scholarly journals RANKL-Induced Btn2a2 – A T Cell Immunomodulatory Molecule – During Osteoclast Differentiation Fine-Tunes Bone Resorption

2021 ◽  
Vol 12 ◽  
Author(s):  
Michael Frech ◽  
Gregor Schuster ◽  
Fabian T. Andes ◽  
Georg Schett ◽  
Mario M. Zaiss ◽  
...  
Keyword(s):  
Immune Cells ◽  
Osteoclast Differentiation ◽  
Fine Tuning ◽  
Bone Architecture ◽  
Marker Genes ◽  
Bone Homeostasis ◽  
Adaptive Immune Cells ◽  
B7 Family

Butyrophilins, which are members of the extended B7 family of immunoregulators structurally related to the B7 family, have diverse functions on immune cells as co-stimulatory and co-inhibitory molecules. Despite recent advances in the understanding on butyrophilins’ role on adaptive immune cells during infectious or autoimmune diseases, nothing is known about their role in bone homeostasis. Here, we analyzed the role of one specific butyrophilin, namely Btn2a2, as we have recently shown that Btn2a2 is expressed on the monocyte/macrophage lineage that also gives rise to bone degrading osteoclasts. We found that expression of Btn2a2 on monocytes and pre-osteoclasts is upregulated by the receptor activator of nuclear factor κ-B ligand (RANKL), an essential protein required for osteoclast formation. Interestingly, in Btn2a2-deficient osteoclasts, typical osteoclast marker genes (Nfatc1, cathepsin K, TRAP, and RANK) were downregulated following RANKL stimulation. In vitro osteoclast assays resulted in decreased TRAP positive osteoclast numbers in Btn2a2-deficient cells. However, Btn2a2-deficient osteoclasts revealed abnormal fusion processes shown by their increased size. In vivo steady state µCT and histological analysis of bone architecture in complete Btn2a2-deficient mice showed differences in bone parameters further highlighting the fine-tuning effect of BTN2a2. Moreover, in rheumatoid arthritis patients and experimental arthritis, we detected significantly decreased serum levels of the secreted soluble Btn2a2 protein. Taken together, we identified the involvement of the immunomodulatory molecule Btn2a2 in osteoclast differentiation with potential future implications in basic and translational osteoimmunology.

scholarly journals Plasma membrane calcium ATPase regulates bone mass by fine-tuning osteoclast differentiation and survival

2012 ◽  
Vol 199 (7) ◽  
pp. 1145-1158 ◽  
Author(s):  
Hyung Joon Kim ◽  
Vikram Prasad ◽  
Seok-Won Hyung ◽  
Zang Hee Lee ◽  
Sang-Won Lee ◽  
...  
Keyword(s):  
Plasma Membrane ◽  
Bone Mass ◽  
Osteoclast Differentiation ◽  
Premenopausal Women ◽  
Fine Tuning ◽  
Bone Homeostasis ◽  
Regulatory Loop ◽  
And Function

The precise regulation of Ca2+ dynamics is crucial for proper differentiation and function of osteoclasts. Here we show the involvement of plasma membrane Ca2+ ATPase (PMCA) isoforms 1 and 4 in osteoclastogenesis. In immature/undifferentiated cells, PMCAs inhibited receptor activator of NF-κB ligand–induced Ca2+ oscillations and osteoclast differentiation in vitro. Interestingly, nuclear factor of activated T cell c1 (NFATc1) directly stimulated PMCA transcription, whereas the PMCA-mediated Ca2+ efflux prevented NFATc1 activation, forming a negative regulatory loop. PMCA4 also had an anti-osteoclastogenic effect by reducing NO, which facilitates preosteoclast fusion. In addition to their role in immature cells, increased expression of PMCAs in mature osteoclasts prevented osteoclast apoptosis both in vitro and in vivo. Mice heterozygous for PMCA1 or null for PMCA4 showed an osteopenic phenotype with more osteoclasts on bone surface. Furthermore, PMCA4 expression levels correlated with peak bone mass in premenopausal women. Thus, our results suggest that PMCAs play important roles for the regulation of bone homeostasis in both mice and humans by modulating Ca2+ signaling in osteoclasts.

Physical plasma and leukocytes – immune or reactive?

