Kang Y, Eger W, Koepp H, Williams J M, Kuettner K E, Homandberg G A
Department of Biochemistry, Rush Medical College at Rush-Presbyterian-St. Luke's Medical Center, Chicago, Illinois 60612-3864, USA.
J Orthop Res. 1999 Nov;17(6):858-69. doi: 10.1002/jor.1100170611.
Hyaluronic acid, recently renamed hyaluronan, has been used as a therapeutic intervention in the treatment of osteoarthritis. We have reported that high-molecular-weight (800 kDa) hyaluronan is effective in blocking the catabolic action of fibronectin fragments in explant cultures of bovine cartilage and in an experimental in vivo model of damage to the rabbit knee joint. The fibronectin fragments induce catabolic cytokines in human cartilage, which, in turn, suppress proteoglycan synthesis and induce matrix metalloproteinases to decrease the proteoglycan content. Since the clinical target of high-molecular-weight hyaluronan is human cartilage, which may differ in certain ways from bovine cartilage, we tested the effect on human knee cartilage. We found that 1 mg/ml hyaluronan completely blocked fibronectin fragment-mediated decreases in proteoglycan content in five of five specimens of cartilage from the human knee. This was associated with binding of exogenous hyaluronan to the superficial surface, suppressed penetration of the fibronectin fragment into the cartilage, decreased expression for the first week in culture of one of the matrix metalloproteinases involved in cartilage degradation, matrix metalloproteinase-3, and proteoglycan synthesis rates that increased to supernormal levels. However, the appearance of the NITEGE and VDIPEN neoepitopes, indices of cartilage degradation, was not blocked but was delayed by 1 week. The addition of hyaluronan to cartilage previously damaged by the fibronectin fragments or to osteoarthritic cartilage fully restored the proteoglycan content to control levels. We conclude that hyaluronan blocked damage at least partly by blocking penetration of the fibronectin fragments and slowing matrix metalloproteinase expression. However, the major effect on blocking damage and promoting repair may be through enhanced proteoglycan synthesis, a mechanism that requires further study. Nonetheless, these data clearly demonstrate that hyaluronan completely protected human cartilage in explant culture and facilitated a full restoration of proteoglycan in damaged cartilage.
透明质酸，最近更名为透明质聚糖，已被用作骨关节炎治疗的一种治疗手段。我们曾报道，高分子量（800 kDa）透明质聚糖在牛软骨外植体培养物以及兔膝关节损伤的实验体内模型中，可有效阻断纤连蛋白片段的分解代谢作用。纤连蛋白片段可在人软骨中诱导分解代谢细胞因子，进而抑制蛋白聚糖合成并诱导基质金属蛋白酶，以降低蛋白聚糖含量。由于高分子量透明质聚糖的临床靶点是人软骨，其可能在某些方面与牛软骨不同，因此我们测试了其对人膝关节软骨的作用。我们发现，1 mg/ml透明质聚糖完全阻断了来自人膝关节的五份软骨标本中，纤连蛋白片段介导的蛋白聚糖含量下降。这与外源性透明质聚糖结合至表面、抑制纤连蛋白片段渗透进入软骨、在培养的第一周降低参与软骨降解的一种基质金属蛋白酶（基质金属蛋白酶-3）的表达以及蛋白聚糖合成速率增加至超常水平有关。然而，软骨降解指标NITEGE和VDIPEN新表位的出现并未被阻断，但延迟了1周。向先前被纤连蛋白片段损伤的软骨或骨关节炎软骨中添加透明质聚糖，可使蛋白聚糖含量完全恢复至对照水平。我们得出结论，透明质聚糖至少部分通过阻断纤连蛋白片段的渗透和减缓基质金属蛋白酶表达来阻断损伤。然而，其对阻断损伤和促进修复的主要作用可能是通过增强蛋白聚糖合成，这一机制需要进一步研究。尽管如此，这些数据清楚地表明，透明质聚糖在体外培养中完全保护了人软骨，并促进了受损软骨中蛋白聚糖的完全恢复。
