Fan Z, Chubinskaya S, Rueger D C, Bau B, Haag J, Aigner T
Department of Pathology, University of Erlangen-Nürnberg, Krankenhausstr. 8-10, D-91054 Erlangen, Germany.
Clin Exp Rheumatol. 2004 Jan-Feb;22(1):103-6.
Osteoarthritis is characterized by dramatic changes in chondrocyte metabolism including the overexpression of catabolic enzymes, but also a lack of anabolic activity. In this respect, osteogenic protein 1 (OP-1) appears to be one of the most potent anabolic factors of chondrocytes. In this study, we were interested in: (1) whether recombinant human OP-1 exerts its anabolic effects also on osteoarthritic chondrocytes, (2) whether OP-1 modulates the expression of catabolic genes, and (3) whether the BMP effects are related to the expression levels of its intracellular mediators (R- and I-Smads).
Chondrocytes were isolated from cartilage of either normal (n = 5) or osteoarthritic (n = 8) human knee joints and cultured in short-term high-density monolayer cultures with and without recombinant OP-1. RNA was isolated and analyzed for mRNA expression levels of anabolic (aggrecan, collagen type II), catabolic (MMP-1, -3, -13, ADAMTS-4), and intracellular signaling mediators (Smad 1, 4, 5, 6, 7, and 8) by quantitative online PCR.
After OP-1 stimulation, the anabolic genes were significantly up-regulated in osteoarthritic chondrocytes in comparison to normal chondrocytes. Neither in normal nor osteoarthritic chondrocytes were significant changes observed for the matrix degrading enzymes. Smads were also expressed in both normal and osteoarthritic cells at roughly the same level with and without stimulation with OP-1.
Osteoarthritic chondrocytes are not hypo-responsive to anabolic stimulation by OP-1. Thus, human recombinant OP-1 could be a suitable anabolic activator of osteoarthritic chondrocytes. This might be of particular interest as chondrocytes themselves showed very low levels of OP-1 expression.
骨关节炎的特征是软骨细胞代谢发生显著变化，包括分解代谢酶的过度表达，同时合成代谢活性也不足。在这方面，骨形成蛋白1（OP-1）似乎是软骨细胞最有效的合成代谢因子之一。在本研究中，我们关注以下几点：（1）重组人OP-1是否也对骨关节炎软骨细胞发挥其合成代谢作用；（2）OP-1是否调节分解代谢基因的表达；（3）骨形态发生蛋白（BMP）的作用是否与其细胞内介质（R-和I-Smads）的表达水平相关。
从正常（n = 5）或骨关节炎（n = 8）人类膝关节软骨中分离软骨细胞，并在有或无重组OP-1的情况下进行短期高密度单层培养。提取RNA，通过定量在线PCR分析合成代谢（聚集蛋白聚糖、II型胶原）、分解代谢（基质金属蛋白酶-1、-3、-13、含血小板反应蛋白基序的解聚蛋白样金属蛋白酶-4）和细胞内信号介质（Smad 1、4、5、6、7和8）的mRNA表达水平。
与正常软骨细胞相比，OP-1刺激后，骨关节炎软骨细胞中的合成代谢基因显著上调。在正常和骨关节炎软骨细胞中，均未观察到基质降解酶有显著变化。无论有无OP-1刺激，Smads在正常和骨关节炎细胞中的表达水平大致相同。
骨关节炎软骨细胞对OP-1的合成代谢刺激并非反应低下。因此，重组人OP-1可能是骨关节炎软骨细胞合适的合成代谢激活剂。鉴于软骨细胞自身OP-1表达水平非常低，这一点可能尤为重要。
