Beecher B R, Martin J A, Pedersen D R, Heiner A D, Buckwalter J A
Department of Orthopaedics and Rehabilitation, University of Iowa, Iowa City, IA 52242, USA.
Iowa Orthop J. 2007;27:1-8.
Articular cartilage in congruous joints benefits from the moderate stresses and strains associated with normal cyclic loading. However, loading of joints with surface incongruities can lead to local stress and strain elevation at "step-off' sites where cartilage is not fully buttressed b ysurrounding matrix. Excessive stresses and strains predicted to occur at such sites may induce apoptosis, a process thought to promote cartilage degeneration and osteoarthritis (OA) through chondrocyte attrition. We hypothesized that the induction of apoptosis is mediated by oxidants, and that antioxidants can reduce elevated stress-induced chondrocyte attrition. To test this we exposed cylindrical cartilage explants from human articular cartilage to radially unconfined cyclic axial compression (3600 cycles, 1 Hz, 50% duty cycle) using two different physiologic loads (2MPa and 5 MPa). We found that 30% of chondrocytes in the superficial zone died within 24 hours of exposure to loading with 5 MPa axial compression, whereas mortality was limited to less than 15% with 2 MPa axial compression. Similarly, lactate accumulation in the medium was suppressed by compression with 5 MPa, but not 2 MPa. Approximately 80% of cell death induced by 5 MPa compression was blocked by pre-incubation of the explants in a variety of anti-oxidants including vitamin E, n-acetyl cysteine (NAC), and a superoxide dismutase mimetic (SOD). SOD and NAC also prevented the suppression of lactate secretion after 5 MPa compression. These observations support the hypothesis that the harmful effects of abnormal cyclic loading are mediated by oxidants and suggest that treatments to prevent OA may include methods of minimizing oxidative damage to chondrocytes.
在匹配良好的关节中，关节软骨受益于与正常周期性负荷相关的适度应力和应变。然而，对于存在表面不匹配的关节，负荷会导致在“台阶状”部位出现局部应力和应变升高，在这些部位软骨无法得到周围基质的充分支撑。预计在这些部位会出现的过大应力和应变可能会诱导细胞凋亡，这一过程被认为会通过软骨细胞损耗促进软骨退变和骨关节炎（OA）。我们假设细胞凋亡的诱导是由氧化剂介导的，并且抗氧化剂可以减少应力升高引起的软骨细胞损耗。为了验证这一点，我们使用两种不同的生理负荷（2MPa和5MPa），对来自人关节软骨的圆柱形软骨外植体施加径向无约束的周期性轴向压缩（3600次循环，1Hz，50%占空比）。我们发现，在暴露于5MPa轴向压缩负荷的24小时内，表层区域30%的软骨细胞死亡，而在2MPa轴向压缩时，死亡率限制在15%以下。同样，5MPa压缩会抑制培养基中乳酸的积累，而2MPa压缩则不会。通过在包括维生素E、N-乙酰半胱氨酸（NAC）和超氧化物歧化酶模拟物（SOD）等多种抗氧化剂中预孵育外植体，可阻止约80%由5MPa压缩诱导的细胞死亡。SOD和NAC还可防止5MPa压缩后乳酸分泌的抑制。这些观察结果支持了异常周期性负荷的有害影响是由氧化剂介导的这一假设，并表明预防OA的治疗方法可能包括尽量减少对软骨细胞氧化损伤的方法。
