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Inhibition of the PI3K-Akt Signaling Pathway Reduces Tumor Necrosis Factor-α Production in Response to Titanium Particles in Vitro
Matthew V. Smith, MD1; Michael J. Lee, MD1; Andrew S. Islam, MD1; Jacqueline L. Rohrer, BS2; Victor M. Goldberg, MD1; Michelle A. Beidelschies, BS3; Edward M. Greenfield, PhD3
1 Department of Orthopaedics, Case Western Reserve University/University Hospitals of Cleveland, 11100 Euclid Avenue, Cleveland, OH 44106. E-mail address for M.V. Smith: mvsmith23@gmail.com
2 4675 Arbour Green Drive, Akron, OH 44333
3 Departments of Physiology and Biophysics (M.A.B.) and Orthopaedics (E.M.G.), Case Medical Center, Case Western Reserve University, Biomedical Research Building, Room 331, 2109 Adelbert Road, Cleveland, OH 44106. E-mail address for M.A. Beidelschies: mai6@case.edu. E-mail address for E.M. Greenfield: emg3@po.cwru.edu
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Disclosure: In support of their research for or preparation of this work, one or more of the authors received, in any one year, outside funding or grants in excess of $10,000 from the National Institutes of Health (research grant RO1 AR43769 and training grant AR07505) and three authors were supported by Allen Fellowships. Neither they nor a member of their immediate families received payments or other benefits or a commitment or agreement to provide such benefits from a commercial entity. No commercial entity paid or directed, or agreed to pay or direct, any benefits to any research fund, foundation, division, center, clinical practice, or other charitable or nonprofit organization with which the authors, or a member of their immediate families, are affiliated or associated.
Investigation performed at the Departments of Orthopaedics, Physiology and Biophysics, and Pathology, Case Western Reserve University and University Hospitals, Cleveland, Ohio

The Journal of Bone and Joint Surgery, Incorporated
J Bone Joint Surg Am, 2007 May 01;89(5):1019-1027. doi: 10.2106/JBJS.F.00615
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Background: Wear debris contributes to implant loosening after total joint arthroplasty, and few advances have been made in our ability to inhibit the biological response to wear particles. Bacterial endotoxins augment the effects of wear particles in vitro and in vivo. The cytokine, tumor necrosis factor-a (TNF-a), is produced by macrophages in response to bacterial endotoxins and wear particles, and it increases osteoclast activity resulting in bone resorption and implant loosening. The phosphoinositol-3-kinase (PI3K)-Akt intracellular signal transduction pathway contributes to cytokine production in response to soluble endotoxin. We investigated the role of the PI3K-Akt pathway in the production of TNF-a in response to wear particles with adherent endotoxin and so-called endotoxin-free wear particles.

Methods: Cultured RAW264.7 murine macrophages were incubated with titanium particles with adherent endotoxin or with endotoxin-free titanium particles in the presence and absence of specific inhibitors of PI3K (LY294002) or Akt (SH-5). Akt activation was assessed with use of Western blot. TNF-a production was measured with use of enzyme-linked immunosorbent assay. Cytotoxicity was determined by measuring lactic dehydrogenase release.

Results: Titanium particles with adherent endotoxin increased Akt activation, whereas endotoxin-free titanium particles did not. The PI3K inhibitor reduced TNF-a production by 70% in response to titanium with adherent endotoxin without increasing cytotoxicity. Similarly, the Akt inhibitor reduced TNF-a production by 83% in response to titanium particles with adherent endotoxin without increasing cytotoxicity. High concentrations of endotoxin-free titanium particles resulted in a small delayed increase in TNF-a production that was completely blocked by the PI3K inhibitor.

Conclusions: Inhibition of the PI3K-Akt pathway reduces macrophage TNF-a production in response to titanium particles with adherent endotoxin and endotoxin-free particles in vitro.

Clinical Relevance: In vivo studies are needed as these results suggest a possible pharmacological target to reduce wear particle-induced osteolysis and subsequent implant loosening.

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    These activities have been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of the American Academy of Orthopaedic Surgeons and The Journal of Bone and Joint Surgery, Inc. The American Academy of Orthopaedic Surgeons is accredited by the ACCME to provide continuing medical education for physicians.
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