2018 ◽  
Vol 400 (1) ◽  
pp. 63-75 ◽  
Author(s):  
Sander Bekeschus ◽  
Christian Seebauer ◽  
Kristian Wende ◽  
Anke Schmidt
Keyword(s):  
Wound Healing ◽  
Immune System ◽  
Plasma Treatment ◽  
Immune Cells ◽  
The Body ◽  
Adaptive Immune ◽  
Adaptive Immune Cells ◽  
Physical Plasma

AbstractLeukocytes are professionals in recognizing and removing pathogenic or unwanted material. They are present in virtually all tissues, and highly motile to enter or leave specific sites throughout the body. Less than a decade ago, physical plasmas entered the field of medicine to deliver their delicate mix of reactive species and other physical agents for mainly dermatological or oncological therapy. Plasma treatment thus affects leukocytes via direct or indirect means: immune cells are either present in tissues during treatment, or infiltrate or exfiltrate plasma-treated areas. The immune system is crucial for human health and resolution of many types of diseases. It is therefore vital to study the response of leukocytes after plasma treatmentin vitroandin vivo. This review gathers together the major themes in the plasma treatment of innate and adaptive immune cells, and puts these into the context of wound healing and oncology, the two major topics in plasma medicine.

scholarly journals Constitutive Activation of β-Catenin in Differentiated Osteoclasts Induces Bone Loss in Mice

2018 ◽  
Vol 48 (5) ◽  
pp. 2091-2102 ◽  
Author(s):  
Xin Sui ◽  
Shijian Deng ◽  
Mengmeng Liu ◽  
Linlin Fan ◽  
Yunfei Wang ◽  
...  
Keyword(s):  
Bone Loss ◽  
Bone Mass ◽  
Bone Growth ◽  
Osteoclast Differentiation ◽  
Marker Genes ◽  
Tartrate Resistant Acid Phosphatase ◽  
Bone Homeostasis ◽  
Micro Computed Tomography ◽  
Constitutive Activation

Background/Aims: Activation of the Wnt/β-catenin signalling pathway has been widely investigated in bone biology and shown to promote bone formation. However, its specific effects on osteoclast differentiation have not been fully elucidated. Our study aimed to identify the role of β-catenin in osteoclastogenesis and bone homeostasis. Methods: In the present study, exon 3 in the β-catenin gene (Ctnnb1) allele encoding phosphorylation target serine/threonine residues was flanked by floxP sequences. We generated mice exhibiting conditional β-catenin activation (Ctsk-Cre;Ctnnb1flox(exon3)/+, designated CA-β-catenin) by crossing Ctnnb1flox(exon3)/flox(exon3) mice with osteoclast-specific Ctsk-Cre mice. Bone growth and bone mass were analysed by micro-computed tomography (micro-CT) and histomorphometry. To further examine osteoclast activity, osteoclasts were induced from bone marrow monocytes (BMMs) isolated from CA-β-catenin and Control mice in vitro. Osteoclast differentiation was detected by tartrate-resistant acid phosphatase (TRAP) staining, immunofluorescence staining and reverse transcription-quantitative PCR (RT–qPCR) analysis. Results: Growth retardation and low bone mass were observed in CA-β-catenin mice. Compared to controls, CA-β-catenin mice had significantly reduced trabecular bone numbers under growth plates as well as thinner cortical bones. Moreover, increased TRAP-positive osteoclasts were observed on the surfaces of trabecular bones and cortical bones in the CA-β-catenin mice; consistent results were observed in vitro. In the CA-β-catenin group, excessive numbers of osteoclasts were induced from BMMs, accompanied by the increased expression of osteoclast-associated marker genes. Conclusion: These results indicated that the constitutive activation of β-catenin in osteoclasts promotes osteoclast formation, resulting in bone loss.

scholarly journals The immunoregulation of mesenchymal stem cells plays a critical role in improving the prognosis of liver transplantation

2019 ◽  
Vol 17 (1) ◽  
Author(s):  
Chenxia Hu ◽  
Lanjuan Li
Keyword(s):  
Liver Transplantation ◽  
Natural Killer ◽  
Immune Cells ◽  
Adaptive Systems ◽  
Critical Role ◽  
Arterial System ◽  
Cell Mediated Immunity ◽  
Adaptive Immune Cells

