Prostaglandin (PG)D(2) and 15-deoxy-Delta(12,14)-PGJ(2), but not PGE(2), mediate shear-induced chondrocyte apoptosis via protein kinase A-dependent regulation of polo-like kinases.
Prostaglandin (PG)D(2) and 15-deoxy-Delta(12,14)-PGJ(2), but not PGE(2), mediate shear-induced chondrocyte apoptosis via protein kinase A-dependent regulation of polo-like kinases.
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DOI：
10.1038/cdd.2010.13
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发表时间：
2010-08
影响因子：
12.4
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中科院分区：
文献类型：
--
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软骨承受过度的机械负荷产生静水压力、拉伸应变和流体流动，这会导致软骨细胞凋亡和骨关节炎。高流体流动会诱导受剪切的软骨细胞中环氧合酶 - 2（COX - 2）的表达，这会抑制它们的抗氧化能力并促使细胞凋亡。COX - 2在剪切诱导的软骨细胞凋亡中的关键作用以及关于前列腺素（PG）E2、PGD2及其代谢产物15 - 脱氧 - Δ12,14 - PGJ2（15d - PGJ2）在软骨细胞凋亡中作用的相互矛盾的文献数据促使我们去研究在此过程中涉及哪种COX - 2衍生的PG。我们表明，在静态条件下，外源性添加的PGD2和15d - PGJ2（而非PGE2）会降低人T/C - 28a2软骨细胞的活力。与这些观察结果一致，L - PGD合酶（L - PGDS）的敲低可消除剪切诱导的软骨细胞凋亡。通过将cDNA微阵列与聚类算法相结合，我们提出了一种新的信号通路，即高流体剪切介导COX - 2/L - PGDS依赖的软骨细胞凋亡，并且通过分子干预得到了验证。我们证明L - PGDS控制蛋白激酶A（PKA）的下调，而PKA反过来调节Polo样激酶1（Plk1）和Plk3。Plks作用于p53，p53控制参与软骨细胞凋亡的p53效应物（TP53INPs、FAS和Bax）的转录。重建调节软骨细胞凋亡的信号网络可能为优化生物反应器中人工软骨培养条件以及开发关节炎疾病的治疗策略提供见解。
Excessive mechanical loading of cartilage producing hydrostatic stress, tensile strain and fluid flow leads to chondrocyte apoptosis and osteoarthritis. High fluid flow induces cyclooxygenase-2 (COX-2) expression in sheared chondrocytes, which suppresses their antioxidant capacity and contributes to apoptosis. The pivotal role of COX-2 in shear-induced chondrocyte apoptosis and the conflicting literature data on the roles of prostaglandin (PG)E2, PGD2 and its metabolite 15-deoxy-Δ12,14-PGJ2 (15d-PGJ2) in chondrocyte apoptosis prompted us to investigate which COX-2-derived PG is involved in this process. We show that exogenously added PGD2 and 15d-PGJ2, but not PGE2, diminish the viability of human T/C-28a2 chondrocytes under static conditions. In agreement with these observations, knockdown of L-PGD synthase (L-PGDS) abolishes shear-induced chondrocyte apoptosis. Using cDNA microarrays in conjunction with clustering algorithms, we propose a novel signaling pathway by which high fluid shear mediates COX-2/L-PGDS-dependent chondrocyte apoptosis, which is validated by molecular interventions. We demonstrate that L-PGDS controls the downregulation of Protein Kinase A (PKA), which in turn regulates Polo-like kinase1 (Plk1) and Plk3. Plks target p53, which controls the transcription of p53 effectors (TP53INPs, FAS and Bax) involved in chondrocyte apoptosis. Reconstructing the signaling network regulating chondrocyte apoptosis may provide insights to optimize conditions for culturing artificial cartilage in bioreactors and for developing therapeutic strategies for arthritic disorders.
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