The P2X7 Receptor: A Key Player in Immune-Mediated Bone Loss?

Inflammatory diseases are often multiorganic diseases with manifestations not related directly to the primary affected organ. They are often complicated by a generalized bone loss that subsequently leads to osteoporosis and bone fractures. The exact mechanism for the accompanying bone loss is not understood in full detail, but factors such as glucocorticoid treatment, immobilization, malnutrition, and insufficient intake of vitamin D play a role. However, it has become evident that the inflammatory process itself is involved and the resulting bone loss is termed immune-mediated bone loss. It stems from an increase in bone resorption and the pro-inflammatory cytokines tumor necrosis factor alpha and interleukin 1 beta and has been shown to not only mediate the inflammatory response but also to strongly stimulate bone degradation. The purinergic P2X7 receptor is central in the processing of these two cytokines and in the initiation of the inflammatory response, and it is a key molecule in the regulation of both bone formation and bone resorption. The aim of this review is therefore to provide evidence-based novel hypotheses of the role of ATP-mediated purinergic signalling via the P2X7 receptor in immune-mediated bone loss and -osteoporosis.

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Capsaicin, a TRPV1 Ligand, Suppresses Bone Resorption by Inhibiting the Prostaglandin E Production of Osteoblasts, and Attenuates the Inflammatory Bone Loss Induced by Lipopolysaccharide

ISRN Pharmacology ◽

10.5402/2012/439860 ◽

2012 ◽

Vol 2012 ◽

pp. 1-6 ◽

Cited By ~ 11

Author(s):

Megumi Kobayashi ◽

Kenta Watanabe ◽

Satoshi Yokoyama ◽

Chiho Matsumoto ◽

Michiko Hirata ◽

...

Keyword(s):

Bone Resorption ◽

Bone Loss ◽

Transient Receptor Potential ◽

Interleukin 1 ◽

Osteoclast Differentiation ◽

Bone Diseases ◽

Prostaglandin E ◽

Transient Receptor Potential Vanilloid ◽

Cox 2

Capsaicin, a transient receptor potential vanilloid type 1 (TRPV1) ligand, regulates nerve-related pain-sensitive signals, inflammation, and cancer growth. Capsaicin suppresses interleukin-1-induced osteoclast differentiation, but its roles in bone tissues and bone diseases are not known. This study examined the effects of capsaicin on inflammatory bone resorption and prostaglandin E (PGE) production induced by lipopolysaccharide (LPS) in vitro and on bone mass in LPS-treated mice in vivo. Capsaicin suppressed osteoclast formation, bone resorption, and PGE production induced by LPS in vitro. Capsaicin suppressed the expression of cyclooxygenase-2 (COX-2) and membrane-bound PGE synthase-1 (mPGES-1) mRNAs and PGE production induced by LPS in osteoblasts. Capsaicin may suppress PGE production by inhibiting the expression of COX-2 and mPGES-1 in osteoblasts and LPS-induced bone resorption by TRPV1 signals because osteoblasts express TRPV1. LPS treatment markedly induced bone loss in the femur in mice, and capsaicin significantly restored the inflammatory bone loss induced by LPS in mice. TRPV1 ligands like capsaicin may therefore be potentially useful as clinical drugs targeting bone diseases associated with inflammatory bone resorption.

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Biological reaction to debris in relation to joint prostheses

Proceedings of the Institution of Mechanical Engineers Part H Journal of Engineering in Medicine ◽

10.1243/0954411971534304 ◽

1997 ◽

Vol 211 (2) ◽

pp. 187-197 ◽

Cited By ~ 145

Author(s):

P A Revell ◽

N AL-Saffar ◽

A Kobayashi

Keyword(s):

Bone Resorption ◽

Bone Loss ◽

Inflammatory Response ◽

Joint Replacement ◽

Total Joint Replacement ◽

Wear Particles ◽

Cellular Reaction ◽

Biological Reaction ◽

Joint Prostheses

Bone loss induced by the inflammatory response to wear particles is a major cause of long-term failure of total joint replacement. This review describes the cellular reaction occurring in response to these particles and what is currently known about the inflammatory mechanisms contributing to bone resorption.

