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Protective effect of P188 in the Model of Acute Trauma to Human Ankle Cartilage: The Mechanism of Action

Bajaj, Sarvottam BS*‡; Shoemaker, Thomas BS*; Hakimiyan, Arnavaz A BS*; Rappoport, Lev MD*; Pascual-Garrido, Cecilia MD*†; Oegema, Theodore R PhD*†; Wimmer, Markus A PhD*†‡; Chubinskaya, Susan PhD*†§

doi: 10.1097/BOT.0b013e3181ec4712
Original Article

Objective: Because P188 poloxamer is effective in promoting cell survival in models of acute trauma, the objectives were to understand the mechanism of its action focusing on glycogen synthase kinase-3 (GSK3) activation, interleukin-6 (IL-6), and p38 signaling.

Design: Sixteen normal human tali were impacted using a 4-mm diameter indenter with an impulse of 1 Ns. Eight-millimeter cartilage plugs containing the 4-mm impacted core and 4-mm adjacent nonimpacted ring were removed and cultured with or without P188. Cell lysates were analyzed using Western blots with antibodies against total and phosphorylated extracellular signal-regulated protein kinase (ERK), c-Jun NH(2)-terminal kinase (JNK), p38, ATF-2, GSK3, Stat1, and Stat3. Additional tests were performed with the p38 inhibitor (p38i) SB203580.

Results: Studied pathways were activated after impaction with the peak of activity at 1 hour. P188 completely attenuated phosphorylation of Stat1 and ATF-2 and inhibited p38, Stat3, JNK, ERK, and GSK3. The p38i partially offset phosphorylation of Stat3, GSK3, and ERK suggesting a role of p38 in these three pathways. Additionally, the p38i improved cell survival (P = 0.053) and reduced apoptosis (by approximately 20%, P = 0.046, versus almost 40% by P188), thus confirming that P188 acts (at least in part) through the p38 pathway.

Conclusion: Our results report a novel mechanism through which P188 exerts its protective effects on cartilage in the model of acute injury. In addition to its effect on cellular membrane, P188 affects stress-related p38 signaling, apoptosis-related GSK3, and inflammation-related IL-6 signaling. Taken together, these findings suggest that P188 alone or in combination with proanabolic agents may have a therapeutic potential in preventing progressive cartilage degeneration and the development of posttraumatic osteoarthritis.

From the Departments of *Biochemistry; †Orthopedic Surgery; ‡Anatomy and Cell Biology; and §Section of Rheumatology, Rush University Medical Center, Chicago, IL.

Accepted for publication June 10, 2010.

This work was supported by the National Institutes of Health (NIH) SCOR grant P50 AR 39239 (TO), NFL Charity Foundation (SC), NIH T32 training grant AR052272 (fellowship for SB), Rush Medical College Dean's Fellowship (TS), and Dr. Jorge Galante's fellowship (CPG).

None of the authors have financial or personal relationships with other people or organizations that could inappropriately influence (bias) this work.

Reprints: Susan Chubinskaya, PhD, Rush University Medical Center, Department of Biochemistry, Orthopedic Surgery & Rheumatology, 1735 W Harrison Street, Chicago, IL 60612 (e-mail:

© 2010 Lippincott Williams & Wilkins, Inc.