Protective effect of p38 MAPK inhibitor on wear debris-induced inflammatory osteolysis through downregulating RANK/RANKL in a mouse model.
Aseptic loosening associated with wear particle-induced inflammation is a major cause of joint implant failure. Recent studies have demonstrated the therapeutic effects of p38 mitogen-activated protein kinase (MAPK)-based therapies on chronic inflammatory diseases. The purpose of this study was to investigate whether SB203580, a p38 MAPK inhibitor, inhibits wear debris-induced inflammatory osteolysis in mice through downregulation of receptor activator of nuclear factor kβ (RANK)/RANK ligand (RANKL). We used a murine osteolysis model to study the effect of SB203580 on RANKL/RANK signaling and titanium particle-induced osteolysis in vivo. Pouch membranes with intact bone implants were analyzed using histological analysis and transmission electron microscopy, and the levels of RANK and RANKL protein and mRNA were evaluated by immunohistological staining and real-time reverse transcriptase-polymerase chain reaction. SB203580 had less of an effect on RANK and RANKL expression under wear debris-induced conditions. The number of TRAP-positive cells was remarkably reduced in Ti-particle-induced pouch tissues. These effects were confirmed through the transmission electron microscopy results. These results suggest that p38 MAPK-based therapies are beneficial in preventing aseptic loosening associated with total joint replacement by modulating RANK-RANKL signaling.
Department of Orthopaedics, The General Hospital of Ningxia Medical University, Yinchuan, Hui Autonomous Region, China.
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Chen
Basic Medical Science College, Ningxia Medical University, Yinchuan, Ningxia Hui Autonomous Region, China.
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Li
Basic Medical Science College, Ningxia Medical University, Yinchuan, Ningxia Hui Autonomous Region, China.
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Guo
Department of Orthopaedics, The General Hospital of Ningxia Medical University, Yinchuan, Hui Autonomous Region, China.
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Lu
Basic Medical Science College, Ningxia Medical University, Yinchuan, Ningxia Hui Autonomous Region, China.
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C
Hei
Department of Orthopaedics, The General Hospital of Ningxia Medical University, Yinchuan, Hui Autonomous Region, China.
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Li
Department of Orthopaedics, The General Hospital of Ningxia Medical University, Yinchuan, Hui Autonomous Region, China chendeshengsci@163.com.
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Jin
D000135:Acid Phosphatase / Q000378:metabolism; D000818:Animals; D001842:Bone and Bones / Q000187:drug effects / Q000473:pathology; D039021:Colonic Pouches; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000187:drug effects*; D005260:Female; D007150:Immunohistochemistry; D007249:Inflammation / Q000188:drug therapy / Q000209:etiology* / Q000235:genetics / Q000473:pathology; D007527:Isoenzymes / Q000378:metabolism; D008807:Mice, Inbred BALB C; D010014:Osteolysis / Q000188:drug therapy / Q000209:etiology* / Q000235:genetics / Q000473:pathology; D019736:Prostheses and Implants / Q000009:adverse effects*; D020011:Protective Agents / Q000494:pharmacology / Q000627:therapeutic use; D047428:Protein Kinase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D053245:RANK Ligand / Q000235:genetics* / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D053246:Receptor Activator of Nuclear Factor-kappa B / Q000235:genetics* / Q000378:metabolism; D000071681:Tartrate-Resistant Acid Phosphatase; D014025:Titanium / Q000009:adverse effects; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism
D007527:Isoenzymes; D020011:Protective Agents; D047428:Protein Kinase Inhibitors; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; C505687:Tnfrsf11a protein, mouse; D014025:Titanium; D048051:p38 Mitogen-Activated Protein Kinases; D000135:Acid Phosphatase; C000605511:Acp5 protein, mouse; D000071681:Tartrate-Resistant Acid Phosphatase