A selected small molecule prevents inflammatory osteolysis through restraining osteoclastogenesis by modulating PTEN activity
- Clin Transl Med. 2020 Dec;10(8):e240. doi: 10.1002/ctm2.240.
- 1. Department of Biomedical Materials Science, Third Military Medical University (Army Medical University), Chongqing, PR China.
- 2. Department of Orthopaedics, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, PR China.
- 3. National Engineering Research Center of Immunological Products & Department of Microbiology and Biochemical Pharmacy, College of Pharmacy, Third Military Medical University (Army Medical University), Chongqing, PR China.
- 4. School of Chemistry and Chemical Engineering, Southwest University, Chongqing, PR China.
- 5. State Key Laboratory of Trauma, Burns and Combined Injury, Third Military Medical University (Army Medical University), Chongqing, PR China.
Background: Inflammatory osteolysis is a severe infectious bone disorder that occurs during orthopaedic surgery and is caused by disruptions in the dynamic balance of bone matrix homeostasis, which makes this condition a burden on surgical procedures. Developing novel therapeutic drugs about inhibiting excessive osteoclastogenesis acts as an efficient approach to preventing inflammatory bone destruction.
Methods: To study this, we explored the potential effects and mechanisms of compound 17 on inflammatory osteolysis in vitro. Meanwhile, a lipopolysaccharide (LPS)-induced calvarial osteolysis mouse model was used to evaluate the protective effect of compound 17 on inflammatory bone destruction in vivo.
Results: In our study, we found that compound 17 could inhibit osteoclast (OC) differentiation and bone resorption during RANKL and LPS stimulation in a time- and dose-dependent manner, while compounds 5 and 13 did not have the same effects. Mechanistically, compound 17 promoted Phosphatase and tensin homologue (PTEN) activity by reducing PTEN ubiquitination, thereby restraining the RANKL-induced NF-κB pathway, resulting in the inhibition of the expression of osteoclastogenesis-related genes and the formation of the NLRP3 inflammasome. Additionally, we also investigated whether compound 17 could negatively modulate macrophage polarization and repolarization due to its anti-inflammatory effects. Moreover, compound 17 also plays an important role in osteoblast differentiation and mineralization. In vivo experiments showed that compound 17 could effectively protect mice from LPS-induced inflammatory bone destruction by inhibiting osteoclastogenesis and inflammation.
Conclusions: Taken together, these results show that compound 17 might play protective role in inflammatory bone destruction through inhibiting osteoclastogenesis and inflammation. These findings imply a possible role of compound 17 in inflammatory osteolysis-related diseases.