czernik B Rosen CJ Kawai M Skeletal aging and the adipocyte program: new insights from an “old” molecule. Cell cycle (2010 ) 9(18):3648–54.

    Not in our library10.4161/cc.9.18.13046

  76. 76.

    Goto H Hozumi A Osaki M Fukushima T Sakamoto K Yonekura A Primary human bone marrow adipocytes support TNF-alpha-induced osteoclast differentiation and function through RANKL expression. Cytokine (2011 ) 56(3):662–8.

    Not in our library10.1016/j.cyto.2011.09.005

  77. 77.

    Hozumi A Osaki M Goto H Sakamoto K Inokuchi S Shindo H. Bone marrow adipocytes support dexamethasone-induced osteoclast differentiation. Biochem Biophys Res Commun (2009 ) 382(4):780–4.

    Not in our library10.1016/j.bbrc.2009.03.111

  78. 78.
    Identification of a subpopulation of marrow MSC-derived medullary adipocytes that express osteoclast-regulating molecules: marrow adipocytes express osteoclast mediators. · 2014
    Not checked
  79. 79.

    Devlin MJ Rosen CJ. The bone-fat interface: basic and clinical implications of marrow adiposity. Lancet Diabetes Endocrinol (2015 ) 3(2):141–7.

    Not in our library10.1016/s2213-8587(14)70007-5

  80. 80.

    Laharrague P Fontanilles AM Tkaczuk J Corberand JX Penicaud L Casteilla L. Inflammatory/haematopoietic cytokine production by human bone marrow adipocytes. Eur Cytokine Netw (2000 ) 11(4):634–9.

    Not in our library

  81. 81.

    Halade GV El Jamali A Williams PJ Fajardo RJ Fernandes G. Obesity-mediated inflammatory microenvironment stimulates osteoclastogenesis and bone loss in mice. Exp Gerontol (2011 ) 46(1):43–52.

    Not in our library10.1016/j.exger.2010.09.014

  82. 82.

    Hardaway AL Herroon MK Rajagurubandara E Podgorski I. Marrow adipocyte-derived CXCL1 and CXCL2 contribute to osteolysis in metastatic prostate cancer. Clin Exp Metastasis (2015 ) 32(4):353–68.

    Not in our library10.1007/s10585-015-9714-5

  83. 83.

    Sapir-Koren R Livshits G. Postmenopausal osteoporosis in rheumatoid arthritis: the estrogen deficiency-immune mechanisms link. Bone (2017 ) 103:102–15.

    Not in our library10.1016/j.bone.2017.06.020

  84. 84.

    Schacke H Docke WD Asadullah K. Mechanisms involved in the side effects of glucocorticoids. Pharmacol Ther (2002 ) 96(1):23–43.

    Not in our library10.1016/s0163-7258(02)00297-8

  85. 85.

    Toussirot E Biologics in spondyloarthritis: TNFalpha inhibitors and other agents. Immunotherapy (2015 ) 7(6):669–81.

    Not in our library10.2217/imt.15.28

  86. 86.

    Guerri-Fernandez R Villar-Garcia J Diez-Perez A Prieto-Alhambra D. HIV infection, bone metabolism, and fractures. Arq Bras Endocrinol Metabol (2014 ) 58(5):478–83.

    Not in our library10.1590/0004-2730000003323

  87. 87.

    Weitzmann MN. Bone and the immune system. Toxicol Pathol (2017 ) 45(7):911–24.

    Not in our library10.1177/0192623317735316

  88. 88.

    Schoenborn JR Wilson CB. Regulation of interferon-gamma during innate and adaptive immune responses. Adv Immunol (2007 ) 96:41–101.

    Not in our library10.1016/s0065-2776(07)96002-2

  89. 89.

    Zaidi MR Merlino G The two faces of interferon-gamma in cancer. Clin Cancer Res (2011 ) 17(19):6118–24.

    Not in our library10.1158/1078-0432.ccr-11-0482

  90. 90.

    Miller CH Maher SG Young HA. Clinical use of interferon-gamma. Ann N Y Acad Sci (2009 ) 1182:69–79.

    Not in our library10.1111/j.1749-6632.2009.05069.x

  91. 91.

    de Bruin AM Voermans C Nolte MA Impact of interferon-gamma on hematopoiesis. Blood (2014 ) 124(16):2479–86.

    Not in our library10.1182/blood-2014-04-568451

  92. 92.

    McLaren JE Ramji DP. Interferon gamma: a master regulator of atherosclerosis. Cytokine Growth Factor Rev (2009 ) 20(2):125–35.

    Not in our library10.1016/j.cytogfr.2008.11.003

  93. 93.

    Schroder K Hertzog PJ Ravasi T Hume DA. Interferon-gamma: an overview of signals, mechanisms and functions. J Leukoc Biol (2004 ) 75(2):163–89.

