Factor XIIIA mobilizes transglutaminase 2 to induce chondrocyte hypertrophic differentiation
Factor XIIIA mobilizes transglutaminase 2 to induce chondrocyte hypertrophic differentiation
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DOI：
10.1242/jcs.011262
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发表时间：
2008-07-01
影响因子：
4
通讯作者：
Terkeltaub, Robert A.
中科院分区：
文献类型：
--
作者：
Johnson, Kristen A.;Rose, David M.;Terkeltaub, Robert A.
两种转氨酶（TG），因子XIIIA（FXIIIA）和TG 2，在生长板肥大软骨细胞中经历生理性上调，在骨关节炎软骨中经历病理性上调。鸟嘌呤核苷酸结合的TG2的外化驱动软骨细胞成熟至肥大，这是一种与基质重塑和钙化相关的状态。在这里，我们测试了FXIIIA也促进肥大分化的假设。使用人关节软骨细胞，我们确定细胞外FXIIIA诱导软骨细胞肥大与TG 2快速移动到细胞表面。定点突变显示，FXIIIA Pro37毗邻凝血酶内切蛋白水解Arg38-Gly39位点，但不是固有的TG催化活性，是FXIIIA诱导软骨细胞肥大所必需的。已证明TG与某些整合素相互作用，并且在骨关节炎（OA）期间，α 1 β 1整合素上调并与肥大软骨细胞相关。FXIIIA参与软骨细胞中的α 1 β 1整联蛋白。α 1 β 1整联蛋白动员的TG 2的抗体交联。相反，α 1 β 1-整联蛋白特异性阻断抗体抑制FXIIIA诱导TG 2向细胞表面移动、p38 MAP激酶磷酸化和软骨细胞肥大的能力。我们的研究结果确定了一个独特的功能网络之间的两个软骨TG同工酶，加速软骨细胞成熟，而不需要TG催化转酰胺由TG。
Two transglutaminases (TGs), factor XIIIA (FXIIIA) and TG2, undergo physiologic upregulation in growth plate hypertrophic chondrocytes, and pathological upregulation in osteoarthritic cartilage. Externalization of guanine-nucleotide-bound TG2 drives chondrocyte maturation to hypertrophy, a state linked to matrix remodeling and calcification. Here, we tested the hypothesis that FXIIIA also promotes hypertrophic differentiation. Using human articular chondrocytes, we determined that extracellular FXIIIA induced chondrocyte hypertrophy associated with rapid movement of TG2 to the cell surface. Site-directed mutagenesis revealed that FXIIIA Pro37 bordering the thrombin endoproteolytic Arg38-Gly39 site, but not intrinsic TG catalytic activity, were necessary for FXIIIA to induce chondrocyte hypertrophy. TGs have been demonstrated to interact with certain integrins and, during osteoarthritis (OA), alpha 1 beta 1 integrin is upregulated and associated with hypertrophic chondrocytes. FXIIIA engaged alpha 1 beta 1 integrin in chondrocytes. Antibody crosslinking of alpha 1 beta 1 integrin mobilized TG2. Conversely, an alpha 1 beta 1-integrin-specific blocking antibody inhibited the capacity of FXIIIA to induce TG2 mobilization to the cell surface, phosphorylation of p38 MAP kinase, and chondrocyte hypertrophy. Our results identify a unique functional network between two cartilage TG isoenzymes that accelerates chondrocyte maturation without requirement for TG-catalyzed transamidation by either TG.