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Angiogenin Reduces Immune Inflammation via Inhibition of TANK-Binding Kinase 1 Expression in Human Corneal Fibroblast Cells

Mediators of Inflammation ◽

10.1155/2014/861435 ◽

2014 ◽

Vol 2014 ◽

pp. 1-12 ◽

Cited By ~ 13

Author(s):

Seung Hoon Lee ◽

Kyoung Woo Kim ◽

Kyong-Mi Min ◽

Kyu-Wan Kim ◽

Soo-Ik Chang ◽

...

Keyword(s):

Inflammatory Response ◽

Mrna Expression ◽

Nuclear Translocation ◽

Inflammatory Diseases ◽

Interleukin 1 ◽

Necrosis Factor Alpha ◽

Protein Levels ◽

Immune Mediated ◽

Chemotactic Protein ◽

Anti Inflammatory

Angiogenin (ANG) is reportedly multifunctional, with roles in angiogenesis and autoimmune diseases. This protein is involved in the innate immune system and has been implicated in several inflammatory diseases. Although ANG may be involved in the anti-inflammatory response, there is no evidence that it has direct anti-inflammatory effects. In this study we sought to determine whether ANG has an anti-inflammatory effect in human corneal fibroblasts (HCFs) exposed to media containing tumor necrosis factor-alpha (TNF-α). We found that ANG reduced the mRNA expression of interleukin-1 beta (IL-1β), -6, -8 and TNF-αreceptors (TNFR) 1 and 2. In contrast, ANG increased the mRNA expression of IL-4 and -10. Protein levels of TANK-binding kinase 1 (TBK1) were reduced by ANG in HCFs treated with TNF-α. Moreover, ANG diminished the expression of IL-6 and -8 and monocyte chemotactic protein- (MCP-) 1. The protein expression of nuclear factor-κB (NF-κB) was downregulated by ANG treatment. These findings suggest that ANG suppressed the TNF-α-induced inflammatory response in HCFs through inhibition of TBK1-mediated NF-κB nuclear translocation. These novel results are likely to play a significant role in the selection of immune-mediated inflammatory therapeutic targets and may shed light on the pathogenesis of immune-mediated inflammatory diseases.

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Interleukin-1 is essential for systemic inflammatory bone loss

Annals of the Rheumatic Diseases ◽

10.1136/ard.2008.104786 ◽

2009 ◽

Vol 69 (01) ◽

pp. 284-290 ◽

Cited By ~ 70

Author(s):

K Polzer ◽

L Joosten ◽

J Gasser ◽

J H Distler ◽

G Ruiz ◽

...

Keyword(s):

Bone Resorption ◽

Bone Loss ◽

Bone Microarchitecture ◽

Structural Parameters ◽

Interleukin 1 ◽

Ct Scanning ◽

Osteoclast Formation ◽

Bone Architecture ◽

Wild Type ◽

Systemic Bone Loss

Objectives:Chronic inflammation is a major risk factor for systemic bone loss leading to osteoporotic fracture and substantial morbidity and mortality. Inflammatory cytokines, particularly tumour necrosis factor (TNF) and interleukin-1 (IL1), are thought to play a key role in the pathogenesis of inflammation-induced bone loss, but their exact roles are yet to be determined.Methods:To determine whether TNF directly triggers bone loss or requires IL1, human TNFα mice (hTNFtg) were crossed with mice lacking IL1α and IL1β (IL1−/−hTNFtg). Systemic bone architecture was evaluated using CT scanning, static and dynamic bone histomorphometry and serum markers of bone metabolism.Results:hTNFtg mice developed severe bone loss accompanied by a severe distortion of bone microarchitecture. Bone trabeculae were thinner and decreased in numbers, resulting in increased trabecular separation. Histomorphometric analyses revealed strongly increased bone resorption in hTNFtg mice compared with wild-type mice. In contrast, IL1−/−hTNFtg mice were fully protected from systemic bone loss despite still developing inflammation in their joints. Lack of IL1 completely reversed increased osteoclast formation and bone resorption in hTNFtg mice and the increased levels of RANKL in these mice. Structural parameters and osteoclast and osteoblast numbers were indistinguishable from wild-type mice.Conclusions:These data indicate that IL1 is essential for TNF-mediated bone loss. Despite TNF-mediated inflammatory arthritis, systemic bone is fully protected by the absence of IL1, which suggests that IL1 is an essential mediator of inflammatory osteopenia.

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Interleukin-1 receptor antagonist decreases bone loss and bone resorption in ovariectomized rats.

