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A selected small molecule prevents inflammatory osteolysis through restraining osteoclastogenesis by modulating PTEN

Yueqi Chen^1,2, Wenhui Hu¹, Yiran Wang¹

¹Department of Biomedical Materials Science, Third Military Medical University (Army Medical University), Chongqing, PR China.

Clinical and Translational Medicine

|December 30, 2020

Abstract

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.

Insights

Compound 17 effectively inhibits inflammatory osteolysis by suppressing osteoclast differentiation and bone resorption. This novel therapeutic agent shows promise for treating bone destruction in inflammatory conditions.

Area of Science:

Biomedical Science
Pharmacology
Orthopaedics

Background:

Inflammatory osteolysis is a severe bone disorder complicating orthopaedic surgery.
It arises from disrupted bone homeostasis and excessive osteoclast activity.
Inhibiting osteoclastogenesis is a key strategy for preventing bone destruction.

Purpose of the Study:

To investigate the therapeutic potential of compound 17 against inflammatory osteolysis.
To elucidate the mechanisms underlying compound 17's effects on osteoclastogenesis and inflammation.

Main Methods:

In vitro studies assessed compound 17's effects on osteoclast differentiation and bone resorption.
A lipopolysaccharide (LPS)-induced mouse model evaluated compound 17's in vivo efficacy.
Mechanistic studies explored compound 17's impact on PTEN activity, NF-κB signaling, and macrophage polarization.

Main Results:

Compound 17 dose-dependently inhibited osteoclast differentiation and bone resorption.
It promoted phosphatase and tensin homologue (PTEN) activity, suppressed the NF-κB pathway, and reduced osteoclastogenesis-related gene expression.
Compound 17 demonstrated anti-inflammatory effects, modulated macrophage polarization, and supported osteoblast differentiation.
In vivo, compound 17 protected against LPS-induced bone destruction by inhibiting osteoclastogenesis and inflammation.

Conclusions:

Compound 17 exhibits protective effects against inflammatory bone destruction.
It acts by inhibiting osteoclastogenesis and inflammation, suggesting therapeutic potential for inflammatory osteolysis-related diseases.

Read full analysis

Keywords:

PTEN inflammatory osteolysis osteoclastogenesis small molecule

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