    Not in our library10.1189/jlb.0603252

  94. 94.

    Di Marzio P Puddu P Conti L Belardelli F Gessani S. Interferon gamma upregulates its own gene expression in mouse peritoneal macrophages. J Exp Med (1994 ) 179(5):1731–6.

    Not in our library10.1084/jem.179.5.1731

  95. 95.

    Neumann C Sorg C Immune interferon. I. Production by lymphokine-activated murine macrophages. Eur J Immunol (1977 ) 7(10):719–25.

    Not in our library10.1002/eji.1830071014

  96. 96.

    Frucht DM Fukao T Bogdan C Schindler H O’Shea JJ Koyasu S. IFN-gamma production by antigen-presenting cells: mechanisms emerge. Trends Immunol (2001 ) 22(10):556–60.

    Not in our library10.1016/s1471-4906(01)02005-1

  97. 97.

    Sturge CR Benson A Raetz M Wilhelm CL Mirpuri J Vitetta ES TLR-independent neutrophil-derived IFN-gamma is important for host resistance to intracellular pathogens. Proc Natl Acad Sci U S A (2013 ) 110(26):10711–6.

    Not in our library10.1073/pnas.1307868110

  98. 98.

    Lees JR. Interferon gamma in autoimmunity: a complicated player on a complex stage. Cytokine (2015 ) 74(1):18–26.

    Not in our library10.1016/j.cyto.2014.10.014

  99. 99.

    Dormady SP Bashayan O Dougherty R Zhang XM Basch RS. Immortalized multipotential mesenchymal cells and the hematopoietic microenvironment. J Hematother Stem Cell Res (2001 ) 10(1):125–40.

    Not in our library10.1089/152581601750098372

  100. 100.

    Thomas H Jager M Mauel K Brandau S Lask S Flohe SB. Interaction with mesenchymal stem cells provokes natural killer cells for enhanced IL-12/IL-18-induced interferon-gamma secretion. Mediators Inflamm (2014 ) 2014:143463.

    Not in our library10.1155/2014/143463

  101. 101.

    Bach EA Aguet M Schreiber RD. The IFN gamma receptor: a paradigm for cytokine receptor signaling. Annu Rev Immunol (1997 ) 15:563–91.

    Not in our library10.1146/annurev.immunol.15.1.563

  102. 102.

    Schreiber RD Farrar MA Hershey GK Fernandez-Luna J. The structure and function of interferon-gamma receptors. Int J Immunopharmacol (1992 ) 14(3):413–9.

    Not in our library10.1016/0192-0561(92)90171-g

  103. 103.

    Marsters SA Pennica D Bach E Schreiber RD Ashkenazi A. Interferon gamma signals via a high-affinity multisubunit receptor complex that contains two types of polypeptide chain. Proc Natl Acad Sci U S A (1995 ) 92(12):5401–5.

    Not in our library10.1073/pnas.92.12.5401

  104. 104.

    Horvath CM. The Jak-STAT pathway stimulated by interferon gamma. Sci STKE (2004 ) 2004(260):tr8.

    Not in our library10.1126/stke.2602004tr8

  105. 105.

    Schneider WM Chevillotte MD Rice CM. Interferon-stimulated genes: a complex web of host defenses. Annu Rev Immunol (2014 ) 32:513–45.

    Not in our library10.1146/annurev-immunol-032713-120231

  106. 106.

    Gough DJ Levy DE Johnstone RW Clarke CJ. IFNgamma signaling-does it mean JAK-STAT? Cytokine Growth Factor Rev (2008 ) 19(5–6):383–94.

    Not in our library10.1016/j.cytogfr.2008.08.004

  107. 107.

    Sakatsume M Stancato LF David M Silvennoinen O Saharinen P Pierce J Interferon gamma activation of Raf-1 is Jak1-dependent and p21ras-independent. J Biol Chem (1998 ) 273(5):3021–6.

    Not in our library10.1074/jbc.273.5.3021

  108. 108.

    Alsayed Y Uddin S Ahmad S Majchrzak B Druker BJ Fish EN IFN-gamma activates the C3G/Rap1 signaling pathway. J Immunol (2000 ) 164(4):1800–6.

    Not in our library10.4049/jimmunol.164.4.1800

  109. 109.

    Hu J Roy SK Shapiro PS Rodig SR Reddy SP Platanias LC ERK1 and ERK2 activate CCAAAT/enhancer-binding protein-beta-dependent gene transcription in response to interferon-gamma. J Biol Chem (2001 ) 276(1):287–97.

    Not in our library10.1074/jbc.m004885200

  110. 110.

    Behera AK Kumar M Lockey RF Mohapatra SS. Adenovirus-mediated interferon gamma gene therapy for allergic asthma: involvement of interleukin 12 and STAT4 signaling. Hum Gene Ther (2002 ) 13(14):1697–709.

