Osteoimmunology: The Conceptual Framework Unifying the Immune and Skeletal Systems

The immune and skeletal systems share a variety of molecules, including cytokines, chemokines, hormones, receptors, and transcription factors. Bone cells interact with immune cells under physiological and pathological conditions. Osteoimmunology was created as a new interdisciplinary field in large part to highlight the shared molecules and reciprocal interactions between the two systems in both heath and disease. Receptor activator of NF-κB ligand (RANKL) plays an essential role not only in the development of immune organs and bones, but also in autoimmune diseases affecting bone, thus effectively comprising the molecule that links the two systems. Here we review the function, gene regulation, and signal transduction of osteoimmune molecules, including RANKL, in the context of osteoclastogenesis as well as multiple other regulatory functions. Osteoimmunology has become indispensable for understanding the pathogenesis of a number of diseases such as rheumatoid arthritis (RA). We review the various osteoimmune pathologies, including the bone destruction in RA, in which pathogenic helper T cell subsets [such as IL-17-expressing helper T (Th17) cells] induce bone erosion through aberrant RANKL expression. We also focus on cellular interactions and the identification of the communication factors in the bone marrow, discussing the contribution of bone cells to the maintenance and regulation of hematopoietic stem and progenitors cells. Thus the time has come for a basic reappraisal of the framework for understanding both the immune and bone systems. The concept of a unified osteoimmune system will be absolutely indispensable for basic and translational approaches to diseases related to bone and/or the immune system.

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The roles of osteocytes in alveolar bone destruction in periodontitis

Journal of Translational Medicine ◽

10.1186/s12967-020-02664-7 ◽

2020 ◽

Vol 18 (1) ◽

Author(s):

Xiaofei Huang ◽

Mengru Xie ◽

Yanling Xie ◽

Feng Mei ◽

Xiaofeng Lu ◽

...

Keyword(s):

Bone Loss ◽

Bone Remodeling ◽

Alveolar Bone ◽

Bone Cells ◽

Bone Destruction ◽

Alveolar Bone Loss ◽

Receptor Activator ◽

Local Destruction ◽

Underlying Mechanisms

AbstractPeriodontitis, a bacterium-induced inflammatory disease that is characterized by alveolar bone loss, is highly prevalent worldwide. Elucidating the underlying mechanisms of alveolar bone loss in periodontitis is crucial for understanding its pathogenesis. Classically, bone cells, such as osteoclasts, osteoblasts and bone marrow stromal cells, are thought to dominate the development of bone destruction in periodontitis. Recently, osteocytes, the cells embedded in the mineral matrix, have gained attention. This review demonstrates the key contributing role of osteocytes in periodontitis, especially in alveolar bone loss. Osteocytes not only initiate physiological bone remodeling but also assist in inflammation-related changes in bone remodeling. The latest evidence suggests that osteocytes are involved in regulating bone anabolism and catabolism in the progression of periodontitis. The altered secretion of receptor activator of NF-κB ligand (RANKL), sclerostin and Dickkopf-related protein 1 (DKK1) by osteocytes affects the balance of bone resorption and formation and promotes bone loss. In addition, the accumulation of prematurely senescent and apoptotic osteocytes observed in alveolar bone may exacerbate local destruction. Based on their communication with the bloodstream, it is noteworthy that osteocytes may participate in the interaction between local periodontitis lesions and systemic diseases. Overall, further investigations of osteocytes may provide vital insights that improve our understanding of the pathophysiology of periodontitis.

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Infection by Streptococcus pyogenes Induces the Receptor Activator of NF-κB Ligand Expression in Mouse Osteoblastic Cells

Infection and Immunity ◽

10.1128/iai.71.2.948-955.2003 ◽

2003 ◽

Vol 71 (2) ◽

pp. 948-955 ◽

Cited By ~ 21

Author(s):

Nobuo Okahashi ◽

Atsuo Sakurai ◽

Ichiro Nakagawa ◽

Taku Fujiwara ◽

Shigetada Kawabata ◽

...

