Iacob Stanca, Knudson Cheryl B
Department of Biochemistry, Rush University Medical Center, 1653 West Congress Parkway, Cohn 516, Chicago, IL 60612, USA.
Int J Biochem Cell Biol. 2006 Jan;38(1):123-33. doi: 10.1016/j.biocel.2005.08.011. Epub 2005 Sep 8.
Chondrocyte CD44 receptors anchor hyaluronan to the cell surface, enabling the assembly and retention of proteoglycan aggregates in the pericellular matrix. Hyaluronan-CD44 interactions also provide signaling important for maintaining cartilage homeostasis. Disruption of chondrocyte-hyaluronan contact alters CD44 occupancy, initiating alternative signaling cascades. Treatment with hyaluronan oligosaccharides is one approach to uncouple CD44 receptors from its native ligand, hyaluronan. In bovine articular chondrocytes, treatment with hyaluronan oligosaccharides or purified hyaluronan hexasaccharides induced the production of nitric oxide that mirrored nitric oxide production following interleukin-1 treatment. In contrast, 120 and 1,260 kDa hyaluronan did not induce production of nitric oxide. Human chondrocytes responded similarly to treatment with hyaluronan or hyaluronan oligosaccharides. Nitric oxide production from chondrocytes was mediated by activation of the inducible nitric oxide synthase, as confirmed by mRNA expression and inhibition of nitric oxide production by diphenyleneiodonium. Co-treatment of chondrocytes with hyaluronan oligosaccharides and interleukin-1 did not demonstrate additive effects. Blocking interleukin-1 receptors with an antagonist did not abolish the production of nitric oxide induced by treatment with hyaluronan oligosaccharides. Moreover, only COS-7 following transfection with a pCD44, not the CD44-null parental cells, responded to treatment with hyaluronan oligosaccharides by releasing nitric oxide. This study demonstrates a novel signaling potential by hyaluronan fragments, in lieu of endogenous hyaluronan-chondrocyte interactions, resulting in the activation of inducible nitric oxide synthase.
软骨细胞的CD44受体将透明质酸锚定在细胞表面，使蛋白聚糖聚集体能够在细胞周围基质中组装并保留。透明质酸与CD44的相互作用对于维持软骨内环境稳定也具有重要的信号传导作用。软骨细胞与透明质酸接触的破坏会改变CD44的占有率，从而启动其他信号级联反应。用透明质酸寡糖进行处理是使CD44受体与其天然配体透明质酸解偶联的一种方法。在牛关节软骨细胞中，用透明质酸寡糖或纯化的透明质酸六糖处理可诱导一氧化氮的产生，这与白细胞介素-1处理后一氧化氮的产生情况相似。相比之下，120 kDa和1,260 kDa的透明质酸不会诱导一氧化氮的产生。人软骨细胞对透明质酸或透明质酸寡糖处理的反应相似。软骨细胞产生一氧化氮是由诱导型一氧化氮合酶的激活介导的，这通过mRNA表达以及二苯碘鎓对一氧化氮产生的抑制作用得到证实。用透明质酸寡糖和白细胞介素-1共同处理软骨细胞未显示出相加效应。用拮抗剂阻断白细胞介素-1受体并不能消除透明质酸寡糖处理诱导的一氧化氮产生。此外，只有在用pCD44转染后的COS-7细胞，而不是缺乏CD44的亲本细胞，在用透明质酸寡糖处理时会释放一氧化氮。本研究证明了透明质酸片段具有一种新的信号传导潜能，可替代内源性透明质酸与软骨细胞的相互作用，从而导致诱导型一氧化氮合酶的激活。
