CCR2 chemokine receptor signaling mediates pain in experimental osteoarthritis
CCR2 chemokine receptor signaling mediates pain in experimental osteoarthritis
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DOI：
10.1073/pnas.1209294110
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发表时间：
2012-12-11
影响因子：
11.1
通讯作者：
Malfait, Anne-Marie
中科院分区：
文献类型：
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作者：
Miller, Rachel E.;Tran, Phuong B.;Malfait, Anne-Marie
骨关节炎是慢性疼痛的主要原因之一，但对于介导骨关节炎相关关节疼痛的机制和分子几乎一无所知。因此，治疗选择仍然不足，关节置换往往是不可避免的。在这里，我们使用手术小鼠模型来捕获膝骨关节炎的长期进展，以纵向评估疼痛相关行为以及支配背根神经节（DRG）的伴随变化。我们证明单核细胞趋化蛋白 (MCP)-1 (CCL2) 及其高亲和力受体趋化因子（C-C 基序）受体 2 (CCR2) 对于膝骨关节炎相关疼痛的发生至关重要。内侧半月板不稳定后，小鼠出现早发性继发性机械异常性疼痛，并持续 16 周。术后 8 周，支配 DRG 的 MCP-1 和 CCR2 mRNA、蛋白质和信号传导活性暂时上调。这一结果与运动引起的疼痛行为的表现相关，该行为持续长达 16 周。缺乏 Ccr2 的小鼠也会出现机械性异常性疼痛，但这种情况从 8 周起开始消失。尽管与野生型小鼠一样存在严重的异常性疼痛和结构性膝关节损伤，但 Ccr2 缺失小鼠在第 8 周时并未出现运动引起的疼痛行为。在野生型小鼠中，巨噬细胞在 8 周时浸润 DRG，并且这种情况在手术后持续了 16 周。相反，在 Ccr2 缺失小鼠中未观察到巨噬细胞浸润。这些观察结果表明 MCP-1/CCR2 通路在骨关节炎疼痛的形成中发挥着关键作用。
Osteoarthritis is one of the leading causes of chronic pain, but almost nothing is known about the mechanisms and molecules that mediate osteoarthritis-associated joint pain. Consequently, treatment options remain inadequate and joint replacement is often inevitable. Here, we use a surgical mouse model that captures the long-term progression of knee osteoarthritis to longitudinally assess pain-related behaviors and concomitant changes in the innervating dorsal root ganglia (DRG). We demonstrate that monocyte chemoattractant protein (MCP)-1 (CCL2) and its high-affinity receptor, chemokine (C-C motif) receptor 2 (CCR2), are central to the development of pain associated with knee osteoarthritis. After destabilization of the medial meniscus, mice developed early-onset secondary mechanical allodynia that was maintained for 16 wk. MCP-1 and CCR2 mRNA, protein, and signaling activity were temporarily up-regulated in the innervating DRG at 8 wk after surgery. This result correlated with the presentation of movement-provoked pain behaviors, which were maintained up to 16 wk. Mice that lack Ccr2 also developed mechanical allodynia, but this started to resolve from 8 wk onwards. Despite severe allodynia and structural knee joint damage equal to wild-type mice, Ccr2-null mice did not develop movement-provoked pain behaviors at 8 wk. In wild-type mice, macrophages infiltrated the DRG by 8 wk and this was maintained through 16 wk after surgery. In contrast, macrophage infiltration was not observed in Ccr2-null mice. These observations suggest a key role for the MCP-1/CCR2 pathway in establishing osteoarthritis pain.