Efficacy of a p38 mitogen activated protein kinase inhibitor in mitigating an established inflammatory reaction to polyethylene particles in vivo.
The inhibitor of p38 mitogen-activated protein kinase (MAPK) is of interest in the nonoperative treatment of periprosthetic osteolysis due to wear particles. Previous studies demonstrated that an oral p38 MAPK inhibitor did not suppress bone formation when given during the initial phase of tissue differentiation. However, the oral p38 MAPK inhibitor also did not curtail the foreign body and chronic inflammatory response to particles when given simultaneously. The purpose of the current study was to examine the efficacy of a p38 MAPK inhibitor, SCIO-323, on mitigating an established inflammatory reaction that parallels the clinical situation more closely. The Bone Harvest Chamber was implanted in rabbits and submicron polyethylene particles were placed in the chamber for 6 weeks. The contents of the chambers were harvested every 6 weeks. Oral treatment with the SCIO-323 included delivery for 3 weeks and stopping for 3 weeks, delivery for 3 weeks after an initial 3-week delay, and delivery for 6 weeks continuously. Administration of the SCIO-323 continuously for 6 weeks with/without the presence of particles, or for the initial 3 of 6 weeks had minor effects on bone ingrowth. After establishing a particle-induced chronic inflammatory reaction for 3 weeks, administration of SCIO-323 for a subsequent 3 weeks suppressed net bone formation. The activity of osteoclast-like cells remained low among all treatments when compared with the first control. Using the present model, the oral p38 MAPK inhibitor was ineffective in improving bone ingrowth in the presence of polyethylene particles.
Ma
T
T
Department of Orthopaedic Surgery, Stanford University, Stanford, California, USA.
Ren
P-G
PG
Larsen
D M
DM
Suenaga
E
E
Zilber
S
S
Genovese
M
M
Smith
R L
RL
Goodman
S B
SB
D000818:Animals; D001672:Biocompatible Materials / Q000378:metabolism; D001842:Bone and Bones / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D006801:Humans; D020007:Implants, Experimental; D007249:Inflammation / Q000188:drug therapy*; D008297:Male; D008422:Materials Testing; D020959:Polyethylene / Q000276:immunology*; D011817:Rabbits; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors*
D001672:Biocompatible Materials; D004791:Enzyme Inhibitors; D020959:Polyethylene; D048051:p38 Mitogen-Activated Protein Kinases