AbstractThe liver is supplied by a dual blood supply, including the portal venous system and the hepatic arterial system; thus, the liver organ is exposed to multiple gut microbial products, metabolic products, and toxins; is sensitive to extraneous pathogens; and can develop liver failure, liver cirrhosis and hepatocellular carcinoma (HCC) after short-term or long-term injury. Although liver transplantation (LT) serves as the only effective treatment for patients with end-stage liver diseases, it is not very popular because of the complications and low survival rates. Although the liver is generally termed an immune and tolerogenic organ with adaptive systems consisting of humoral immunity and cell-mediated immunity, a high rejection rate is still the main complication in patients with LT. Growing evidence has shown that mesenchymal stromal cell (MSC) transplantation could serve as an effective immunomodulatory strategy to induce tolerance in various immune-related disorders. MSCs are reported to inhibit the immune response from innate immune cells, including macrophages, dendritic cells (DCs), natural killer cells (NK cells), and natural killer T (NKT) cells, and that from adaptive immune cells, including T cells, B cells and other liver-specific immune cells, for the generation of a tolerogenic microenvironment. In this review, we summarized the relationship between LT and immunoregulation, and we focused on how to improve the effects of MSC transplantation to improve the prognosis of LT. Only after exhaustive clarification of the potential immunoregulatory mechanisms of MSCs in vitro and in vivo can we implement MSC protocols in routine clinical practice to improve LT outcome.

scholarly journals Transcriptional Modulator Ifrd1 Regulates Osteoclast Differentiation through Enhancing the NF-κB/NFATc1 Pathway

2016 ◽  
Vol 36 (19) ◽  
pp. 2451-2463 ◽  
Author(s):  
Takashi Iezaki ◽  
Kazuya Fukasawa ◽  
Gyujin Park ◽  
Tetsuhiro Horie ◽  
Takashi Kanayama ◽  
...  
Keyword(s):  
Bone Loss ◽  
Osteoclast Differentiation ◽  
Nuclear Factor Κb ◽  
Bone Diseases ◽  
Nuclear Factor ◽  
Activator Protein 1 ◽  
Bone Homeostasis ◽  
Activated T Cells

Bone homeostasis is maintained by the synergistic actions of bone-resorbing osteoclasts and bone-forming osteoblasts. Here, we show that the transcriptional coactivator/repressor interferon-related developmental regulator 1 (Ifrd1) is expressed in osteoclast lineages and represents a component of the machinery that regulates bone homeostasis. Ifrd1 expression was transcriptionally regulated in preosteoclasts by receptor activator of nuclear factor κB (NF-κB) ligand (RANKL) through activator protein 1. Global deletion of murineIfrd1increased bone formation and decreased bone resorption, leading to a higher bone mass. Deletion ofIfrd1in osteoclast precursors prevented RANKL-induced bone loss, although no bone loss was observed under normal physiological conditions. RANKL-dependent osteoclastogenesis was impairedin vitroinIfrd1-deleted bone marrow macrophages (BMMs).Ifrd1deficiency increased the acetylation of p65 at residues K122 and K123 via the inhibition of histone deacetylase-dependent deacetylation in BMMs. This repressed the NF-κB-dependent transcription of nuclear factor of activated T cells, cytoplasmic 1 (NFATc1), an essential regulator of osteoclastogenesis. These findings suggest that an Ifrd1/NF-κB/NFATc1 axis plays a pivotal role in bone remodelingin vivoand represents a therapeutic target for bone diseases.

scholarly journals NLRP12 provides a critical checkpoint for osteoclast differentiation

2015 ◽  
Vol 112 (33) ◽  
pp. 10455-10460 ◽  
Author(s):  
Jennifer L. Krauss ◽  
Rong Zeng ◽  
Cynthia L. Hickman-Brecks ◽  
Justin E. Wilson ◽  
Jenny P.-Y. Ting ◽  
...  
Keyword(s):  
Nuclear Factor Kappa B ◽  
Nuclear Translocation ◽  
Osteoclast Differentiation ◽  
Disease Model ◽  
Nuclear Factor ◽  
Bone Homeostasis ◽  
Genetic Ablation ◽  
Nuclear Factor Kappa