    Not in our library10.1089/104303402760293547

  111. 111.

    Nair JS DaFonseca CJ Tjernberg A Sun W Darnell JE Jr Chait BT Requirement of Ca2+ and CaMKII for Stat1 Ser-727 phosphorylation in response to IFN-gamma. Proc Natl Acad Sci U S A (2002 ) 99(9):5971–6.

    Not in our library10.1073/pnas.052159099

  112. 112.

    Deb DK Sassano A Lekmine F Majchrzak B Verma A Kambhampati S Activation of protein kinase C delta by IFN-gamma. J Immunol (2003 ) 171(1):267–73.

    Not in our library10.4049/jimmunol.171.1.267

  113. 113.

    Heller NM Matsukura S Georas SN Boothby MR Rothman PB Stellato C Interferon-gamma inhibits STAT6 signal transduction and gene expression in human airway epithelial cells. Am J Respir Cell Mol Biol (2004 ) 31(5):573–82.

    Not in our library10.1165/rcmb.2004-0195oc

  114. 114.

    Liu L Wang Y Fan Y Li CL Chang ZL. IFN-gamma activates cAMP/PKA/CREB signaling pathway in murine peritoneal macrophages. J Interferon Cytokine Res (2004 ) 24(6):334–42.

    Not in our library10.1089/107999004323142196

  115. 115.

    Park EJ Ji KA Jeon SB Choi WH Han IO You HJ Rac1 contributes to maximal activation of STAT1 and STAT3 in IFN-gamma-stimulated rat astrocytes. J Immunol (2004 ) 173(9):5697–703.

    Not in our library10.4049/jimmunol.173.9.5697

  116. 116.

    Zhang XF Guo SZ Lu KH Li HY Li XD Zhang LX Different roles of PKC and PKA in effect of interferon-gamma on proliferation and collagen synthesis of fibroblasts. Acta Pharmacol Sin (2004 ) 25(10):1320–6.

    Not in our library

  117. 117.

    Venkatesan BA Mahimainathan L Ghosh-Choudhury N Gorin Y Bhandari B Valente AJ PI 3 kinase-dependent Akt kinase and PKCepsilon independently regulate interferon-gamma-induced STAT1alpha serine phosphorylation to induce monocyte chemotactic protein-1 expression. Cell Signal (2006 ) 18(4):508–18.

    Not in our library10.1016/j.cellsig.2005.05.022

  118. 118.

    Cho HJ Kim SK Jin SM Hwang EM Kim YS Huh K IFN-gamma-induced BACE1 expression is mediated by activation of JAK2 and ERK1/2 signaling pathways and direct binding of STAT1 to BACE1 promoter in astrocytes. Glia (2007 ) 55(3):253–62.

    Not in our library10.1002/glia.20451

  119. 119.

    Wei B Baker S Wieckiewicz J Wood KJ. IFN-gamma triggered STAT1-PKB/AKT signalling pathway influences the function of alloantigen reactive regulatory T cells. Am J Transplant (2010 ) 10(1):69–80.

    Not in our library10.1111/j.1600-6143.2009.02858.x

  120. 120.

    Deng J Qian Y Geng L Xie H Wang Y Jiang G Involvement of ERK and JNK pathways in IFN-gamma-induced B7-DC expression on tumor cells. J Cancer Res Clin Oncol (2011 ) 137(2):243–50.

    Not in our library10.1007/s00432-010-0876-x

  121. 121.

    Li W Henderson LJ Major EO Al-Harthi L. IFN-gamma mediates enhancement of HIV replication in astrocytes by inducing an antagonist of the beta-catenin pathway (DKK1) in a STAT 3-dependent manner. J Immunol (2011 ) 186(12):6771–8.

    Not in our library10.4049/jimmunol.1100099

  122. 122.

    Smyth D McKay CM Gulbransen BD Phan VC Wang A McKay DM. Interferon-gamma signals via an ERK1/2-ARF6 pathway to promote bacterial internalization by gut epithelia. Cell Microbiol (2012 ) 14(8):1257–70.

    Not in our library10.1111/j.1462-5822.2012.01796.x

  123. 123.

    Lee WH Chung MH Tsai YH Chang JL Huang HM Interferon-gamma suppresses activin A/NF-E2 induction of erythroid gene expression through the NF-kappaB/c-Jun pathway. Am J Physiol Cell Physiol (2014 ) 306(4):C407–14.

    Not in our library10.1152/ajpcell.00312.2013

  124. 124.

    Yang S Yu M Sun L Xiao W Yang X Sun L Interferon-gamma-induced intestinal epithelial barrier dysfunction by NF-kappaB/HIF-1alpha pathway. J Interferon Cytokine Res (2014 ) 34(3):195–203.

