Related Experiment Videos
Hyperglycemia Suppresses RANKL-Induced Osteoclast Differentiation through LXRβ Expression in RAW264.7 Cells
Teruyoshi Tanaka1, Yuichiro Takei, Nobuhiro Zaima
1Division of Vascular Surgery, Department of Surgery, University of Wisconsin School of Medicine and Public Health.
Abstract:
There have been reports that hyperglycemia suppresses osteoclast (OCL) differentiation, although the underlying mechanism is poorly understood. Here we demonstrated that high glucose suppresses OCL differentiation through activation of liver X receptor (LXR) β, a recently reported glucose-sensing nuclear receptor. The effect of hyperglycemia on osteoclastogenesis was tested in RAW264.7 cells, a murine macrophage cell line. Cells were treated with receptor activator of NF-κB ligand (RANKL) under normoglycemic (5.5 mM glucose), normoglycemic with high osmotic pressure (5.5 mM glucose + 10.0 mM mannitol), and hyperglycemic (15.5 mM glucose) conditions. RANKL-induced osteoclastogenesis was significantly suppressed by high-glucose treatment. Mannitol treatment also significantly suppressed osteoclastogenesis, but the inhibitory effect was lower than for high-glucose treatment. The suppression of mRNA expression of Lxrβ by RANKL was significantly restored by high glucose, but not mannitol. Additionally, the deactivation of Lxrβ by siRNA attenuated high-glucose-induced suppression of osteoclastogenesis. Although further validation of the underlying pathway is necessary, targeting LXRβ is a potential therapeutic approach to treating osteoporosis.
Insights
High glucose suppresses osteoclast differentiation by activating the liver X receptor beta (LXRβ). This finding offers a potential therapeutic target for osteoporosis treatment.
Area of Science:
- Endocrinology
- Cell Biology
- Bone Biology
Background:
- Hyperglycemia is known to affect bone metabolism, but the precise mechanisms are unclear.
- Osteoclast differentiation is crucial for bone remodeling and is implicated in bone diseases like osteoporosis.
Purpose of the Study:
- To elucidate the mechanism by which high glucose suppresses osteoclast differentiation.
- To investigate the role of liver X receptor beta (LXRβ) in high glucose-mediated effects on osteoclastogenesis.
Main Methods:
- Osteoclast differentiation was induced in RAW264.7 cells using receptor activator of NF-κB ligand (RANKL) under varying glucose conditions (normoglycemic, hyperglycemic).
- The effect of high glucose and mannitol on osteoclastogenesis was assessed.
- Messenger RNA (mRNA) expression of LXRβ was analyzed.
- The impact of LXRβ knockdown using small interfering RNA (siRNA) on high glucose-induced suppression was evaluated.
Main Results:
- High glucose significantly suppressed RANKL-induced osteoclast differentiation.
- Mannitol also suppressed osteoclastogenesis, but to a lesser extent than high glucose.
- High glucose treatment restored the suppression of LXRβ mRNA expression induced by RANKL.
- Knockdown of LXRβ attenuated the inhibitory effect of high glucose on osteoclast differentiation.
Conclusions:
- Liver X receptor beta (LXRβ) activation mediates the suppressive effect of hyperglycemia on osteoclast differentiation.
- Targeting LXRβ presents a potential therapeutic strategy for managing osteoporosis in hyperglycemic conditions.