α-Tocopheryl Succinate Inhibits Osteoclast Formation by Suppressing Receptor Activator of Nuclear Factor-kappaB Ligand (RANKL) Expression and Bone Resorption

Receptor activator of nuclear factorκB ligand (RANKL) plays a crucial role in the bone erosion of rheumatoid arthritis (RA) by prompting osteoclastogenesis. Considering that 1,25(OH)2D3has been suggested as a potent inducer of RANKL expression, it should clarify whether vitamin D supplement could result in RANKL overexpression and thereby facilitate excessive osteoclastogenesis and bone resorption in RA. Here, we investigated modulatory effect of 1,25(OH)2D3on the expression of RANKL and its decoy receptor osteoprotegerin (OPG) in an inflammatory condition of human rheumatoid synoviocyte MH7A. MH7A cells were stimulated with IL1βand then treated with different concentrations of 1,25(OH)2D3for 48 h. A significantly elevated OPG/RANKL ratio and markedly decreased levels of IL-6 and TNFβmRNA expression in cells and IL-6 protein in supernatants were observed in IL1β-induced MH7A in the presence of 1,25(OH)2D3compared with those in the absence of it. Osteoclast formation was obviously decreased when RAW264.7 cells were treated with both 1,25(OH)2D3and IL1β. In summary, although it has a biological function to induce RANKL expression, 1,25(OH)2D3could upregulate OPG/RANKL ratio and mediate anti-inflammatory action in an inflammatory milieu of synoviocyte, contributing to the inhibition of inflammation-induced osteoclastogenesis in RA.

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Receptor Activator for Nuclear Factor Kappab Ligand and Osteoprotegerin: Regulators of Bone Physiology and Immune Responses/Potential Therapeutic Agents and Biochemical Markers

Annals of Clinical Biochemistry International Journal of Laboratory Medicine ◽

10.1177/000456320203900602 ◽

2002 ◽

Vol 39 (6) ◽

pp. 551-556 ◽

Cited By ~ 14

Author(s):

Katherine A Buckley ◽

William D Fraser

Keyword(s):

Osteoclast Formation ◽

Bone Diseases ◽

Bone Cancer Pain ◽

Current Evidence ◽

Nuclear Factor Kappab ◽

Nuclear Factor ◽

Bone Biology ◽

Phase I Clinical Trials ◽

Post Menopausal Osteoporosis ◽

Receptor Activator

The discovery of receptor activator for nuclear factor kappaB ligand (RANKL) and osteoprotegerin (OPG) as the fundamental factors in controlling osteoclast formation and activation has led to a greater understanding of bone biology over the past few years. Here we discuss the role of these molecules in immunology and skeletal remodelling and assess their involvement in diseases of bones and joints, including rheumatoid arthritis, Paget's disease, post-menopausal osteoporosis and malignant bone diseases. OPG has been identified as a potential anabolic agent for treating conditions in which there is net bone loss and is currently in Phase I clinical trials. This review examines the current evidence indicating that OPG increases bone mass, and discusses other possible beneficial effects of OPG, such as inhibition of tumour growth and relief from bone cancer pain. OPG can be measured in human serum, and numerous studies have suggested that increased or decreased serum concentrations of this molecule can indicate the existence of remodelling disorders. Here we discuss how abnomnal serum OPG concentrations could potentially be used to indicate imbalances of bone resorption and formation. The possible applications of serum OPG concentration as a marker for non-skeletal disease conditions are also considered.

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Osteoporosis in thalassaemia

Thalassemia Reports ◽

10.4081/thal.2018.7487 ◽

2018 ◽

Vol 8 (1) ◽

Author(s):

Ersi Voskaridou ◽

Maria Dimopoulou ◽

Evangelos Terpos

Keyword(s):

