Roles of inflammatory and anabolic cytokines in cartilage metabolism: signals and multiple effectors converge upon MMP-13 regulation in osteoarthritis.
Roles of inflammatory and anabolic cytokines in cartilage metabolism: signals and multiple effectors converge upon MMP-13 regulation in osteoarthritis.
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DOI：
10.22203/ecm.v021a16
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发表时间：
2011-02-24
影响因子：
3.1
通讯作者：
Marcu KB
中科院分区：
文献类型：
--
作者：
Goldring MB;Otero M;Plumb DA;Dragomir C;Favero M;El Hachem K;Hashimoto K;Roach HI;Olivotto E;Borzì RM;Marcu KB
人体软骨是一种由基质蛋白组成的复杂组织，从表层到深层，从负载区到卸载区，其数量和方向各不相同。通过干细胞和其他组织工程策略修复软骨的一个主要挑战是，现有的软骨细胞无法形成具有与原始形成时相同结构和弹性特性的新基质。胶原蛋白网络尤其如此，一旦蛋白聚糖耗尽，胶原蛋白网络很容易被切割。因此，深入了解发育、骨关节炎和衰老过程中软骨重塑机制的相似性，特别是显著差异，可能会带来更有效的预防软骨损伤和促进修复的策略。为了识别和表征这些过程中软骨重塑的效应因子或调节因子，我们正在使用人类和小鼠原代软骨细胞和细胞系的培养模型以及小鼠遗传模型来操纵导致基质重塑和随后的软骨细胞肥厚分化的基因表达程序，这两个关键过程都在OA疾病中误入歧途。基质金属蛋白酶(MMP)-13是主要的II型胶原降解酶，受应激、炎症和分化诱导的信号调节，这些信号不仅有助于骨性关节炎中不可逆的关节损伤（进展），而且重要的是，在起始/发病阶段，关节软骨中的软骨细胞离开其自然生长和分化停滞状态。我们的工作指出了在手术和遗传小鼠模型中人类OA软骨和OA早期到晚期的这些过程的共同介质。
Human cartilage is a complex tissue of matrix proteins that vary in amount and orientation from superficial to deep layers and from loaded to unloaded zones. A major challenge to efforts to repair cartilage by stem cell-based and other tissue engineering strategies is the inability of the resident chondrocytes to lay down new matrix with the same structural and resilient properties that it had upon its original formation. This is particularly true for the collagen network, which is susceptible to cleavage once proteoglycans are depleted. Thus, a thorough understanding of the similarities and particularly the marked differences in mechanisms of cartilage remodeling during development, osteoarthritis, and aging may lead to more effective strategies for preventing cartilage damage and promoting repair. To identify and characterize effectors or regulators of cartilage remodeling in these processes, we are using culture models of primary human and mouse chondrocytes and cell lines and mouse genetic models to manipulate gene expression programs leading to matrix remodeling and subsequent chondrocyte hypertrophic differentiation, pivotal processes which both go astray in OA disease. Matrix metalloproteinase (MMP)-13, the major type II collagen-degrading collagenase, is regulated by stress-, inflammation-, and differentiation-induced signals that not only contribute to irreversible joint damage (progression) in OA, but importantly, also to the initiation/onset phase, wherein chondrocytes in articular cartilage leave their natural growth- and differentiation-arrested state. Our work points to common mediators of these processes in human OA cartilage and in early through late stages of OA in surgical and genetic mouse models.