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

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.

Download Full-text

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.

Download Full-text

Denosumab in the Treatment of Giant Cell Tumor of Bone

Oncology & Hematology Review (US) ◽

10.17925/ohr.2010.06.0.39 ◽

2010 ◽

Vol 06 ◽

pp. 39

Author(s):

David Thomas ◽

Keyword(s):

Giant Cell Tumor ◽

Giant Cell ◽

Cell Population ◽

Osteoclast Differentiation ◽

Bone Destruction ◽

Osteoclast Formation ◽

Cell Tumor ◽

Rare Benign Tumor ◽

And Function

Giant cell tumor of bone (GCT) is a rare, benign tumor characterized by localized bone destruction. GCT is thought to be biphenotypic, comprising a neoplastic stromal cell population and an osteoclast-like giant cell population. Recent studies have established that receptor activator of NF κβ ligand (RANKL) plays an important role in GCT. Although its actions are not fully understood, RANKL acts as an obligate signal for normal osteoclast formation and function. The development of an antagonist to RANKL, denosumab, has led to clinical trials in osteoporosis, bone metastases in cancer, and GCT. Generally well-tolerated, denosumab is an extremely effective inhibitor of osteoclast differentiation and function in humans. A preliminary study of the use of denosumab in patients with advanced or unresectable GCT has suggested considerable activity and clinical benefit. The eventual role of denosumab in GCT is currently the subject of an ongoing clinical trial.

Download Full-text