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Effects of N-methyl-d-aspartate receptor antagonist MK-801 (dizocilpine) on bone homeostasis in mice
Shuichi Kiyohara1, Nobuhiro Sakai2, Kazuaki Handa3
1Department of Pharmacology, Showa University School of Dentistry, 1-5-8 Hatanodai Shinagawa, Tokyo, 142-8555 Japan; Department of Implant Dentistry, Showa University School of Dentistry, 2-1-1 Kitasenzoku, Ota, Tokyo, 145-8515, Japan; Pharmacological Research Center, Showa University, 1-5-8 Hatanodai Shinagawa, Tokyo, 142-8555, Japan.
Objectives:
To gain insight into the role of the N-methyl-d-aspartate (NMDA) receptor in bone metabolism by examining the effects of its noncompetitive antagonist, MK-801 (dizocilpine), on bone homeostasis and bone healing in mice.
Methods:
MK-801 (2.5 mg/kg) or saline (in control groups) was intravenously administered to healthy mice and mice with bone-defects daily for seven to 14 days. Bone defects were artificially created in femurs using a drill and reamer. Following euthanasia, bones were extracted and processed for microcomputed tomography (μCT) and histological analyses. The effects of MK-801 on osteoclast differentiation by bone marrow macrophages (BMMs) were examined in vitro. mRNA expressionlevels of Grin3b levels were also examined using reverse-transcription polymerase chain reaction (RT-PCR).
Results:
Bone volume was significantly decreased in mice administered MK-801 for 14 days. Additionally, the number of osteoclasts was reduced, while number of osteoblasts and rate of bone formation were increased in these mice. MK-801 inhibited osteoclast differentiation dose-dependently in vitro. RT-PCR findings suggested expression of Grin3b, a subunit of the NMDA receptor, in BMMs. During the healing process of artificially created defects in femurs, no significant differences were found between the control and MK-801-treated groups, indicating no stimulatory or inhibitory effects by MK-801 administration.
Conclusions:
These results indicate that blockade of the NMDA receptor by MK-801 administration affects bone metabolism but not the healing process of artificial bone defects.
