Seol Dongrim, McCabe Daniel J, Choe Hyeonghun, Zheng Hongjun, Yu Yin, Jang Keewoong, Walter Morgan W, Lehman Abigail D, Ding Lei, Buckwalter Joseph A, Martin James A
Dongrim Seol, PhD, Daniel J. McCabe, BS, Hyeonghun Choe, ME, Hongjun Zheng, PhD, Yin Yu, BM, Keewoong Jang, MS, Morgan W. Walter, BS, Abigail D. Lehman, BS, Lei Ding, PhD, James A. Martin, PhD: University of Iowa, Iowa City.
Joseph A. Buckwalter, MD: University of Iowa and VA Medical Center, Iowa City, Iowa.
Arthritis Rheum. 2012 Nov;64(11):3626-3637. doi: 10.1002/art.34613.
Hypocellularity resulting from chondrocyte death in the aftermath of mechanical injury is thought to contribute to posttraumatic osteoarthritis. However, we observed that nonviable areas in cartilage injured by blunt impact were repopulated within 7-14 days by cells that appeared to migrate from the surrounding matrix. The aim of this study was to assess our hypothesis that the migrating cell population included chondrogenic progenitor cells that were drawn to injured cartilage by alarmins.
Osteochondral explants obtained from mature cattle were injured by blunt impact or scratching, resulting in localized chondrocyte death. Injured sites were serially imaged by confocal microscopy, and migrating cells were evaluated for chondrogenic progenitor characteristics. Chemotaxis assays were used to measure the responses to chemokines, injury-conditioned medium, dead cell debris, and high mobility group box chromosomal protein 1 (HMGB-1).
Migrating cells were highly clonogenic and multipotent and expressed markers associated with chondrogenic progenitor cells. Compared with chondrocytes, these cells overexpressed genes involved in proliferation and migration and underexpressed cartilage matrix genes. They were more active than chondrocytes in chemotaxis assays and responded to cell lysates, conditioned medium, and HMGB-1. Glycyrrhizin, a chelator of HMGB-1 and a blocking antibody to receptor for advanced glycation end products (RAGE), inhibited responses to cell debris and conditioned medium and reduced the numbers of migrating cells on injured explants.
Injuries that caused chondrocyte death stimulated the emergence and homing of chondrogenic progenitor cells, in part via HMGB-1 release and RAGE-mediated chemotaxis. Their repopulation of the matrix could promote the repair of chondral damage that might otherwise contribute to progressive cartilage loss.
机械损伤后软骨细胞死亡导致的细胞减少被认为是创伤后骨关节炎的一个原因。然而，我们观察到钝性撞击损伤的软骨中的无活力区域在7 - 14天内被似乎从周围基质迁移而来的细胞重新填充。本研究的目的是评估我们的假设，即迁移细胞群体包括被警报素吸引至损伤软骨的软骨生成祖细胞。
从成年牛获取的骨软骨外植体通过钝性撞击或刮擦造成损伤，导致局部软骨细胞死亡。通过共聚焦显微镜对损伤部位进行连续成像，并评估迁移细胞的软骨生成祖细胞特征。采用趋化性测定法测量对趋化因子、损伤条件培养基、死细胞碎片和高迁移率族蛋白B1（HMGB - 1）的反应。
迁移细胞具有高度克隆性和多能性，并表达与软骨生成祖细胞相关的标志物。与软骨细胞相比，这些细胞过度表达参与增殖和迁移的基因，而软骨基质基因表达不足。在趋化性测定中它们比软骨细胞更活跃，并对细胞裂解物、条件培养基和HMGB - 1有反应。甘草酸，一种HMGB - 1螯合剂和晚期糖基化终产物受体（RAGE）阻断抗体，抑制了对细胞碎片和条件培养基的反应，并减少了损伤外植体上迁移细胞的数量。
导致软骨细胞死亡的损伤刺激了软骨生成祖细胞的出现和归巢，部分是通过HMGB - 1释放和RAGE介导的趋化作用。它们对基质的重新填充可促进软骨损伤的修复，否则这种损伤可能导致软骨的渐进性丢失。
