Apoptotic pathways of macrophages within osteolytic interface membrane in periprosthestic osteolysis after total hip
Guoyin Liu1,2, Ting Guo1, Yong Zhang2
1Department of Orthopaedics, Jinling Hospital affiliated to School of Medicine, Nanjing University and State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing, China.
Abstract:
Macrophage apoptosis in interface membrane, which occurs through either death receptor, mitochondrion, or endoplasmic reticulum (ER) stress pathways, has been suggested to play an important role in promoting osteolysis. However, how and why macrophage apoptosis originates and the correlation among these apoptotic pathways is not yet clear. The objective of this study was to identify the apoptotic mechanism of macrophages, and to explore the relationship between the apoptotic pathways and progression of osteolysis. Transmission electron microscopy (TEM) was utilized to analyze the tissue ultrastructure of wear particles, and in situ apoptotic macrophage identification was performed by TUNEL staining. We analyzed the expression of the key biomarkers of apoptotic pathways via immunohistochemistry and Western blotting. Our results demonstrated that the majority of wear particles within osteolytic interface membrane was in the 30-60 nm range, and that macrophage apoptotic ratio increased along with osteolysis progression. Normal hip dysplasia and mechanical loosening of tissues showed low expression levels of biomarkers for ER stress (Ca2+ , JNK, cleaved Caspase-4, IRE1-α, Grp78/Bip, and CHOP), mitochondrion (Bcl-2, Bax, and Cytochrome c), and death receptor (Fas and cleaved Caspase-8) pathways, while osteolytic interface membrane tissues expressed high levels of these biomarkers. In addition, we found that the ER stress intensity was in complete conformity with mitochondrial dysfunction and was consistent with the results of death receptor activation. Thus, our findings suggested that wear particles generated at implant interface can accelerate macrophage apoptosis through changes in apoptotic pathways and ultimately aggravate the symptom of osteolysis. These data represent a preferential apoptotic signaling pathway of macrophages as specific target points for the prevention and therapeutic modulation of periprosthetic osteolysis.
Insights
Wear particles trigger macrophage apoptosis via endoplasmic reticulum stress, mitochondrial dysfunction, and death receptor pathways, worsening osteolysis. Targeting these pathways may prevent periprosthetic osteolysis.
Area of Science:
- Biomedical Engineering
- Immunology
- Orthopedic Surgery
Background:
- Macrophage apoptosis is implicated in osteolysis, but the underlying mechanisms and pathway correlations remain unclear.
- Understanding macrophage apoptosis pathways is crucial for addressing periprosthetic osteolysis progression.
Purpose of the Study:
- To elucidate the apoptotic mechanisms of macrophages in osteolysis.
- To investigate the relationship between apoptotic pathways and osteolysis progression.
Main Methods:
- Transmission electron microscopy (TEM) for wear particle ultrastructure analysis.
- TUNEL staining for in situ apoptotic macrophage identification.
- Immunohistochemistry and Western blotting for apoptotic biomarker expression analysis.
Main Results:
- Wear particles in the 30-60 nm range were prevalent in osteolytic interface membranes.
- Macrophage apoptosis ratio correlated positively with osteolysis progression.
- Elevated biomarkers for ER stress, mitochondrial dysfunction, and death receptor pathways were observed in osteolytic tissues.
Conclusions:
- Implant-generated wear particles accelerate macrophage apoptosis via interconnected ER stress, mitochondrial, and death receptor pathways.
- These apoptotic pathways are significantly altered in periprosthetic osteolysis.
- Targeting these specific macrophage apoptotic pathways offers potential for preventing and treating periprosthetic osteolysis.
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