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

被引:35
作者
Bajaj, Sarvottam [1 ,3 ]
Shoemaker, Thomas [1 ]
Hakimiyan, Arnavaz A. [1 ]
Rappoport, Lev [1 ]
Pascual-Garrido, Cecilia [1 ,2 ]
Oegema, Theodore R. [1 ,2 ]
Wimmer, Markus A. [1 ,2 ,3 ]
Chubinskaya, Susan [1 ,2 ,4 ]
机构
[1] Rush Univ, Med Ctr, Dept Biochem, Chicago, IL 60612 USA
[2] Rush Univ, Med Ctr, Dept Orthoped Surg, Chicago, IL 60612 USA
[3] Rush Univ, Med Ctr, Dept Anat & Cell Biol, Chicago, IL 60612 USA
[4] Rush Univ, Med Ctr, Rheumatol Sect, Chicago, IL 60612 USA
基金
美国国家卫生研究院;
关键词
chondrocyte viability; apoptosis; histology; impact; ankle cartilage; ARTICULAR CARTILAGE; OSTEOARTHRITIS; CHONDROCYTES; APOPTOSIS;
D O I
10.1097/BOT.0b013e3181ec4712
中图分类号
R826.8 [整形外科学]; R782.2 [口腔颌面部整形外科学]; R726.2 [小儿整形外科学]; R62 [整形外科学(修复外科学)];
学科分类号
摘要
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
引用
收藏
页码:571 / 576
页数:6
相关论文
共 14 条
[1]  
Abramoff M.D., 2004, Biophotonics International, V11, P36
[2]   Signaling transduction: target in osteoarthritis [J].
Berenbaum, F .
CURRENT OPINION IN RHEUMATOLOGY, 2004, 16 (05) :616-622
[3]   The paradoxical pro- and anti-apoptotic actions of GSK3 in the intrinsic and extrinsic apoptosis signaling pathways [J].
Beurel, Eleonore ;
Jope, Richard S. .
PROGRESS IN NEUROBIOLOGY, 2006, 79 (04) :173-189
[4]   Posttraumatic osteoarthritis: A first estimate of incidence, prevalence, and burden of disease [J].
Brown, Thomas D. ;
Johnston, Richard C. ;
Saltzman, Charles L. ;
Marsh, J. Lawrence ;
Buckwalter, Joseph A. .
JOURNAL OF ORTHOPAEDIC TRAUMA, 2006, 20 (10) :739-744
[5]  
Collins DH, 1949, PATHOLOGY ARTICULAR, P74
[6]   Human chondrocyte apoptosis in response to mechanical injury [J].
D'Lima, DD ;
Hashimoto, S ;
Chen, PC ;
Colwell, CW ;
Lotz, MK .
OSTEOARTHRITIS AND CARTILAGE, 2001, 9 (08) :712-719
[7]   Anti-apoptotic treatments prevent cartilage degradation after acute trauma to human ankle cartilage [J].
Garrido, C. Pascual ;
Hakimiyan, A. A. ;
Rappoport, L. ;
Oegema, T. R. ;
Wimmer, M. A. ;
Chubinskaya, S. .
OSTEOARTHRITIS AND CARTILAGE, 2009, 17 (09) :1244-1251
[8]   Joint injury in young adults and risk for subsequent knee and hip osteoarthritis [J].
Gelber, AC ;
Hochberg, MC ;
Mead, LA ;
Wang, NY ;
Wigley, FM ;
Klag, MJ .
ANNALS OF INTERNAL MEDICINE, 2000, 133 (05) :321-328
[9]   Acute Repair of Chondrocytes in the Rabbit Tibiofemoral Joint following Blunt Impact Using P188 Surfactant and a Preliminary Investigation of Its Long-Term Efficacy [J].
Isaac, Daniel I. ;
Golenberg, Nurit ;
Haut, Roger C. .
JOURNAL OF ORTHOPAEDIC RESEARCH, 2010, 28 (04) :553-558
[10]  
KERN D, 1988, RADIOL CLIN N AM, V26, P1349