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

Objective: Because P188 poloxamer is effective in promoting cell survival in models of acute trauma. the objectives wet e 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 kine (ERK), c-Jun NH(2)-terminal kinase (INK), p38, ATF-2, GSK3, Stall, 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 I hour P188 completely attenuated phosphorylation of Statl 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 I through which P188 exerts its protective effects on cartilage in the model of acute injury In addition to its effect on cellular membrane, P 88 affects stress-related 1)38 signaling, apoptosis-related GSK3, and inflammation-related IL-6 signaling Taken together. these findings suggest that P188 alone or in combination with proanabohc agents may have a therapeutic potential in preventing progressive cartilage degeneration and the development of posttraumatic osteoarthrms