Journal of Clinical Investigation ◽

10.1172/jci117187 ◽

1994 ◽

Vol 93 (5) ◽

pp. 1959-1967 ◽

Cited By ~ 179

Author(s):

R B Kimble ◽

J L Vannice ◽

D C Bloedow ◽

R C Thompson ◽

W Hopfer ◽

...

Keyword(s):

Bone Resorption ◽

Bone Loss ◽

Receptor Antagonist ◽

Interleukin 1 ◽

Ovariectomized Rats ◽

Interleukin 1 Receptor Antagonist

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Decitabine Inhibits Bone Resorption in Periodontitis by Upregulating Anti-Inflammatory Cytokines and Suppressing Osteoclastogenesis

Biomedicines ◽

10.3390/biomedicines9020199 ◽

2021 ◽

Vol 9 (2) ◽

pp. 199

Author(s):

Urara Tanaka ◽

Shunichi Kajioka ◽

Livia S. Finoti ◽

Daniela B. Palioto ◽

Denis F. Kinane ◽

...

Keyword(s):

Dna Methylation ◽

Bone Resorption ◽

Bone Loss ◽

Inflammatory Cytokines ◽

Osteoclast Differentiation ◽

Tartrate Resistant Acid Phosphatase ◽

Dependent Manner ◽

Bone Homeostasis ◽

Osteoblastic Cell Line ◽

Anti Inflammatory

DNA methylation controls several inflammatory genes affecting bone homeostasis. Hitherto, inhibition of DNA methylation in vivo in the context of periodontitis and osteoclastogenesis has not been attempted. Ligature-induced periodontitis in C57BL/6J mice was induced by placing ligature for five days with Decitabine (5-aza-2′-deoxycytidine) (1 mg/kg/day) or vehicle treatment. We evaluated bone resorption, osteoclast differentiation by tartrate-resistant acid phosphatase (TRAP) and mRNA expression of anti-inflammatory molecules using cluster differentiation 14 positive (CD14+) monocytes from human peripheral blood. Our data showed that decitabine inhibited bone loss and osteoclast differentiation experimental periodontitis, and suppressed osteoclast CD14+ human monocytes; and conversely, that it increased bone mineralization in osteoblastic cell line MC3T3-E1 in a concentration-dependent manner. In addition to increasing IL10 (interleukin-10), TGFB (transforming growth factor beta-1) in CD14+ monocytes, decitabine upregulated KLF2 (Krüppel-like factor-2) expression. Overexpression of KLF2 protein enhanced the transcription of IL10 and TGFB. On the contrary, site-directed mutagenesis of KLF2 binding site in IL10 and TFGB abrogated luciferase activity in HEK293T cells. Decitabine reduces bone loss in a mouse model of periodontitis by inhibiting osteoclastogenesis through the upregulation of anti-inflammatory cytokines via KLF2 dependent mechanisms. DNA methyltransferase inhibitors merit further investigation as a possible novel therapy for periodontitis.

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Estrogen Decreases Cytoskeletal Organization by Forming an ERα/SHP2/c-Src Complex in Osteoclasts to Protect against Ovariectomy-Induced Bone Loss in Mice

Antioxidants ◽

10.3390/antiox10040619 ◽

2021 ◽

Vol 10 (4) ◽

pp. 619

Author(s):

Hyun-Jung Park ◽

Malihatosadat Gholam-Zadeh ◽

Sun-Young Yoon ◽

Jae-Hee Suh ◽

Hye-Seon Choi

Keyword(s):

