1. Inhibition of the PI3K-Akt Signaling Pathway Reduces Tumor Necrosis Factor-α Production in Response to Titanium Particles in Vitro by Matthew V. Smith, Michael J. Lee, Andrew S. Islam, Jacqueline L. Rohrer, Victor M. Goldberg, Michelle A. Beidelschies, and Edward M. Greenfield J Bone Joint Surg Am Volume 89(5):1019-1027 May 1, 2007 ©2007 by The Journal of Bone and Joint Surgery, Inc.

2. Activation of the PI3K-Akt pathway. Matthew V. Smith et al. J Bone Joint Surg Am 2007;89:1019- 1027 ©2007 by The Journal of Bone and Joint Surgery, Inc.

3. Titanium (Ti) particles with adherent endotoxin increased Akt activation (A and B) and TNF-α production (C) while so-called endotoxin-free titanium particles did not (B and C). Matthew V. Smith et al. J Bone Joint Surg Am 2007;89:1019- 1027 ©2007 by The Journal of Bone and Joint Surgery, Inc.

4. The specific PI3K inhibitor, LY294002, dose-dependently reduced TNF-α production and Akt activation (A) without increasing cytotoxicity (B). Matthew V. Smith et al. J Bone Joint Surg Am 2007;89:1019- 1027 ©2007 by The Journal of Bone and Joint Surgery, Inc.

5. The specific Akt inhibitor, SH-5, dose-dependently reduced TNF-α production and Akt activation (A) without increasing cytotoxicity (B). Matthew V. Smith et al. J Bone Joint Surg Am 2007;89:1019- 1027 ©2007 by The Journal of Bone and Joint Surgery, Inc.

6. LY294002 inhibits TNF-α production induced by endotoxin-free titanium (Ti) particles (A) and causes a small increase in cytotoxicity that does not account for the inhibition of TNF-α production (B). Matthew V. Smith et al. J Bone Joint Surg Am 2007;89:1019- 1027 ©2007 by The Journal of Bone and Joint Surgery, Inc.

7. Titanium (Ti) particles activate ERK1/2, NF-κB, and the PI3K-Akt signaling pathways in macrophages to increase production of TNF-α (A). Matthew V. Smith et al. J Bone Joint Surg Am 2007;89:1019- 1027 ©2007 by The Journal of Bone and Joint Surgery, Inc.