title: Apoptotic pathways of macrophages within osteolytic interface membrane in periprosthestic osteolysis after total hip replacement.
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.
authors.affiliation: Department 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.|Department of Orthopaedics, Bayi Hospital Affiliated Nanjing University of Chinese Medicine, Nanjing, China.
authors.forename: Guoyin
authors.initials: G
authors.lastname: Liu
authors.affiliation: Department 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.
authors.forename: Ting
authors.initials: T
authors.lastname: Guo
authors.affiliation: Department of Orthopaedics, Bayi Hospital Affiliated Nanjing University of Chinese Medicine, Nanjing, China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department 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.
authors.forename: Naicheng
authors.initials: N
authors.lastname: Liu
authors.affiliation: Department 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.
authors.forename: Jiangning
authors.initials: J
authors.lastname: Chen
authors.affiliation: Department of Orthopaedics, Bayi Hospital Affiliated Nanjing University of Chinese Medicine, Nanjing, China.
authors.forename: Jianmin
authors.initials: J
authors.lastname: Chen
authors.affiliation: Department 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.
authors.forename: Junfeng
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department 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.
authors.forename: Jianning
authors.initials: J
authors.lastname: Zhao
mesh_terms: D000293:Adolescent; D000368:Aged; D017209:Apoptosis; D019644:Arthroplasty, Replacement, Hip / Q000009:adverse effects*; D015415:Biomarkers / Q000032:analysis; D015153:Blotting, Western; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D008264:Macrophages / Q000502:physiology*; D008297:Male; D046529:Microscopy, Electron, Transmission; D008875:Middle Aged; D008928:Mitochondria / Q000378:metabolism; D010014:Osteolysis / Q000473:pathology*; D019736:Prostheses and Implants / Q000009:adverse effects*
chemical_list: D015415:Biomarkers; D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human
keywords: Osteolysis; apoptosis; death receptor pathway; endoplasmic reticulum stress pathway; macrophages; mitochondrion pathway