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We recently showed that mesenchymal stem\/osteoprogenitor cells (MSCs) are another target, and that endocytosis of titanium (Ti) particles causes reduced MSC proliferation and osteogenic differentiation. Here we investigated the mechanistic aspects of the endocytosis\u2010mediated responses of MSCs to Ti particulates. Dose\u2010dependent effects were observed on cell viability, with doses &gt;300 Ti particles\/cell resulting in drastic cell death. To maintain cell viability and analyze particle\u2010induced effects, doses &lt;300 particles\/cell were used. Increased production of interleukin\u20108 (IL\u20108), but not IL\u20106, was observed in treated MSCs, while levels of TGF\u2010\u03b2, IL\u20101\u03b2, and TNF\u2010\u03b1 were undetectable in treated or control cells, suggesting MSCs as a likely major producer of IL\u20108 in the periprosthetic zone. Disruptions in cytoskeletal and adherens junction organization were also observed in Ti particles\u2010treated MSCs. However, neither IL\u20108 and IL\u20106 treatment nor conditioned medium from Ti particle\u2010treated MSCs failed to affect MSC osteogenic differentiation. Among other Ti particle\u2010induced cytokines, only GM\u2010CSF appeared to mimic the effects of reduced cell viability and osteogenesis. Taken together, these results strongly suggest that MSCs play both responder and initiator roles in mediating the osteolytic effects of the presence of wear debris particles in periprosthetic zones. \u00a9 2011 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. 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