    Not in our library10.1089/jir.2013.0044

  125. 125.

    Johnson S Duncan J Hussain SA Chen G Luo J McLaurin C The IFNgamma-PKR pathway in the prefrontal cortex reactions to chronic excessive alcohol use. Alcohol Clin Exp Res (2015 ) 39(3):476–84.

    Not in our library10.1111/acer.12650

  126. 126.

    Gan H Hao Q Idell S Tang H Interferon-gamma promotes double-stranded RNA-induced TLR3-dependent apoptosis via upregulation of transcription factor Runx3 in airway epithelial cells. Am J Physiol Lung Cell Mol Physiol (2016 ) 311(6):L1101–12.

    Not in our library10.1152/ajplung.00278.2016

  127. 127.

    Kroczynska B Rafidi RL Majchrzak-Kita B Kosciuczuk EM Blyth GT Jemielity J Interferon gamma (IFNgamma) signaling via mechanistic target of rapamycin complex 2 (mTORC2) and regulatory effects in the generation of type II interferon biological responses. J Biol Chem (2016 ) 291(5):2389–96.

    Not in our library10.1074/jbc.m115.664995

  128. 128.

    Wang Y Cao Y Mangalam AK Guo Y LaFrance-Corey RG Gamez JD Neuropilin-1 modulates interferon-gamma-stimulated signaling in brain microvascular endothelial cells. J Cell Sci (2016 ) 129(20):3911–21.

    Not in our library10.1242/jcs.190702

  129. 129.

    Skaria SD Yang J Condos R Smaldone GC. Inhaled interferon and diffusion capacity in Idiopathic Pulmonary Fibrosis (IPF). Sarcoidosis Vasc Diffuse Lung Dis (2015 ) 32(1):37–42.

    Not in our library

  130. 130.
    Interferon-gamma as adjunctive immunotherapy for invasive fungal infections: a case series · 2014
    No notice
  131. 131.

    Muir AJ Sylvestre PB Rockey DC. Interferon gamma-1b for the treatment of fibrosis in chronic hepatitis C infection. J Viral Hepat (2006 ) 13(5):322–8.

    Not in our library10.1111/j.1365-2893.2005.00689.x

  132. 132.

    Cai WM Effect of interferon-gamma on hepatic fibrosis in chronic hepatitis B virus infection. Clin Gastroenterol Hepatol (2005 ) 3(12):1269

    Not in our library10.1016/s1542-3565(05)00893-1

  133. 133.

    Veys EM Menkes CJ Emery P. A randomized, double-blind study comparing twenty-four-week treatment with recombinant interferon-gamma versus placebo in the treatment of rheumatoid arthritis. Arthritis Rheum (1997 ) 40(1):62–8.

    Not in our library10.1002/art.1780400110

  134. 134.

    Sugaya M Tokura Y Hamada T Tsuboi R Moroi Y Nakahara T Phase II study of i.v. interferon-gamma in Japanese patients with mycosis fungoides. J Dermatol (2014 ) 41(1):50–6.

    Not in our library10.1111/1346-8138.12341

  135. 135.

    Ruiz C Perez E Garcia-Martinez O Diaz-Rodriguez L Arroyo-Morales M Reyes-Botella C. Expression of cytokines IL-4, IL-12, IL-15, IL-18, and IFNgamma and modulation by different growth factors in cultured human osteoblast-like cells. J Bone Miner Metab (2007 ) 25(5):286–92.

    Not in our library10.1007/s00774-007-0767-7

  136. 136.

    Gowen M MacDonald BR Russell RG. Actions of recombinant human gamma-interferon and tumor necrosis factor alpha on the proliferation and osteoblastic characteristics of human trabecular bone cells in vitro. Arthritis Rheum (1988 ) 31(12):1500–7.

    Not in our library10.1002/art.1780311206

  137. 137.

    Maruhashi T Kaifu T Yabe R Seno A Chung SH Fujikado N DCIR maintains bone homeostasis by regulating IFN-gamma production in T cells. J Immunol (2015 ) 194(12):5681–91.

    Not in our library10.4049/jimmunol.1500273

  138. 138.

    Croes M Oner FC van Neerven D Sabir E Kruyt MC Blokhuis TJ Proinflammatory T cells and IL-17 stimulate osteoblast differentiation. Bone (2016 ) 84:262–70.

    Not in our library10.1016/j.bone.2016.01.010

  139. 139.

    Duque G Huang DC Macoritto M Rivas D Yang XF Ste-Marie LG Autocrine regulation of interferon gamma in mesenchymal stem cells plays a role in early osteoblastogenesis. Stem Cells (2009 ) 27(3):550–8.

    Not in our library10.1634/stemcells.2008-0886

  140. 140.

