Department of Molecular Medicine and Surgery, Karolinska Institutet, Karolinska University Hospital, Solna, Stockholm 17176, Sweden Department of Medicine, Centre for Molecular Medicine, Karolinska Institutet, Karolinska University Hospital, Solna, Stockholm 17176, Sweden Department of Clinical Sciences, Danderyd Hospital, Karolinska Institutet, Stockholm 18288, Sweden Department of Pharmaceutical Biosciences, Uppsala University, Uppsala 75105, Sweden Department of Neurobiology, Care Sciences and Society, Center for Family and Community Medicine, Karolinska Institutet, Huddinge 14183, Sweden.
Pain. 2012 Jan;153(1):18-26. doi: 10.1016/j.pain.2011.08.001. Epub 2011 Oct 22.
Osteoarthritis is a degenerative joint disease with pain and loss of joint function as major pathological features. Recent studies show that proteasome inhibitors reduce pain in various pathological conditions. We evaluated the effects of MG132, a reversible proteasome inhibitor on pain and joint destruction in a rat model of osteoarthritis. Osteoarthritis was induced by intraarticular injection of monosodium iodoacetate into the rat knee. Knee joint stiffness was scored and nociception was evaluated by mechanical pressure applied to the respective hind paw. Knee joint destruction was assessed by radiological and histological analyses. Expression of matrix metalloproteinase-3 (MMP-3) was analyzed by quantitative reverse transcription polymerase chain reaction in the knee articular cartilage. Expression of substance P (SP) and calcitonin gene-related peptide (CGRP) was studied in the dorsal root ganglia (L4-L6) by quantitative reverse transcription polymerase chain reaction and in the knee joints by immunohistochemistry. Our results indicate that daily treatment of osteoarthritic rats with MG132 significantly increases their mobility while the swelling, pain thresholds, and pathological features of the affected joints were reduced. Furthermore, the upregulated expression of MMP-3, SP, and CGRP in the arthritic rats was normalized by MG132 administration. We conclude that the proteasome inhibitor MG132 reduces pain and joint destruction, probably by involving the peripheral nervous system, and that changes in SP and CGRP expression correlate with alterations in behavioural responses. Our findings suggest that nontoxic proteasome inhibitors may represent a novel pharmacotherapy for osteoarthritis.
骨关节炎是一种退行性关节疾病，其主要病理特征为疼痛和关节功能丧失。最近的研究表明，蛋白酶体抑制剂可减轻多种病理状态下的疼痛。我们评估了可逆蛋白酶体抑制剂 MG132 对骨关节炎大鼠模型中疼痛和关节破坏的影响。通过向大鼠膝关节腔内注射单碘乙酸钠诱导骨关节炎。通过对相应后爪施加机械压力来评分膝关节僵硬，并评估痛觉。通过放射学和组织学分析评估膝关节破坏。通过定量逆转录聚合酶链反应分析膝关节软骨中基质金属蛋白酶-3（MMP-3）的表达。通过定量逆转录聚合酶链反应研究背根神经节（L4-L6）中 P 物质（SP）和降钙素基因相关肽（CGRP）的表达，并通过免疫组织化学研究膝关节中 SP 和 CGRP 的表达。我们的结果表明，MG132 每日治疗骨关节炎大鼠可显著提高其活动能力，同时减轻受影响关节的肿胀、疼痛阈值和病理特征。此外，MG132 给药可使关节炎大鼠中上调的 MMP-3、SP 和 CGRP 表达正常化。我们得出结论，蛋白酶体抑制剂 MG132 可减轻疼痛和关节破坏，可能涉及外周神经系统，并且 SP 和 CGRP 表达的变化与行为反应的改变相关。我们的研究结果表明，非毒性蛋白酶体抑制剂可能代表骨关节炎的一种新的药物治疗方法。
