CCL2 But Not CCR2 Is Required for Spontaneous Articular Cartilage Regeneration Post-Injury
CCL2 But Not CCR2 Is Required for Spontaneous Articular Cartilage Regeneration Post-Injury
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DOI：
10.1002/jor.24444
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发表时间：
2019-08-30
影响因子：
2.8
通讯作者：
Krawetz, Roman J.
中科院分区：
文献类型：
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作者：
Jablonski, Christina L.;Leonard, Catherine;Krawetz, Roman J.
炎症反应在关节软骨退变和/或修复中的作用经常被争论。趋化因子网络在将免疫细胞募集到损伤部位方面起着关键作用，并已被证明可调节细胞行为。在这项研究中，我们研究了CCL 2/CCR 2信号轴在软骨再生和退变中的作用。使CCL 2（-/-）、CCR 2（-/-）、CCL 2（-/-）CCR 2（-/-）和对照（C57）小鼠在股骨沟内经受全层软骨缺损（FTCD）损伤（n = 9/组）。使用14分组织学评分量表评估FTCD后4周和12周的软骨再生。使用免疫荧光定量关节内的间充质干细胞（MSC）（Sca-1（+）、CD 140 a（+））、巨噬细胞（M1：CD 38（+）、M2：CD 206（+）和M0：F4/80（+））和增殖细胞（Ki 67（+））。对所有小鼠品系测定Sca 1（+）MSC的多谱系分化能力。采用ACL横断（ACL-x）来确定CCL 2（-/-）CCR 2（-/-）小鼠是否受到保护以免受骨关节炎（OA）（n = 6/组）。不存在CCR 2，但不存在CCL 2或两者（CCL 2和CCR 2），增强FTCD后4周的自发性关节软骨再生。此外，在源自CCR 2（-/-）小鼠的MSC中观察到增加的软骨形成。CCL 2缺陷促进MSC归巢到相邻的滑膜和FTCD在损伤后4周和12周;在其余菌株中，FTCD表面不存在MSC。与C57小鼠相比，在ACL-x后12周，在CCL 2（-/-）CCR 2（-/-）小鼠中观察到较低的OA评分。我们的研究结果证明了CCR 2在损伤后软骨再生中的抑制作用，而CCL 2是再生所需的，通过CCR 2独立机制起作用。
The role of the inflammatory response in articular cartilage degeneration and/or repair is often debated. Chemokine networks play a critical role in directing the recruitment of immune cells to sites of injury and have been shown to regulate cell behavior. In this study, we investigated the role of the CCL2/CCR2 signaling axis in cartilage regeneration and degeneration. CCL2(-/-), CCR2(-/-), CCL2(-/-)CCR2(-/-), and control (C57) mice were subjected to full-thickness cartilage defect (FTCD) injuries (n = 9/group) within the femoral groove. Cartilage regeneration at 4 and 12 weeks post-FTCD was assessed using a 14-point histological scoring scale. Mesenchymal stem cells (MSCs) (Sca-1(+), CD140a(+)), macrophages (M1:CD38(+), M2:CD206(+), and M0:F4/80(+)) and proliferating cells (Ki67(+)) were quantified within joints using immunofluorescence. The multi-lineage differentiation capacity of Sca1(+) MSCs was determined for all mouse strains. ACL transection (ACL-x) was employed to determine if CCL2(-/-)CCR2(-/-) mice were protected against osteoarthritis (OA) (n = 6/group). Absence of CCR2, but not CCL2 nor both (CCL2 and CCR2), enhanced spontaneous articular cartilage regeneration by 4 weeks post-FTCD. Furthermore, increased chondrogenesis was observed in MSCs derived from CCR2(-/-) mice. CCL2 deficiency promoted MSC homing to the adjacent synovium and FTCD at both 4 and 12 weeks post-injury; with no MSCs present at the surface of the FTCD in the remaining strains. Lower OA scores were observed in CCL2(-/-)CCR2(-/-) mice at 12 weeks post-ACL-x compared with C57 mice. Our findings demonstrate an inhibitory role for CCR2 in cartilage regeneration after injury, while CCL2 is required for regeneration, acting through a CCR2 independent mechanism.