Keyword(s):

Western Blot ◽

Streptococcus Pyogenes ◽

Blot Analysis ◽

Western Blot Analysis ◽

Bone Cells ◽

Specific Inhibitor ◽

Bone Destruction ◽

Mitogen Activated Protein Kinase ◽

No Production ◽

Receptor Activator

ABSTRACT Group A Streptococcus pyogenes is known to induce nongonococcal septic arthritis in addition to pharyngitis, scarlet fever, and poststreptococcal sequelae. However, little is known about the interaction between S. pyogenes and bone cells. We report here that S. pyogenes strain JRS4 (M6) attached to and invaded mouse primary osteoblasts. Reverse transcription-PCR demonstrated that S. pyogenes infection of osteoblasts stimulated expression of mRNA for the receptor activator of NF-κB ligand (RANKL). Western blot analysis followed by ligand precipitation with the receptor activator of NF-κB receptor showed that there was an increase in RANKL protein in infected osteoblasts. Production of interleukin-6 was also stimulated, but no production of interleukin-1β or tumor necrosis factor alpha was observed. Stimulation of RANKL production was not observed in osteoblasts stimulated with heat-inactivated S. pyogenes, suggesting that an active interaction of S. pyogenes with osteoblasts is essential for this phenomenon. A Western blot analysis performed with antibodies specific for phosphorylated signal transduction proteins demonstrated that S. pyogenes infection induces phosphorylation of p38 mitogen-activated protein kinase. A specific inhibitor of this kinase, SB203580, inhibited RANKL production by infected osteoblasts. These results suggest that infection of osteoblasts by S. pyogenes stimulates RANKL production and may trigger bone destruction in infected bone tissue.

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RANKL is a therapeutic target of bone destruction in rheumatoid arthritis

F1000Research ◽

10.12688/f1000research.17296.1 ◽

2019 ◽

Vol 8 ◽

pp. 533 ◽

Cited By ~ 7

Author(s):

Sakae Tanaka

Keyword(s):

Rheumatoid Arthritis ◽

Nuclear Factor Kappa B ◽

Bone Erosion ◽

Therapeutic Option ◽

Osteoclast Differentiation ◽

Bone Destruction ◽

Cartilage Destruction ◽

Human Antibody ◽

Receptor Activator ◽

Made In

Although remarkable advances have been made in the treatment of rheumatoid arthritis (RA), novel therapeutic options with different mechanisms of action and fewer side effects have been expected. Recent studies have demonstrated that bone-resorbing osteoclasts are critically involved in the bone destruction associated with RA. Denosumab, a human antibody against receptor activator of nuclear factor-kappa B ligand (RANKL), efficiently suppressed the progression of bone erosion in patients with RA by suppressing osteoclast differentiation and activation in several clinical studies, although it had no effect on inflammation or cartilage destruction. Denosumab, in combination with anti-rheumatic drugs, is considered a pivotal therapeutic option for the prevention of bone destruction in RA.

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The Impact of Proinflammatory Cytokynes of Rheumatoid Polyarthritis on the Generalized Loss of Bone Mass

Revista de Chimie ◽

10.37358/rc.18.9.6572 ◽

2018 ◽

Vol 69 (9) ◽

pp. 2541-2545

Author(s):

Raluca Barzoi ◽

Elena Rezus ◽

Codruta Badescu ◽

Razan Al Namat ◽

Manuela Ciocoiu

Keyword(s):

Rheumatoid Arthritis ◽

Immune Cells ◽

Osteoclast Differentiation ◽

Bone Destruction ◽

Nuclear Factor ◽

Receptor Activator ◽

Level Function ◽

Rheumatoid Polyarthritis ◽

The Impact ◽

Nuclear Factor Kb

There is a bidirectional interaction between most immune cells and osteoblasts, osteoclasts and their precursor cells. The receptor activator of nuclear factor-kB ligand (RANKL)/RANK/osteoprotegerin (OPG) system plays an essential role in the formation of osteoblasts, but it also has implications in osteoclast biology and implicitly on the diseases characterized by bone loss. Proinflammatory cytokines existing at synovial level function as direct or indirect stimulators of osteoclast differentiation, but also of its survival or activity, although some cytokines may also play an antiosteocastogenic role. The fate of bone destruction is determined by the balance between osteoclastogenic and antiosteoclastogenic mediators. Our study has shown that the early initiation of the therapy with anti-TNF and anti-IL6 biological agents, in patients with rheumatoid arthritis, inhibits bone destruction, regardless of the anti-inflammatory activity in patients with rheumatoid arthritis.

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Osteosarcoma of the jaws: a literature review

Current Medical Imaging Formerly Current Medical Imaging Reviews ◽

10.2174/1573405616666200806173948 ◽

2020 ◽

Vol 16 ◽

Author(s):

Francesco Ricotta ◽

Massimo Bassi ◽

Nicola Tomasetti ◽

Angelo Campobassi ◽

Vincenzo Maiolo ◽

...