    Vidal C Bermeo S Li W Huang D Kremer R Duque G. Interferon gamma inhibits adipogenesis in vitro and prevents marrow fat infiltration in oophorectomized mice. Stem Cells (2012 ) 30(5):1042–8.

    Not in our library10.1002/stem.1063

  141. 141.

    Duque G Huang DC Dion N Macoritto M Rivas D Li W Interferon-gamma plays a role in bone formation in vivo and rescues osteoporosis in ovariectomized mice. J Bone Miner Res (2011 ) 26(7):1472–83.

    Not in our library10.1002/jbmr.350

  142. 142.

    Yamaguchi T Movila A Kataoka S Wisitrasameewong W Ruiz Torruella M Murakoshi M Proinflammatory M1 macrophages inhibit RANKL-induced osteoclastogenesis. Infect Immun (2016 ) 84(10):2802–12.

    Not in our library10.1128/iai.00461-16

  143. 143.

    Takayanagi H Ogasawara K Hida S Chiba T Murata S Sato K T-cell-mediated regulation of osteoclastogenesis by signalling cross-talk between RANKL and IFN-gamma. Nature (2000 ) 408(6812):600–5.

    Not in our library10.1038/35046102

  144. 144.

    Shinoda K Sugiyama E Taki H Harada S Mino T Maruyama M Resting T cells negatively regulate osteoclast generation from peripheral blood monocytes. Bone (2003 ) 33(4):711–20.

    Not in our library10.1016/s8756-3282(03)00230-8

  145. 145.

    Ji JD Park-Min KH Shen Z Fajardo RJ Goldring SR McHugh KP Inhibition of RANK expression and osteoclastogenesis by TLRs and IFN-gamma in human osteoclast precursors. J Immunol (2009 ) 183(11):7223–33.

    Not in our library10.4049/jimmunol.0900072

  146. 146.

    Xiong Q Zhang L Ge W Tang P. The roles of interferons in osteoclasts and osteoclastogenesis. Joint Bone Spine (2016 ) 83(3):276–81.

    Not in our library10.1016/j.jbspin.2015.07.010

  147. 147.

    Huang W O’Keefe RJ Schwarz EM. Exposure to receptor-activator of NFkappaB ligand renders pre-osteoclasts resistant to IFN-gamma by inducing terminal differentiation. Arthritis Res Ther (2003 ) 5(1):R49–59.

    Not in our library10.1186/ar679

  148. 148.

    Cheng J Liu J Shi Z Jules J Xu D Luo S Molecular mechanisms of the biphasic effects of interferon-gamma on osteoclastogenesis. J Interferon Cytokine Res (2012 ) 32(1):34–45.

    Not in our library10.1089/jir.2011.0019

  149. 149.

    Kohara H Kitaura H Fujimura Y Yoshimatsu M Morita Y Eguchi T IFN-gamma directly inhibits TNF-alpha-induced osteoclastogenesis in vitro and in vivo and induces apoptosis mediated by Fas/Fas ligand interactions. Immunol Lett (2011 ) 137(1–2):53–61.

    Not in our library10.1016/j.imlet.2011.02.017

  150. 150.

    Wang L Liu S Zhao Y Liu D Liu Y Chen C Osteoblast-induced osteoclast apoptosis by fas ligand/FAS pathway is required for maintenance of bone mass. Cell Death Differ (2015 ) 22(10):1654–64.

    Not in our library10.1038/cdd.2015.14

  151. 151.

    van’t Hof RJ Ralston SH. Cytokine-induced nitric oxide inhibits bone resorption by inducing apoptosis of osteoclast progenitors and suppressing osteoclast activity. J Bone Miner Res (1997 ) 12(11):1797–804.

    Not in our library10.1359/jbmr.1997.12.11.1797

  152. 152.

    Miyamoto T Regulators of osteoclast differentiation and cell-cell fusion. Keio J Med (2011 ) 60(4):101–5.

    Not in our library10.2302/kjm.60.101

  153. 153.

    Kim JW Lee MS Lee CH Kim HY Chae SU Kwak HB Effect of interferon-gamma on the fusion of mononuclear osteoclasts into bone-resorbing osteoclasts. BMB Rep (2012 ) 45(5):281–6.

    Not in our library10.5483/bmbrep.2012.45.5.281

  154. 154.

    Cenci S Toraldo G Weitzmann MN Roggia C Gao Y Qian WP Estrogen deficiency induces bone loss by increasing T cell proliferation and lifespan through IFN-gamma-induced class II transactivator. Proc Natl Acad Sci U S A (2003 ) 100(18):10405–10.

    Not in our library10.1073/pnas.1533207100

  155. 155.

