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Tanshinone IIA inhibits osteoclastogenesis in rheumatoid arthritis via LDHC-regulated ROS generation
Qiuwei Peng1, Jian Wang1, Man Han1
1Department of Rheumatology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, 100053, China.
Abstract:
Rheumatoid arthritis (RA) is characterized by bone destruction in the afflicted joints, and during the process of bone destruction, osteoclasts play a crucial role. Tanshinone IIA (Tan IIA) has shown anti-inflammatory effects in RA. However, the exact molecular mechanisms by which it delays bone destruction remain largely unexplained. Here, we found that Tan IIA decreased the severity of and ameliorated bone loss in an AIA rat model. In vitro, Tan IIA inhibited RANKL-induced osteoclast differentiation. By activity-based protein analysis (ABPP) combined with LC‒MS/MS, we discovered that Tan IIA covalently binds to the lactate dehydrogenase subunit LDHC and inhibits its enzymatic activity. Moreover, we found that Tan IIA inhibits the generation of osteoclast-specific markers by reducing the accumulation of reactive oxygen species (ROS), thus reducing osteoclast differentiation. Finally, our results reveal that Tan IIA suppresses osteoclast differentiation via LDHC-mediated ROS generation in osteoclasts. Tan IIA can thus be regarded as an effective drug for the treatment of bone damage in RA.
Insights
Tanshinone IIA (Tan IIA) effectively reduces bone loss in rheumatoid arthritis (RA) by inhibiting osteoclast differentiation. It targets lactate dehydrogenase C (LDHC), decreasing reactive oxygen species (ROS) and protecting joints.
Area of Science:
- Biochemistry
- Immunology
- Pharmacology
Background:
- Rheumatoid arthritis (RA) involves joint bone destruction mediated by osteoclasts.
- Tanshinone IIA (Tan IIA) exhibits anti-inflammatory properties in RA, but its mechanism against bone destruction is unclear.
Purpose of the Study:
- To elucidate the molecular mechanisms by which Tan IIA mitigates bone destruction in RA.
- To investigate Tan IIA's effect on osteoclast differentiation and identify its molecular targets.
Main Methods:
- Utilized an arthritis-induced arthritis (AIA) rat model to assess bone loss.
- Performed in vitro studies on RANKL-induced osteoclast differentiation.
- Employed activity-based protein analysis (ABPP) coupled with LC–MS/MS to identify Tan IIA targets.
- Measured reactive oxygen species (ROS) generation and osteoclast-specific markers.
Main Results:
- Tan IIA treatment decreased bone destruction severity and bone loss in the AIA rat model.
- In vitro, Tan IIA inhibited RANKL-induced osteoclast differentiation.
- Tan IIA was found to covalently bind and inhibit lactate dehydrogenase C (LDHC).
- Tan IIA reduced ROS generation and osteoclast differentiation, suppressing osteoclast-specific markers.
Conclusions:
- Tan IIA suppresses osteoclast differentiation through LDHC-mediated inhibition of ROS generation.
- Tan IIA demonstrates potential as a therapeutic agent for treating bone damage in RA.
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