Article
CA074Me attenuates titanium nanoparticle-induced osteolysis via inhibition of macrophage NLRP3 inflammasome activation and osteoclast differentiation
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Authors
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Frank A. Schildberg
- Department of Orthopedics and Trauma Surgery, University Hospital Bonn, Bonn, Germany
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Li Zhang
- Department of Orthopedics and Trauma Surgery, University Hospital Bonn, Bonn, Germany
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Mengbo Zhu
- Department of Orthopedics and Trauma Surgery, University Hospital Bonn, Bonn, Germany
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El-Mustapha Haddouti
- Department of Orthopedics and Trauma Surgery, University Hospital Bonn, Bonn, Germany
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Florian I. Schmidt
- Institute of Innate Immunity, University Hospital Bonn, Bonn, Germany
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Christof Burger
- Department of Orthopedics and Trauma Surgery, University Hospital Bonn, Bonn, Germany
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Dieter C. Wirtz
- Department of Orthopedics and Trauma Surgery, University Hospital Bonn, Bonn, Germany
| Published: | October 21, 2024 |
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Outline
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Objectives: Aseptic loosening due to peri-implant osteolysis remains the leading cause of long-term implant failure. Increasing evidence suggests that wear debris-induced NLRP3 inflammasome activation in macrophages and subsequent inflammatory osteoclast activation play an essential role in the progression of osteolysis. CA074Me, a specific inhibitor of cathepsin B, has been reported to be a potent anti-inflammatory agent and has achieved considerable therapeutic efficacy in many inflammatory diseases. However, the effect of CA074Me on particle-induced osteolysis is still unknown.
In this study, we investigated the effect of CA074Me on osteoclast differentiation and NLRP3 inflammasome activation in response to titanium nanoparticles (TiNPs) in macrophages.
Methods: Cellular responses to TiNPs and CA074Me were evaluated in THP-1 monocytes and bone marrow-derived macrophages by assessing NLRP3 inflammasome activation, Western blotting and microscopy. The study examined osteoclast differentiation and the therapeutic effects of CA074Me were verified in a murine calvaria osteolysis model, including micro-CT assessment and histology.
Results and conclusion: CA074Me deactivated the cathepsin B/NLRP3/caspase-1/IL-1b pathway in titanium nanoparticle (TiNP)-challenged macrophages and inhibited subsequent inflammatory osteoclast activation. In addition, CA074Me inhibited osteoclast differentiation. The therapeutic effects of CA074Me were evaluated in a murine osteolysis model. Our results showed that subcutaneous injection of CA074Me over the skull successfully attenuated TiNP-induced osteolysis in a murine calvaria model.
In conclusion, TiNPs exposure resulted in lysosomal cathepsin B release and NLRP3/IL-1b pathway activation in macrophages. CA074Me, a cathepsin B inhibitor, could not only directly inhibit osteoclast differentiation, but also effectively inhibit the cathepsin B/NLRP3/IL-1b pathway in macrophages, thereby alleviating the peri-implant inflammatory environment that favors osteoclast maturation and osteolysis. Therefore, CA074Me may be a promising therapeutic agent to limit aseptic loosening.