    Gao Y Grassi F Ryan MR Terauchi M Page K Yang X IFN-gamma stimulates osteoclast formation and bone loss in vivo via antigen-driven T cell activation. J Clin Invest (2007 ) 117(1):122–32.

    Not in our library10.1172/jci30074

  156. 156.

    Kwak HB Ha H Kim HN Lee JH Kim HS Lee S Reciprocal cross-talk between RANKL and interferon-gamma-inducible protein 10 is responsible for bone-erosive experimental arthritis. Arthritis Rheum (2008 ) 58(5):1332–42.

    Not in our library10.1002/art.23372

  157. 157.

    Luster AD Ravetch JV. Biochemical characterization of a gamma interferon-inducible cytokine (IP-10). J Exp Med (1987 ) 166(4):1084–97.

    Not in our library10.1084/jem.166.4.1084

  158. 158.

    Xu Z Hurchla MA Deng H Uluckan O Bu F Berdy A Interferon-gamma targets cancer cells and osteoclasts to prevent tumor-associated bone loss and bone metastases. J Biol Chem (2009 ) 284(7):4658–66.

    Not in our library10.1074/jbc.m804812200

  159. 159.

    Shankar L Gerritsen EJ Key LL Jr Osteopetrosis: pathogenesis and rationale for the use of interferon-gamma-1b. BioDrugs (1997 ) 7(1):23–9.

    Not in our library10.2165/00063030-199707010-00004

  160. 160.

    Mann GN Jacobs TW Buchinsky FJ Armstrong EC Li M Ke HZ Interferon-gamma causes loss of bone volume in vivo and fails to ameliorate cyclosporin A-induced osteopenia. Endocrinology (1994 ) 135(3):1077–83.

    Not in our library10.1210/endo.135.3.8070349

  161. 161.

    Walsh NC Gravallese EM. Bone remodeling in rheumatic disease: a question of balance. Immunol Rev (2010 ) 233(1):301–12.

    Not in our library10.1111/j.0105-2896.2009.00857.x

  162. 162.

    Baum R Gravallese EM. Bone as a target organ in rheumatic disease: impact on osteoclasts and osteoblasts. Clin Rev Allergy Immunol (2016 ) 51(1):1–15.

    Not in our library10.1007/s12016-015-8515-6

  163. 163.

    Gough AK Lilley J Eyre S Holder RL Emery P. Generalised bone loss in patients with early rheumatoid arthritis. Lancet (1994 ) 344(8914):23–7.

    Not in our library10.1016/s0140-6736(94)91049-9

  164. 164.

    Angelotti F Parma A Cafaro G Capecchi R Alunno A Puxeddu I. One year in review 2017: pathogenesis of rheumatoid arthritis. Clin Exp Rheumatol (2017 ) 35(3):368–78.

    Not in our library

  165. 165.

    Shim JH Stavre Z Gravallese EM Bone loss in rheumatoid arthritis: basic mechanisms and clinical implications. Calcif Tissue Int (2017 ) 102(5):533–46.

    Not in our library10.1007/s00223-017-0373-1

  166. 166.

    Hou Y Lin H Zhu L Liu Z Hu F Shi J The inhibitory effect of IFN-gamma on protease HTRA1 expression in rheumatoid arthritis. J Immunol (2014 ) 193(1):130–8.

    Not in our library10.4049/jimmunol.1302700

  167. 167.

    Thanapati S Ganu M Giri P Kulkarni S Sharma M Babar P Impaired NK cell functionality and increased TNF-alpha production as biomarkers of chronic chikungunya arthritis and rheumatoid arthritis. Hum Immunol (2017 ) 78(4):370–4.

    Not in our library10.1016/j.humimm.2017.02.006

  168. 168.

    Steiner G Tohidast-Akrad M Witzmann G Vesely M Studnicka-Benke A Gal A Cytokine production by synovial T cells in rheumatoid arthritis. Rheumatology (Oxford) (1999 ) 38(3):202–13.

    Not in our library10.1093/rheumatology/38.3.202

  169. 169.

    Morita Y Yamamura M Kawashima M Harada S Tsuji K Shibuya K Flow cytometric single-cell analysis of cytokine production by CD4+ T cells in synovial tissue and peripheral blood from patients with rheumatoid arthritis. Arthritis Rheum (1998 ) 41(9):1669–76.

    Not in our library10.1002/1529-0131(199809)41:9<1669::aid-art19>3.0.co;2-g

  170. 170.

    Olalekan SA Cao Y Hamel KM Finnegan A B cells expressing IFN-gamma suppress Treg-cell differentiation and promote autoimmune experimental arthritis. Eur J Immunol (2015 ) 45(4):988–98.

    Not in our library10.1002/eji.201445036

  171. 171.