Bone Resorption ◽

Bone Loss ◽

Ring Formation ◽

Tartrate Resistant Acid Phosphatase ◽

Actin Ring ◽

Collagen Crosslinks ◽

Trap Staining ◽

Src Activation

Loss of ovarian function is closely related to estrogen (E2) deficiency, which is responsible for increased osteoclast (OC) differentiation and activity. We aimed to investigate the action mechanism of E2 to decrease bone resorption in OCs to protect from ovariectomy (OVX)-induced bone loss in mice. In vivo, tartrate-resistant acid phosphatase (TRAP) staining in femur and serum carboxy-terminal collagen crosslinks-1 (CTX-1) were analyzed upon E2 injection after OVX in mice. In vitro, OCs were analyzed by TRAP staining, actin ring formation, carboxymethylation, determination of reactive oxygen species (ROS) level, and immunoprecipitation coupled with Western blot. In vivo and in vitro, E2 decreased OC size more dramatically than OC number and Methyl-piperidino-pyrazole hydrate dihydrochloride (MPPD), an estrogen receptor alpha (ERα) antagonist, augmented the OC size. ERα was found in plasma membranes and E2/ERα signaling affected receptor activator of nuclear factor κB ligand (RANKL)-induced actin ring formation by rapidly decreasing a proto-oncogene tyrosine-protein kinase, cellular sarcoma (c-Src) (Y416) phosphorylation in OCs. E2 exposure decreased physical interactions between NADPH oxidase 1 (NOX1) and the oxidized form of c-Src homology 2 (SH2)-containing protein tyrosine phosphatase 2 (SHP2), leading to higher levels of reduced SHP2. ERα formed a complex with the reduced form of SHP2 and c-Src to decrease c-Src activation upon E2 exposure, which blocked a signal for actin ring formation by decreased Vav guanine nucleotide exchange factor 3 (Vav3) (p–Y) and Ras-related C3 botulinum toxin substrate 1 (Rac1) (GTP) activation in OCs. E2/ERα signals consistently inhibited bone resorption in vitro. In conclusion, our study suggests that E2-binding to ERα forms a complex with SHP2/c-Src to attenuate c-Src activation that was induced upon RANKL stimulation in a non-genomic manner, resulting in an impaired actin ring formation and reducing bone resorption.

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Structural basis for the functional properties of the P2X7 receptor for extracellular ATP

Purinergic Signalling ◽

10.1007/s11302-021-09790-x ◽

2021 ◽

Author(s):

Lin-Hua Jiang ◽

Emily A. Caseley ◽

Steve P. Muench ◽

Sébastien Roger

Keyword(s):

Functional Properties ◽

P2x7 Receptor ◽

Site Directed Mutagenesis ◽

P2x Receptor ◽

Structural Basis ◽

Structure Characteristic ◽

Purinergic Signalling ◽

Directed Mutagenesis ◽

Important Mediator ◽

Receptor Family

AbstractThe P2X7 receptor, originally known as the P2Z receptor due to its distinctive functional properties, has a structure characteristic of the ATP-gated ion channel P2X receptor family. The P2X7 receptor is an important mediator of ATP-induced purinergic signalling and is involved the pathogenesis of numerous conditions as well as in the regulation of diverse physiological functions. Functional characterisations, in conjunction with site-directed mutagenesis, molecular modelling, and, recently, structural determination, have provided significant insights into the structure–function relationships of the P2X7 receptor. This review discusses the current understanding of the structural basis for the functional properties of the P2X7 receptor.

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Physiological plasma levels of androgens reduce bone loss in the ovariectomized rat

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.1998.274.2.e328 ◽

1998 ◽

Vol 274 (2) ◽

pp. E328-E335 ◽

Cited By ~ 5

Author(s):

C. K. Lea ◽

A. M. Flanagan

Keyword(s):

Bone Resorption ◽

Bone Loss ◽

Protective Effect ◽

Cancellous Bone ◽

Plasma Levels ◽

Slow Release ◽

Bone Volume ◽

Ovariectomized Rat ◽

Ovx Rats ◽

Reduce Bone Loss

The effect of androstenedione (ADIONE) slow-release pellets on cancellous bone volume (BV/TV) at the tibial metaphysis was investigated in ovariectomized (OVX) rats at various times from 21 to 180 days. Plasma levels of ADIONE and testosterone (T) in OVX rats were significantly reduced at 21 days and were restored close to levels in the sham rats with the 1.5-mg ADIONE pellet. OVX animals with and without ADIONE pellets resulted in close to a 50% reduction in BV/TV by day 21. By day 180, OVX rats had only ∼5% BV/TV, whereas that in ADIONE-treated OVX rats was significantly greater at ∼12%. The reduced BV/TV was associated with increased bone resorption and formation. In a separate 90-day experiment, we found that the antiandrogen, Casodex, abrogated the ADIONE-induced skeletal-protective effect in OVX rats, whereas the antiaromatase, Arimidex, had no effect. This provides evidence that ADIONE protects against the development of osteopenia in the estrogen-deficient rat and mediates its effect through androgens and not estrogens.

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