The alternative or noncanonical nuclear factor kappa B (NF-κB) pathway regulates the osteoclast (OC) response to receptor activator of nuclear factor kappa B ligand (RANKL) and thus bone metabolism. Although several lines of evidence support the emerging concept that nucleotide-binding leucine-rich repeat and pyrin domain-containing receptor 12 (NLRP12) impedes alternative NF-κB activation in innate immune cells, a functional role for NLRP12 outside an inflammatory disease model has yet to be reported. Our study demonstrates that NLRP12 has a protective role in bone via suppression of alternative NF-κB–induced osteoclastogenesis and is down-modulated in response to osteoclastogenic stimuli. Here, we show that retroviral overexpression of NLRP12 suppressed RelB nuclear translocation and OC formation. Conversely, genetic ablation of NLRP12 promoted NIK stabilization, RelB nuclear translocation, and increased osteoclastogenesis in vitro. Using radiation chimeras, we demonstrated these in vitro observations dovetail with our in vivo findings that NLRP12 deficiency leads to enhanced OC numbers accompanied by a significant decline in bone mass under physiological conditions. Consistent with the basal bone phenotype, we also observed an enhanced osteolytic response following RANKL injection over the calvaria of NLRP12-deficient chimeric mice compared with wild-type control mice. Thus, modulation of NLRP12 levels controls alternative NF-κB signaling in OC precursors, altering bone homeostasis and osteolytic responses.

scholarly journals Autoamplification of NFATc1 expression determines its essential role in bone homeostasis

2005 ◽  
Vol 202 (9) ◽  
pp. 1261-1269 ◽  
Author(s):  
Masataka Asagiri ◽  
Kojiro Sato ◽  
Takako Usami ◽  
Sae Ochi ◽  
Hiroshi Nishina ◽  
...  
Keyword(s):  
Essential Role ◽  
Osteoclast Differentiation ◽  
Ectopic Expression ◽  
Epigenetic Mechanism ◽  
Bone Homeostasis ◽  
Hematopoietic Stem ◽  
Vitro Effect

NFATc1 and NFATc2 are functionally redundant in the immune system, but it was suggested that NFATc1 is required exclusively for differentiation of osteoclasts in the skeletal system. Here we provide genetic evidence that NFATc1 is essential for osteoclast differentiation in vivo by adoptive transfer of NFATc1−/− hematopoietic stem cells to osteoclast-deficient Fos−/− mice, and by Fos−/− blastocyst complementation, thus avoiding the embryonic lethality of NFATc1−/− mice. However, in vitro osteoclastogenesis in NFATc1-deficient cells was rescued by ectopic expression of NFATc2. The discrepancy between the in vivo essential role of NFATc1 and the in vitro effect of NFATc2 was attributed to selective autoregulation of the NFATc1 gene by NFAT through its promoter region. This suggested that an epigenetic mechanism contributes to the essential function of NFATc1 in cell lineage commitment. Thus, this study establishes that NFATc1 represents a potential therapeutic target for bone disease and reveals a mechanism that underlies the essential role of NFATc1 in bone homeostasis.

scholarly journals Toddalolactone Protects Against Osteoarthritis by Ameliorating Chondrocyte Inflammation and Suppressing Osteoclastogenesis

2021 ◽  
Author(s):  
Yiming Xu ◽  
Song Xue ◽  
Tian Zhang ◽  
Xinmeng Jin ◽  
Cong Wang ◽  
...  
Keyword(s):  
Cruciate Ligament ◽  
Osteoclast Differentiation ◽  
Joint Disease ◽  
Marker Genes ◽  
Mapk Signalling ◽  
Cartilage Erosion ◽  
Anterior Cruciate ◽  
Toddalia Asiatica

Abstract Background: Osteoarthritis (OA) is widely recognized as the most common chronic joint disease accompanied by progressive cartilage and subchondral bone damage. Toddalolactone (TOD), a natural compound extracted from Toddalia asiatica (L.) Lam., has been widely used in the treatment of stroke, rheumatoid arthritis, and oedema. Nevertheless, what TOD acts as in the pathogenesis and progression of OA hasn’t been reported. In this investigation, we have aimed to determine how TOD affects OA in vitro and in vivo.Methods: LPS (10μg/ml) was employed to induce chondrocyte inflammation or RANKL to induce osteoclast differentiation in bone marrow derived macrophages (BMMs); Meanwhile, the effects of TOD on chondrocyte inflammation and osteoclast differentiation were evaluated. Anterior cruciate ligament transection (ACLT) was performed to develop an OA animal model and study the effects of TOD.Results: We found that TOD inhibited the expression of inflammatory and catabolic mediators ( IL-6, IL-8, TNF-α, MMP2, MMP9, and MMP13) in LPS-treated chondrocytes in vitro. Furthermore, TOD was proven to inhibit RANKL-induced-osteoclastogenesis and inhibit the expression of marker genes (NFATc1 and c-fos). Our data also confirmed that TOD suppressed the destruction of articular cartilage and osteoclastogenesis by inhibiting the activation of the NF-κB and MAPK signalling pathways. In the ACLT mouse model, we found that TOD attenuated the ACLT-induced cartilage erosion and inhibited bone resorption.Conclusions: These results showed that TOD can be adopted as a potential therapeutic agent for OA.