Bone Resorption ◽

Nuclear Factor Kappa B ◽

Human Monoclonal Antibody ◽

Osteoclast Differentiation ◽

Osteoclast Formation ◽

Nuclear Factor ◽

Receptor Activator ◽

Formation Function ◽

And Function ◽

Markers Of Bone Resorption

Osteoporosis is a prominent cause of morbidity in patients with thalassaemia major (TM) with a complex pathophysiology. Patients with TM and osteoporosis have elevated markers of bone resorption. This increased osteoclast activity seems to be at least partially due to an imbalance in the receptor–activator of nuclear factor-kappa B ligand (RANKL)/osteoprotegerin (OPG) system, which is of great importance for the regulation of osteoclast differentiation and function. Denosumab is a fully human monoclonal antibody that binds to RANKL and thereby inhibits the activation of osteoclasts by RANKL. By blocking RANKL, denosumab inhibits osteoclast formation, function and survival, thereby decreasing bone resorption and increasing bone mass in postmenopausal women and patients with thalassaemia-induced osteoporosis.

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MicroRNA-16-5p Inhibits Osteoclastogenesis in Giant Cell Tumor of Bone

BioMed Research International ◽

10.1155/2017/3173547 ◽

2017 ◽

Vol 2017 ◽

pp. 1-6 ◽

Cited By ~ 14

Author(s):

Shang Sang ◽

Zhichang Zhang ◽

Shu Qin ◽

Changwei Li ◽

Yang Dong

Keyword(s):

Bone Resorption ◽

Giant Cell Tumor ◽

Giant Cell ◽

Therapeutic Target ◽

Bone Destruction ◽

Osteoclast Formation ◽

Cell Tumor ◽

Nuclear Factor ◽

Receptor Activator

Giant cell tumor (GCT) of bone is an aggressive skeletal tumor characterized by localized bone resorption. MicroRNA-16-5p (miR-16-5p) has been reported to be downregulated in lesions of patients with GCT, but little is known about its role in GCT. To explore the underlying function of miR-16-5p in GCT, we first detected its expression in patients with GCT. The results showed that osteoclast formation increased, whereas miR-16-5p expression considerably decreased with the severity of bone destruction. Furthermore, we found that miR-16-5p expression considerably decreased with the progression of receptor activator of nuclear factor-κB ligand- (RANKL-) induced osteoclastogenesis. Functionally, miR-16-5p mimics significantly reduced RANKL-induced osteoclast formation. However, treatment with an inhibitor of miR-16-5p significantly promoted osteoclastogenesis. These findings reveal that miR-16-5p inhibits osteoclastogenesis and that it may represent a therapeutic target for giant cell tumor of bone.

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Overexpression of γ-Glutamyltransferase in Transgenic Mice Accelerates Bone Resorption and Causes Osteoporosis

Endocrinology ◽

10.1210/en.2007-0215 ◽

2007 ◽

Vol 148 (6) ◽

pp. 2708-2715 ◽

Cited By ~ 29

Author(s):

Kiyoshi Hiramatsu ◽

Yutaro Asaba ◽

Sunao Takeshita ◽

Yuji Nimura ◽

Sawako Tatsumi ◽

...

Keyword(s):

Bone Marrow ◽

Bone Resorption ◽

Transgenic Mice ◽

Bone Destruction ◽

Nuclear Factor Κb ◽

Osteoclast Formation ◽

Expression Cloning ◽

Nuclear Factor ◽

Receptor Activator

We previously identified γ-glutamyltransferase (GGT) by expression cloning as a factor inducing osteoclast formation in vitro. To examine its pathogenic role in vivo, we generated transgenic mice that overexpressed GGT in a tissue-specific manner utilizing the Cre-loxP recombination system. Systemic as well as local production of GGT accelerated osteoclast development and bone resorption in vivo by increasing the sensitivity of bone marrow macrophages to receptor activator of nuclear factor-κB ligand, an essential cytokine for osteoclastogenesis. Mutated GGT devoid of enzyme activity was as potent as the wild-type molecule in inducing osteoclast formation, suggesting that GGT acts not as an enzyme but as a cytokine. Recombinant GGT protein increased receptor activator of nuclear factor-κB ligand expression in marrow stromal cells and also stimulated osteoclastogenesis from bone marrow macrophages at lower concentrations. Thus, GGT is implicated as being involved in diseases characterized by accelerated osteoclast development and bone destruction and provides a new target for therapeutic intervention.

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