Keyword(s):

Treatment Guidelines ◽

State Of The Art ◽

Bone Erosion ◽

Tumor Resection ◽

Bone Destruction ◽

Cell Type ◽

Complete Tumor Resection ◽

Predominant Cell Type ◽

Bone Changes ◽

Complete Tumor

: Osteosarcoma of the jaws (OSJ) is a relatively rare disease, accounting for between 2% and 10% of all cases of osteosarcoma, it is morphologically and radiologically identical to the trunk and extremity variant, but distinct in several crucial aspects. : The lesion is characterized by sarcomatous cells which produces a variable amount of osteoid bone. It arises centrally within the bone and can be subdivided into osteoblastic, chondroblastic and fibroblastic subtype, depending on the predominant cell type. : Radiographically, these tumors display a spectrum of bone changes from well-demarcated borders to lytic bone destruction with indefinite margins and variable cortical bone erosion or, in some cases, images of sclerotic bone. Therapeutic options for OSJ include surgery, chemotherapy and radiotherapy, which are employed according to age of the patient, histological classification and localization of the tumor. Today there is no a general consensus in the treatment guidelines for the OSJ though surgery represents the key of the treatment. The main prognostic factor deeply influencing the patient's prognosis remains the complete tumor resection with negative surgical margins. : The aim of the present review is to describe the state of the art regarding diagnostic and surgical treatment aspects of the primary osteosarcoma of the jaws.

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Reduced dose of PTCy followed by adjuvant α-galactosylceramide enhances GVL effect without sacrificing GVHD suppression

Scientific Reports ◽

10.1038/s41598-021-92526-z ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Makoto Nakamura ◽

Yusuke Meguri ◽

Shuntaro Ikegawa ◽

Takumi Kondo ◽

Yuichi Sumii ◽

...

Keyword(s):

T Cells ◽

Stem Cell ◽

T Cell Subsets ◽

Inkt Cells ◽

Early Recovery ◽

Hematopoietic Stem ◽

Graft Versus Host ◽

Reduced Dose ◽

Graft Versus Leukemia ◽

Novel Strategy

AbstractPosttransplantation cyclophosphamide (PTCy) has become a popular option for haploidentical hematopoietic stem cell transplantation (HSCT). However, personalized methods to adjust immune intensity after PTCy for each patient’s condition have not been well studied. Here, we investigated the effects of reducing the dose of PTCy followed by α-galactosylceramide (α-GC), a ligand of iNKT cells, on the reciprocal balance between graft-versus-host disease (GVHD) and the graft-versus-leukemia (GVL) effect. In a murine haploidentical HSCT model, insufficient GVHD prevention after reduced-dose PTCy was efficiently compensated for by multiple administrations of α-GC. The ligand treatment maintained the enhanced GVL effect after reduced-dose PTCy. Phenotypic analyses revealed that donor-derived B cells presented the ligand and induced preferential skewing to the NKT2 phenotype rather than the NKT1 phenotype, which was followed by the early recovery of all T cell subsets, especially CD4+Foxp3+ regulatory T cells. These studies indicate that α-GC administration soon after reduced-dose PTCy restores GVHD-preventing activity and maintains the GVL effect, which is enhanced by reducing the dose of PTCy. Our results provide important information for the development of a novel strategy to optimize PTCy-based transplantation, particularly in patients with a potential relapse risk.

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Gata3 drives development of RORγt+ group 3 innate lymphoid cells

Journal of Experimental Medicine ◽

10.1084/jem.20131038 ◽

2014 ◽

Vol 211 (2) ◽

pp. 199-208 ◽

Cited By ~ 152

Author(s):

Nicolas Serafini ◽

Roel G.J. Klein Wolterink ◽

Naoko Satoh-Takayama ◽

Wei Xu ◽

Christian A.J. Vosshenrich ◽

...

Keyword(s):

T Cell ◽

Fetal Liver ◽

Innate Lymphoid Cells ◽

Lymphoid Cells ◽

T Cell Subsets ◽

Mucosal Barrier ◽

Hematopoietic Stem ◽

Mucosal Surfaces ◽

Gata3 Expression ◽

Group 3

Group 3 innate lymphoid cells (ILC3) include IL-22–producing NKp46+ cells and IL-17A/IL-22–producing CD4+ lymphoid tissue inducerlike cells that express RORγt and are implicated in protective immunity at mucosal surfaces. Whereas the transcription factor Gata3 is essential for T cell and ILC2 development from hematopoietic stem cells (HSCs) and for IL-5 and IL-13 production by T cells and ILC2, the role for Gata3 in the generation or function of other ILC subsets is not known. We found that abundant GATA-3 protein is expressed in mucosa-associated ILC3 subsets with levels intermediate between mature B cells and ILC2. Chimeric mice generated with Gata3-deficient fetal liver hematopoietic precursors lack all intestinal RORγt+ ILC3 subsets, and these mice show defective production of IL-22 early after infection with the intestinal pathogen Citrobacter rodentium, leading to impaired survival. Further analyses demonstrated that ILC3 development requires cell-intrinsic Gata3 expression in fetal liver hematopoietic precursors. Our results demonstrate that Gata3 plays a generalized role in ILC lineage determination and is critical for the development of gut RORγt+ ILC3 subsets that maintain mucosal barrier homeostasis. These results further extend the paradigm of Gata3-dependent regulation of diversified innate ILC and adaptive T cell subsets.

