Reduction in Disease Progression by Inhibition of Transforming Growth Factor α-CCL2 Signaling in Experimental Posttraumatic Osteoarthritis
Reduction in Disease Progression by Inhibition of Transforming Growth Factor α-CCL2 Signaling in Experimental Posttraumatic Osteoarthritis
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DOI：
10.1002/art.39255
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发表时间：
2015-10-01
影响因子：
13.3
通讯作者：
Beier, Frank
中科院分区：
文献类型：
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作者：
Appleton, C. Thomas G.;Usmani, Shirine E.;Beier, Frank
客观的。大鼠和人类骨关节炎 (OA) 软骨中的转化生长因子 α (TGF α) 增加，并改变软骨细胞表型。 CCL2 在 OA 软骨中增加并刺激蛋白聚糖损失。本研究旨在测试 TGF α 和 CCL2 是否协同促进软骨退化，以及抑制任一者是否会在创伤后 OA 大鼠模型中减缓疾病进展。方法。使用微阵列分析来分析创伤后 OA 大鼠模型中 Tgfa、Ccl2 和相关基因的信使 RNA (mRNA) 表达。在存在或不存在 MEK-1/2、p38、磷脂酰肌醇 3-激酶、Rho 相关蛋白激酶或 CCR2 抑制剂的情况下，用 TGF α 处理大鼠原代软骨细胞和关节软骨外植体，并针对软骨降解标记物进行免疫染色。该大鼠模型用于给予 TGF α (AG1478) 和 CCL2 (RS504393) 信号传导药物抑制剂长达 10 周，并评估软骨合成（II 型胶原蛋白 C 前肽 [CPII]）和分解 (C2C) 的组织病理学和血清生物标志物。结果。在创伤后 OA 大鼠模型的关节软骨中，Tgfa 和 Ccl2 mRNA 同时上调。 TGFa 诱导原代软骨细胞中 CCL2、Mmp3 和 Tnf 的表达。 TGF α 诱导的 II 型胶原蛋白和聚集蛋白聚糖（分别由基质金属蛋白酶和 ADAMTS-4/5）的裂解可通过软骨外植体中 CCL2 的药理抑制来阻断。体内药物抑制 TGF α 或 CCL2 信号传导可降低骨关节炎研究协会国际软骨组织病理学评分并增加血清 CPII 水平，但与未治疗的大鼠 OA 软骨相比，仅 TGF α 抑制可降低治疗后的 C2C 水平。结论。 TGF α 信号传导通过 CCL2 依赖性机制刺激软骨降解，但 TGF α-CCL2 轴的药理学抑制可减少体内实验性创伤后 OA 进展。
Objective. Transforming growth factor alpha (TGF alpha) is increased in osteoarthritic (OA) cartilage in rats and humans and modifies chondrocyte phenotype. CCL2 is increased in OA cartilage and stimulates proteoglycan loss. This study was undertaken to test whether TGF alpha and CCL2 cooperate to promote cartilage degradation and whether inhibiting either reduces disease progression in a rat model of posttraumatic OA.Methods. Microarray analysis was used to profile expression of messenger RNA (mRNA) for Tgfa, Ccl2, and related genes in a rat model of posttraumatic OA. Rat primary chondrocytes and articular cartilage explants were treated with TGF alpha in the presence or absence of MEK-1/ 2, p38, phosphatidylinositol 3-kinase, Rho-associated protein kinase, or CCR2 inhibitors and immunostained for markers of cartilage degradation. The rat model was used to administer pharmacologic inhibitors of TGF alpha (AG1478) and CCL2 (RS504393) signaling for up to 10 weeks and assess histopathology and serum biomarkers of cartilage synthesis (C-propeptide of type II collagen [CPII]) and breakdown (C2C).Results. Tgfa and Ccl2 mRNA were simultaneously up-regulated in articular cartilage in the rat model of posttraumatic OA. TGFa induced expression of CCL2, Mmp3, and Tnf in primary chondrocytes. Cleavage of type II collagen and aggrecan (by matrix metalloproteinases and ADAMTS-4/ 5, respectively) induced by TGF alpha was blocked by pharmacologic inhibition of CCL2 in cartilage explants. In vivo pharmacologic inhibition of TGF alpha or CCL2 signaling reduced Osteoarthritis Research Society International cartilage histopathology scores and increased serum CPII levels, but only TGF alpha inhibition reduced C2C levels intreated versus untreated rat OA cartilage.Conclusion. TGF alpha signaling stimulates cartilage degradation via a CCL2-dependent mechanism, but pharmacologic inhibition of the TGF alpha-CCL2 axis reduces experimental posttraumatic OA progression in vivo.