    Karonitsch T von Dalwigk K Steiner CW Bluml S Steiner G Kiener HP Interferon signals and monocytic sensitization of the interferon-gamma signaling pathway in the peripheral blood of patients with rheumatoid arthritis. Arthritis Rheum (2012 ) 64(2):400–8.

    Not in our library10.1002/art.33347

  172. 172.

    Xie YD Jin L Yu QW. [The role of IFN-gamma, IL-10, IL-12 and TRAIL in sera and synovium fluids from patients with rheumatoid arthritis]. Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi (2007 ) 23(6):536–7.

    Not in our library10.3321/j.issn:1007-8738.2007.06.014

  173. 173.

    Kokkonen H Soderstrom I Rocklov J Hallmans G Lejon K Rantapaa Dahlqvist S. Up-regulation of cytokines and chemokines predates the onset of rheumatoid arthritis. Arthritis Rheum (2010 ) 62(2):383–91.

    Not in our library10.1002/art.27186

  174. 174.

    Cacciapaglia F Buzzulini F Arcarese L Ferraro E Afeltra A. The use of an interferon-gamma release assay as a biomarker of response to anti-TNF-alpha treatment. Drug Dev Res (2014 ) 75(Suppl 1):S50–3.

    Not in our library10.1002/ddr.21195

  175. 175.

    Nasonova VA Lukina GV Sigidin Ia A [Neutralisation of interferon gamma – a new trend in therapy of rheumatoid arthritis]. Ter Arkh (2008 ) 80(5):30–7.

    Not in our library

  176. 176.

    Sigidin YA Loukina GV Skurkovich B Skurkovich S. Randomized, double-blind trial of anti-interferon-gamma antibodies in rheumatoid arthritis. Scand J Rheumatol (2001 ) 30(4):203–7.

    Not in our library10.1080/030097401316909530

  177. 177.

    Boissier MC Chiocchia G Bessis N Hajnal J Garotta G Nicoletti F Biphasic effect of interferon-gamma in murine collagen-induced arthritis. Eur J Immunol (1995 ) 25(5):1184–90.

    Not in our library10.1002/eji.1830250508

  178. 178.

    Lemmel EM Brackertz D Franke M Gaus W Hartl PW Machalke K Results of a multicenter placebo-controlled double-blind randomized phase III clinical study of treatment of rheumatoid arthritis with recombinant interferon-gamma. Rheumatol Int (1988 ) 8(2):87–93.

    Not in our library10.1007/bf00271840

  179. 179.

    Cannon GW Emkey RD Denes A Cohen SA Saway PA Wolfe F Prospective 5-year followup of recombinant interferon-gamma in rheumatoid arthritis. J Rheumatol (1993 ) 20(11):1867–73.

    Not in our library

  180. 180.

    Hofschneider P Winter U Lemmel E Brölz B Gaus W Schmid S Double blind controlled phase III multicenter clinical trial with interferon gamma in rheumatoid arthritis. German Lymphokine Study Group. Rheumatol Int (1992 ) 12(5):175–85.

    Not in our library10.1007/bf00302149

  181. 181.

    Lemmel EM Franke M Gaus W Hartl PW Hofschneider PH Miehlke K Results of a phase-II clinical trial on treatment of rheumatoid arthritis with recombinant interferon-gamma. Rheumatol Int (1987 ) 7(3):127–32.

    Not in our library10.1007/bf00270465

  182. 182.

    Vermeire K Heremans H Vandeputte M Huang S Billiau A Matthys P Accelerated collagen-induced arthritis in IFN-gamma receptor-deficient mice. J Immunol (1997 ) 158(11):5507–13.

    Not in our library

  183. 183.

    Nakajima H Takamori H Hiyama Y Tsukada W. The effect of treatment with interferon-gamma on type II collagen-induced arthritis. Clin Exp Immunol (1990 ) 81(3):441–5.

    Not in our library10.1111/j.1365-2249.1990.tb05353.x

  184. 184.

    Sarkar S Cooney LA White P Dunlop DB Endres J Jorns JM Regulation of pathogenic IL-17 responses in collagen-induced arthritis: roles of endogenous interferon-gamma and IL-4. Arthritis Res Ther (2009 ) 11(5):R158.

    Not in our library10.1186/ar2838

  185. 185.

    Guedez YB Whittington KB Clayton JL Joosten LA van de Loo FA van den Berg WB Genetic ablation of interferon-gamma up-regulates interleukin-1beta expression and enables the elicitation of collagen-induced arthritis in a nonsusceptible mouse strain. Arthritis Rheum (2001 ) 44(10):2413–24.

    Not in our library10.1002/1529-0131(200110)44:10<2413::aid-art406>3.0.co;2-e

  186. 186.

    Chu CQ Swart D Alcorn D Tocker J Elkon KB. Interferon-gamma regulates susceptibility to collagen-induced arthritis through suppression of interleukin-17. Arthritis Rheum (2007 ) 56(4):1145–51.

