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Periprosthetic osteolysis is a common reason for failure or revision of joint replacement surgery, and is a result of the inflammatory reaction to debris particles generated by wearing of the implant over time. In this Review, the authors describe the cellular and molecular mediators of this process and how it might be prevented or treated. Joint replacement surgery is one of the success stories of modern medicine, restoring mobility, diminishing pain and improving the overall quality of life for millions of people. Unfortunately, wear of these prostheses over time generates debris, which activates an innate immune response that can ultimately lead to periprosthetic resorption of bone (osteolysis) and failure of the implant. Over the past decade, the biological interactions between the particulate debris from various implant materials and the immune system have begun to be better understood. The wear debris induces a multifaceted immune response encompassing the generation of reactive oxygen species and damage-associated molecular patterns, Toll-like receptor signaling and NALP3 inflammasome activation. Acting alone or in concert, these events generate chronic inflammation, periprosthetic bone loss and decreased osteointegration that ultimately leads to implant failure. Key Points Wear debris is generated by the movements of the articulating surfaces of a joint replacement under load Microparticle wear debris induces “frustrated phagocytosis” and multinucleated giant cell fusion Nanoparticle wear debris induces endosomal destabilization and NALP3 inflammasome activation Ultra-high-molecular-weight polyethylene polymeric wear debris and damage-associated molecular patterns induce activation of Toll-like receptors 2 and 4 Metal wear debris and metal ions can induce a type IV hypersensitivity reaction The multifaceted myelomonocytic inflammatory response induced by wear debris increases osteoclastogenesis and promotes periprosthetic osteolysis

Occupational and environmental exposure to Co and Cr has been previously linked to a wide array of inflammatory and degenerative conditions and cancer. Recently, significant health concerns have been raised by the high levels of Cr and Co ions and corrosion products released by biomedical implants. Herein, we set to analyze the biological responses associated with Co and Cr toxicity. Histological, ultrastructural and elemental analysis, performed on Cr and Co exposed patients reveal the presence of corrosion products, metallic wear debris and metal ions at varying concentrations. Metallic ions and corrosion products were also generated in vitro following macrophage phagocytosis of metal alloys. Ex vivo redox proteomic mapped several oxidatively damaged proteins by Cr(III) and Co(II)-induced Fenton reaction. Importantly, a positive correlation between the tissue amounts of Cr(III) and Co(II) ions and tissue oxidative damage was observed. Immobilized- Cr(III) and Co(II) affinity chromatography indicated that metal ions can also directly bind to several metallo and non-metalloproteins and, as demonstrated for aldolase and catalase, induce loss of their biological function. Altogether, our analysis reveals several biological mechanisms leading to tissue damage, necrosis and inflammation in patients with Cr and Co-associated adverse local tissue reactions.

Summary The role of lymphatic vessels is to transport fluid, soluble molecules, and immune cells to the draining lymph nodes. Here, we analyze how the aging process affects the functionality of the lymphatic collectors and the dynamics of lymph flow. Ultrastructural, biochemical, and proteomic analysis indicates a loss of matrix proteins, and smooth muscle cells in aged collectors resulting in a decrease in contraction frequency, systolic lymph flow velocity, and pumping activity, as measured in vivo in lymphatic collectors. Functionally, this impairment also translated into a reduced ability for in vivo bacterial transport as determined by time-lapse microscopy. Ultrastructural and proteomic analysis also indicates a decrease in the thickness of the endothelial cell glycocalyx and loss of gap junction proteins in aged lymph collectors. Redox proteomic analysis mapped an aging-related increase in the glycation and carboxylation of lymphatic's endothelial cell and matrix proteins. Functionally, these modifications translate into apparent hyperpermeability of the lymphatics with pathogen escaping from the collectors into the surrounding tissue and a decreased ability to control tissue fluid homeostasis. Altogether, our data provide a mechanistic analysis of how the anatomical and biochemical changes, occurring in aged lymphatic vessels, compromise lymph flow, tissue fluid homeostasis, and pathogen transport.