scholarly journals ELMO1 Regulates RANKL-Stimulated Differentiation and Bone Resorption of Osteoclasts

2021 ◽  
Vol 9 ◽  
Author(s):  
Xinyue Liang ◽  
Yafei Hou ◽  
Lijuan Han ◽  
Shuxiang Yu ◽  
Yunyun Zhang ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Bone Resorption ◽  
Bone Erosion ◽  
Osteoclast Differentiation ◽  
Small Gtpases ◽  
Bone Diseases ◽  
Bone Homeostasis ◽  
Nucleotide Exchange

Bone homeostasis is a metabolic balance between the new bone formation by osteoblasts and old bone resorption by osteoclasts. Excessive osteoclastic bone resorption results in low bone mass, which is the major cause of bone diseases such as rheumatoid arthritis. Small GTPases Rac1 is a key regulator of osteoclast differentiation, but its exact mechanism is not fully understood. ELMO and DOCK proteins form complexes that function as guanine nucleotide exchange factors for Rac activation. Here, we report that ELMO1 plays an important role in differentiation and bone resorption of osteoclasts. Osteoclast precursors derived from bone marrow monocytes (BMMs) of Elmo1–/– mice display defective adhesion and migration during differentiation. The cells also have a reduced activation of Rac1, p38, JNK, and AKT in response to RANKL stimulation. Importantly, we show that bone erosion is alleviated in Elmo1–/– mice in a rheumatoid arthritis mouse model. Taken together, our results suggest that ELMO1, as a regulator of Rac1, regulates osteoclast differentiation and bone resorption both in vitro and in vivo.

Sbds is required for Rac2-mediated monocyte migration and signaling downstream of RANK during osteoclastogenesis

Blood ◽  
2011 ◽  
Vol 117 (6) ◽  
pp. 2044-2053 ◽  
Author(s):  
Roland Leung ◽  
Karl Cuddy ◽  
Yongqiang Wang ◽  
Johanna Rommens ◽  
Michael Glogauer
Keyword(s):  
Pancreatic Insufficiency ◽  
Osteoclast Differentiation ◽  
Osteoclast Formation ◽  
Exocrine Pancreatic Insufficiency ◽  
Actin Dynamics ◽  
Bone Homeostasis ◽  
Skeletal Abnormalities ◽  
Monocyte Migration

Abstract Shwachman-Diamond syndrome (SDS) results from mutations in the SBDS gene, characterized by exocrine pancreatic insufficiency and hematologic and skeletal abnormalities. Neutropenia and neutrophil dysfunction are hallmark features of SDS; however, causes for the bone defects are unknown. Dysfunction of bone-resorbing osteoclasts, formed by the fusion of monocytic progenitors derived from the same granulocytic precursors as neutrophils, could be responsible. We report that Sbds is required for in vitro and in vivo osteoclastogenesis (OCG). Sbds-null murine monocytes formed osteoclasts of reduced number and size because of impaired migration and fusion required for OCG. Phenotypically, Sbds-null mice exhibited low-turnover osteoporosis consistent with findings in SDS patients. Western blotting of Rho GTPases that control actin dynamics and migration showed a 5-fold decrease in Rac2, whereas Rac1, Cdc42, and RhoA were unchanged or only mildly reduced. Although migration was rescued on Rac2 supplementation, OCG was not. This was attributed to impaired signaling downstream of receptor activator of nuclear factor-κB (RANK) and reduced expression of the RANK-ligand-dependent fusion receptor DC-STAMP. We conclude that Sbds is required for OCG by regulating monocyte migration via Rac2 and osteoclast differentiation signaling downstream of RANK. Impaired osteoclast formation could disrupt bone homeostasis, resulting in skeletal abnormalities seen in SDS patients.

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