Macrophages derive from human embryonic and fetal stem cells and from human bone marrow-derived blood monocytes. They play a major homeostatic role in tissue remodeling and maintenance facilitated by apoptotic "eat me" opsonins like CRP, serum amyloid P, C1q, C3b, IgM, ficolin, and surfactant proteins. Three subsets of monocytes, classic, intermediate, and nonclassic, are mobilized and transmigrate to tissues. Implant-derived wear particles opsonized by danger signals regulate macrophage priming, polarization (M1, M2, M17, and Mreg), and activation. CD14(+) monocytes in healthy controls and CD16(+) monocytes in inflammation differentiate/polarize to foreign body giant cells/osteoclasts or inflammatory dendritic cells (infDC). These danger signal opsonins can be pathogen- or microbe-associated molecular patterns (PAMPs/MAMPs), but in aseptic loosening, usually are damage-associated molecular patterns (DAMPs). Danger signal-opsonized particles elicit "particle disease" and aseptic loosening. They provide soluble and cell membrane-bound co-stimulatory signals that can lead to cell-mediated immune reactions to metal ions. Metal-on-metal implant failure has disclosed that quite like Ni(2+), its neighbor in the periodic table Co(2+) can directly activate toll-like receptor 4 (TLR4) as a lipopolysaccharide-mimic. "Ion disease" concept needs to be incorporated into the "particle disease" concept, due to the toxic, immune, and inflammatory potential of metal ions.

Department of Clinical Medicine University of Helsinki and ORTON Orthopaedic Hospital of the Invalid Foundation Helsinki Finland

Department of Medicine Institute of Clinical Medicine Helsinki University Central Hospital 00029 HUS Finland; Department of Orthopaedic Surgery Stanford Medical Center Stanford CA 94305 5341 USA

Department of Orthopaedic Surgery Stanford University Medical Center Redwood City CA

Department of Orthopaedic Surgery Yamagata University Faculty of Medicine Yamagata Japan

Department of Orthopaedic Surgery Yamagata University School of Medicine Yamagata Japan

Department of Orthopedics University Hospital and Faculty of Medicine and Dentistry Palacky University Olomouc 775 20 Czech Republic

Laboratoire de Biomecanique et Biomateriaux Osteo Articulaires UMR CNRS 7052 Faculte de Medecine Universite Paris 7 Paris France; Department of Orthopaedic Surgery European Teaching Hospital Assistance Publique Hopitaux de Paris

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Microsporidia (Encephalitozoon cuniculi) in Patients with Degenerative Hip and Knee Disease, Czech Republic

Periprosthetic Osteolysis: Mechanisms, Prevention and Treatment