Plasma membrane budding of Atg-16L-positive vesicles represents a very early event in the generation of the phagophore and in the process of macroautophagy. Here we show that the membrane curvature-inducing protein annexin A2 contributes to the formation of these vesicles and their fusion to form phagophores. Ultrastructural, proteomic and FACS analyses of Atg16L-positive vesicles reveal that 30% of Atg16L-positive vesicles are also annexin A2-positive. Lipidomic analysis of annexin A2-deficient mouse cells indicates that this protein plays a role in recruiting phosphatidylserine and phosphatidylinositides to Atg16L-positive vesicles. Absence of annexin A2 reduces both vesicle formation and homotypic Atg16L vesicle fusion. Ultimately, a reduction in LC3 flux and dampening of macroautophagy are observed in dendritic cells from Anxa2 −/− mice. Together, our analyses highlight the importance of annexin A2 in vesiculation of a population of Atg16L-positive structures from the plasma membrane, and in their homotypic fusion to form phagophore structures. The earliest steps in autophagy are thought to include the budding of Atg16L-containing vesicles from the plasma membrane and their homotypic fusion to form a phagophore. Morozova et al . reveal a role for the membrane curvature-inducing protein Annexin A2 in the formation and fusion of these vesicles.

Endosomal functions are contingent on the integrity of the organelle-limiting membrane, whose disruption induces inflammation and cell death. Here we show that phagocytosis of ultrahigh molecular weight polyethylene particles induces damage to the endosomal-limiting membrane and results in the leakage of cathepsins into the cytosol and NLRP3-inflammasome activation. Annexin A2 recruitment to damaged organelles is shown by two-dimensional DIGE protein profiling, endosomal fractionation, confocal analysis of endogenous and annexin A2–GFP transfected cells, and immunogold labelling. Binding experiments, using fluorescent liposomes, confirms annexin A2 recruitment to endosomes containing phagocytosed polyethylene particles. Finally, an increase in cytosolic cathepsins, NLRP3-inflammasome activation, and IL-1 production is seen in dendritic cells from annexin A2-null mice, following exposure to polyethylene particles. Together, the results indicate a functional role of annexin A2 binding to endosomal membranes following organelle destabilization. Endosomes contain hydrolytic enzymes, and recent reports have suggested that the endosomal membrane can be damaged by wear particles, resulting in the release of their contents and an inflammatory response. In this study, a role for annexin II in the repair of the damaged endosome membrane is reported.

Nature Communications 6: Article number: 5856 (2015); Published 19 January 2015; Updated 30 March 2015. The original version of this Article contained a typographical error in the spelling of the author Sunandini Sridhar, which was incorrectly given as Sunandini Sidhar. This has now been corrected in both the PDF and HTML versions of the Article.

Copper dimethyldithiocarbamate (CDDC) has been recently introduced as an alternative to chromated copper arsenate (CCA) preserved wood. The potential effects on human health and the environment with CDDC-treated wood have not been examined. This study investigated the toxicity and accumulation of copper in the hippocampus of maternal and newborn Long-Evans rats, and in maternal livers and kidneys following a subacute exposure to CDDC. Pregnant rats (220-270 g) were treated daily with 0, 25, 50, or 75 mg/kg CDDC by oral gavage starting from day 6 of gestation and continuing to parturition. Following parturition, maternal and newborn rats were euthanized. Brain, liver, and renal tissues were removed, processed, and stored for analysis. Electron microscopy revealed demyelination and by-products of peroxidative damage in treated maternal hippocampi. Treated newborn hippocampi exhibited numerous degenerating mitochondria, membrane bound inclusion bodies, and vacuoles containing degraded structures. Western blot analysis revealed an induction of stress proteins HO-1 and Hsp70, and the formation of 4-hydroxy-2-nonenal (4HNE) adducts. Overt destruction of liver architecture and renal tissue was observed. Graphite furnace atomic absorption spectrophotometry demonstrated a significant increase in copper concentration in the tissues of treated animals as compared to controls. CDDC was shown to be toxic to the brains, livers, and kidneys at all doses used, and this toxicity is attributable to copper-induced lipid peroxidation.

With all the technicalities of traffic and commerce issues overshadowing our discussions of an energized town center let's not forget that our favorite places usually engage us by our imaginations.