    Not in our library10.1002/art.22453

  187. 187.

    Breuil V Ticchioni M Testa J Roux CH Ferrari P Breittmayer JP Immune changes in post-menopausal osteoporosis: the Immunos study. Osteoporos Int (2010 ) 21(5):805–14.

    Not in our library10.1007/s00198-009-1018-7

  188. 188.

    Faienza MF Ventura A Marzano F Cavallo L. Postmenopausal osteoporosis: the role of immune system cells. Clin Dev Immunol (2013 ) 2013:575936.

    Not in our library10.1155/2013/575936

  189. 189.

    D’Amelio P Grimaldi A Di Bella S Brianza SZ Cristofaro MA Tamone C Estrogen deficiency increases osteoclastogenesis up-regulating T cells activity: a key mechanism in osteoporosis. Bone (2008 ) 43(1):92–100.

    Not in our library10.1016/j.bone.2008.02.017

  190. 190.

    Zhao R. Immune regulation of osteoclast function in postmenopausal osteoporosis: a critical interdisciplinary perspective. Int J Med Sci (2012 ) 9(9):825–32.

    Not in our library10.7150/ijms.5180

  191. 191.

    Molnar I Bohaty I Somogyine-Vari E. IL-17A-mediated sRANK ligand elevation involved in postmenopausal osteoporosis. Osteoporos Int (2014 ) 25(2):783–6.

    Not in our library10.1007/s00198-013-2548-6

  192. 192.

    Shukla P Mansoori MN Kakaji M Shukla M Gupta SK Singh D. Interleukin 27 (IL-27) alleviates bone loss in estrogen-deficient conditions by induction of early growth response-2 gene. J Biol Chem (2017 ) 292(11):4686–99.

    Not in our library10.1074/jbc.m116.764779

  193. 193.

    Zheng SX Vrindts Y Lopez M De Groote D Zangerle PF Collette J Increase in cytokine production (IL-1 beta, IL-6, TNF-alpha but not IFN-gamma, GM-CSF or LIF) by stimulated whole blood cells in postmenopausal osteoporosis. Maturitas (1997 ) 26(1):63–71.

    Not in our library10.1016/s0378-5122(96)01080-8

  194. 194.

    Hustmyer FG Walker E Yu XP Girasole G Sakagami Y Peacock M Cytokine production and surface antigen expression by peripheral blood mononuclear cells in postmenopausal osteoporosis. J Bone Miner Res (1993 ) 8(1):51–9.

    Not in our library10.1002/jbmr.5650080108

  195. 195.

    Roggia C Tamone C Cenci S Pacifici R Isaia GC. Role of TNF-alpha producing T-cells in bone loss induced by estrogen deficiency. Minerva Med (2004 ) 95(2):125–32.

    Not in our library

  196. 196.

    Weitzmann MN Ofotokun I. Physiological and pathophysiological bone turnover – role of the immune system. Nat Rev Endocrinol (2016 ) 12(9):518–32.

    Not in our library10.1038/nrendo.2016.91

  197. 197.

    Jaumdally SZ Picton A Tiemessen CT Paximadis M Jaspan HB Gamieldien H CCR5 expression, haplotype and immune activation in protection from infection in HIV-exposed uninfected individuals in HIV-serodiscordant relationships. Immunology (2017 ) 151(4):464–73.

    Not in our library10.1111/imm.12743

  198. 198.

    Rihn SJ Foster TL Busnadiego I Aziz MA Hughes J Neil SJ The envelope gene of transmitted HIV-1 resists a late interferon gamma-induced block. J Virol (2017 ) 91(7):e02254–16.

    Not in our library10.1128/jvi.02254-16

  199. 199.

    Cardone M Ikeda KN Varano B Gessani S Conti L HIV-1-induced impairment of dendritic cell cross talk with gammadelta T lymphocytes. J Virol (2015 ) 89(9):4798–808.

    Not in our library10.1128/jvi.03681-14

  200. 200.

    Creery D Weiss W Lim WT Aziz Z Angel JB Kumar A. Down-regulation of CXCR-4 and CCR-5 expression by interferon-gamma is associated with inhibition of chemotaxis and human immunodeficiency virus (HIV) replication but not HIV entry into human monocytes. Clin Exp Immunol (2004 ) 137(1):156–65.

    Not in our library10.1111/j.1365-2249.2004.02495.x

  201. 201.

    Fakruddin JM Laurence J. HIV envelope gp120-mediated regulation of osteoclastogenesis via receptor activator of nuclear factor kappa B ligand (RANKL) secretion and its modulation by certain HIV protease inhibitors through interferon-gamma/RANKL cross-talk. J Biol Chem (2003 ) 278(48):48251–8.

    Not in our library10.1074/jbc.m304676200

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