Role of the C-C chemokine receptor-2 in a murine model of injury-induced osteoarthritis.
Role of the C-C chemokine receptor-2 in a murine model of injury-induced osteoarthritis.
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DOI：
10.1016/j.joca.2016.11.004
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发表时间：
2017-06
影响因子：
7
通讯作者：
Spagnoli A
中科院分区：
文献类型：
--
作者：
Longobardi L;Temple JD;Tagliafierro L;Willcockson H;Esposito A;D'Onofrio N;Stein E;Li T;Myers TJ;Ozkan H;Balestrieri ML;Ulici V;Loeser RF;Spagnoli A
我们先前在胚胎研究中发现，通过其唯一受体CCR 2对趋化因子CCL 12进行适当调节，对关节和生长板发育至关重要。在本研究中，我们研究了CCR 2在损伤诱导的骨关节炎（OA）中的作用。我们使用损伤诱导的OA（内侧半月板不稳定，DMM）的小鼠模型，并在疾病进展期间的不同时间使用特异性拮抗剂（RS 504393）全身阻断CCR 2。我们通过评估软骨（软骨损失、软骨细胞肥大、MMP-13表达）和骨病变（骨硬化、骨赘形成），用或不用CCR 2拮抗剂来检查关节退行性变。我们还通过使用IITS失能仪评估正常和关节炎后爪之间的重量分布来进行疼痛行为研究。测试早期与延迟给予CCR 2拮抗剂对关节损伤的不同影响。我们发现，如果在OA发展的早期给予药物CCR 2阻断，关节软骨和骨中的OA变化得到改善：具体地说，在损伤后的前4周内药物靶向CCR 2，减少了OA软骨和骨损伤，后期治疗的效果较差。重要的是，我们的疼痛相关行为研究表明，在早期（术后1- 4周）或中度（术后4- 8周）OA期间阻断CCR 2信号传导足以减少疼痛指标，在治疗停止后的后期阶段持续改善。我们的数据强调了在早期阶段拮抗CCR 2以减缓损伤后OA进展以及改善疼痛症状的潜在功效。
We previously found in our embryonic studies that proper regulation of the chemokine CCL12 through its sole receptor CCR2, is critical for joint and growth plate development. In the present study, we examined the role of CCR2 in injury-induced-osteoarthritis (OA). We used a murine model of injury-induced-OA (destabilization of medial meniscus, DMM), and systemically blocked CCR2 using a specific antagonist (RS504393) at different times during disease progression. We examined joint degeneration by assessing cartilage (cartilage loss, chondrocyte hypertrophy, MMP-13 expression) and bone lesions (bone sclerosis, osteophytes formation) with or without the CCR2 antagonist. We also performed pain behavioral studies by assessing the weight distribution between the normal and arthritic hind paws using the IITS incapacitance meter. Testing early vs. delayed administration of the CCR2 antagonist demonstrated differential effects on joint damage. We found that OA changes in articular cartilage and bone were ameliorated by pharmacological CCR2 blockade, if given early in OA development: specifically, pharmacological targeting of CCR2 during the first 4 weeks following injury, reduced OA cartilage and bone damage, with less effectiveness with later treatments. Importantly, our pain-related behavioral studies showed that blockade of CCR2 signaling during early, 1–4wks post-surgery or moderate, 4–8wks post-surgery, OA was sufficient to decrease pain measures, with sustained improvement at later stages, after treatment was stopped. Our data highlight the potential efficacy of antagonizing CCR2 at early stages to slow the progression of post-injury OA and, in addition, improve pain symptoms.