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Opg, Rank, and Rankl in Tooth Development: Co-ordination of Odontogenesis and Osteogenesis

Journal of Dental Research ◽

10.1177/154405910408300311 ◽

2004 ◽

Vol 83 (3) ◽

pp. 241-244 ◽

Cited By ~ 52

Author(s):

A. Ohazama ◽

J.-M. Courtney ◽

P.T. Sharpe

Keyword(s):

Tooth Development ◽

Nuclear Factor Κb ◽

Cellular Interactions ◽

Rankl Expression ◽

Dental Papilla ◽

Spatiotemporal Expression ◽

Receptor Activator ◽

Explant Cultures ◽

Enamel Epithelium ◽

Tooth Germs

Osteoprotegerin (OPG), receptor activator of nuclear factor-κB (RANK), and RANK ligand (RANKL) are mediators of various cellular interactions, including bone metabolism. We analyzed expression of these three genes during murine odontogenesis from epithelial thickening to cytodifferentiation stages. Opg showed expression in the thickening and bud epithelium. Expression of Opg and Rank was observed in both the internal and the external enamel epithelium as well as in the dental papilla mesenchyme. Although Rankl expression was not detected in tooth epithelium or mesenchyme, it was expressed in pre-osteogenic mesenchymal cells close to developing tooth germs. All three genes were detected in developing dentary bone at P0. The addition of exogenous OPG to explant cultures of tooth primordia produced a delay in tooth development that resulted in reduced mineralization. We propose that the spatiotemporal expression of these molecules in early tooth and bone primordia cells has a role in co-ordinating bone and tooth development.

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Total Flavonoids of Bidens pilosa Ameliorates Bone Destruction in Collagen-Induced Arthritis

Planta Medica ◽

10.1055/a-1352-5124 ◽

2021 ◽

Author(s):

Mengqin Hong ◽

Xingyu Fan ◽

Shengxiang Liang ◽

Wang Xiang ◽

Liting Chen ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Proinflammatory Cytokines ◽

Bone Destruction ◽

Nuclear Factor Κb ◽

Total Flavonoids ◽

Nuclear Factor ◽

Collagen Induced Arthritis ◽

Bidens Pilosa ◽

X Ray ◽

Receptor Activator

AbstractRheumatoid arthritis is a chronic autoimmune disease characterized by the infiltration of synovial inflammatory cells and progressive joint destruction. Total flavonoids of Bidens pilosa have been used against inflammation in rheumatoid arthritis, but its role in bone destruction remains to be explored. The aim of this paper was to study whether total flavonoids of B. pilosa relieve the severity of collagen-induced arthritis in rats, particularly whether it regulates the production of proinflammatory cytokines and the receptor activator of nuclear factor-κB/receptor activator of nuclear factor-κB ligand/osteoprotegerin signaling pathway. In this research, a collagen-induced disease model was induced in adult rats by subcutaneous injection of collagen II. Total flavonoids of B. pilosa at different doses (40, 80, and 160 mg/kg/d) were administered intragastrically, while methotrexate (1 mg/kg/w) was injected intraperitoneally as a positive control. Paw swelling, arthritis score, and body weight were assessed and evaluated. The severity of joint damage was determined using X-ray and confirmed by histopathology. The expression levels of receptor activator of nuclear factor-κB ligand, osteoprotegerin, IL-1β, IL-17, and TNF in the serum and tissue were assayed using ELISA and immunohistochemistry. We found that total flavonoids of B. pilosa attenuated collagen-induced arthritis at the macroscopic level, and total flavonoids of B. pilosa-treated rats showed reduced paw swelling, arthritis scores, and X-ray appearance of collagen-induced arthritis in addition to improved histopathological results. These findings were consistent with reduced serum and tissue receptor activator of nuclear factor-κB ligand, TNF, IL-1β, and IL-17 levels but increased osteoprotegerin levels. Our data suggest that total flavonoids of B. pilosa attenuate collagen-induced arthritis by suppressing the receptor activator of nuclear factor-κB ligand/receptor activator of nuclear factor-κB/osteoprotegerin pathway and the subsequent production of proinflammatory cytokines. In addition, total flavonoids of B. pilosa may be a promising therapeutic candidate for the management of rheumatoid arthritis.

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