All of the over 1 million total joint replacements implanted in the US each year are expected to eventually fail after 15ââ?¬â??25 years\nof use, due to slow progressive subtle inflammation at the bone implant interface. This inflammatory disease state is caused by\nimplant debris acting, primarily, on innate immune cells, that is, macrophages. This slow progressive pathological bone loss or\nââ?¬Å?aseptic looseningââ?¬Â is a potentially life-threatening condition due to the serious complications in older people (>75 yrs) of total joint\nreplacement revision surgery. In some people implant debris (particles and ions from metals) can influence the adaptive immune\nsystem as well, giving rise to the concept of metal sensitivity. However, a consensus of studies agrees that the dominant form of this\nresponse is due to innate reactivity by macrophages to implant debris where both danger (DAMP) and pathogen (PAMP) signalling\nelicit cytokine-based inflammatory responses. This paper discusses implant debris induced release of the cytokines and chemokines\ndue to activation of the innate (and the adaptive) immune system and the subsequent formation of osteolysis. Different mechanisms\nof implant-debris reactivity related to the innate immune system are detailed, for example, danger signalling (e.g., IL-1????, IL-18, IL-\n33, etc.), toll-like receptor activation (e.g., IL-6, TNF-????, etc.), apoptosis (e.g., caspases 3ââ?¬â??9), bone catabolism (e.g., TRAP5b), and\nhypoxia responses (Hif1-????). Cytokine-based clinical and basic science studies are in progress to provide diagnosis and therapeutic\nintervention strategies.
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