Increased bone formation in mice lacking plasminogen activators
Increased bone formation in mice lacking plasminogen activators
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DOI：
10.1359/jbmr.2003.18.7.1167
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发表时间：
2003-07-01
影响因子：
6.2
通讯作者：
Carmeliet, G
中科院分区：
文献类型：
--
作者：
Daci, E;Everts, V;Carmeliet, G
纤溶酶原激活剂tPA和uPA参与组织重塑，但它们在骨生长中的作用尚未确定。缺乏tPA和uPA的小鼠显示骨形成和骨量增加。骨基质的非胶原成分也增加，可能是由于降解不良。这项研究强调了正常endochondrialossification.Introduction：蛋白水解途径的控制骨基质重塑的重要性，建议endochondrialossification发挥作用。为了阐明纤溶酶原激活剂tPA和uPA在这一过程中的参与，我们的特点是在tPA和uPA（tPA（-/-）：uPA（-/-））。材料和方法：2至7天大的tPA（-/-）：uPA（-/-）和野生型（WT）小鼠的骨骼缺乏的长骨表型进行了研究，骨组织形态计量学，电子显微镜分析，骨基质成分的生化评估。细胞介导的代谢标记的骨基质，成骨细胞增殖，成骨细胞分化，无论是在基因和蛋白质水平上，在体外使用来自两个genotype.Results的细胞进行了研究：纤溶酶原激活剂的缺乏导致延长的骨骼和骨量增加（25%以上的骨小梁在胫骨近端干骺端），而不改变生长板的形态。此外，纤溶酶原激活物缺陷小鼠的骨基质组成发生改变，因为检测到蛋白聚糖（2X）、骨钙素（+45%）和纤连蛋白（+36%）的量增加。基质降解试验表明，纤溶酶原激活剂，通过产生纤溶酶，参与成骨细胞介导的骨基质的非胶原成分的降解。此外，来自纤溶酶原激活物缺陷小鼠的原代成骨细胞的增殖增加了35%。最后，在来自tPA（-/-）：uPA（-/-）小鼠的成骨细胞培养物中，成骨细胞分化和矿化骨基质的形成得到增强。所提供的数据表明纤溶酶原系统在骨基质的非胶原成分的降解中的重要性，并表明这些蛋白质在骨基质中的积累-如在纤溶酶原激活剂缺乏期间发生的-可能反过来刺激成骨细胞功能，导致骨形成增加。
Plasminogen activators tPA and uPA are involved in tissue remodeling, but their role in bone growth is undefined. Mice lacking tPA and uPA show increased bone formation and bone mass. The noncollagenous components of bone matrix are also increased, probably from defective degradation. This study underlines the importance of controlled bone matrix remodeling for normal endochondral ossification.Introduction: Proteolytic pathways are suggested to play a role in endochondral ossification. To elucidate the involvement of the plasminogen activators tPA and uPA in this process, we characterized the long bone phenotype in mice deficient in both tPA and uPA (tPA(-/-):uPA(-/-)).Materials and Methods: Bones of 2- to 7-day-old tPA(-/-):uPA(-/-) and wild-type (WT) mice were studied using bone histomorphometry, electron microscopy analysis, and biochemical assessment of bone matrix components. Cell-mediated degradation of metabolically labeled bone matrix, osteoblast proliferation, and osteoblast differentiation, both at the gene and protein level, were studied in vitro using cells derived from both genotypes.Results: Deficiency of the plasminogen activators led to elongation of the bones and to increased bone mass (25% more trabecular bone in the proximal tibial metaphysis), without altering the morphology of the growth plate. In addition, the composition of bone matrix was modified in plasminogen activator deficient mice, because an increased amount of proteoglycans (2X), osteocalcin (+45%), and fibronectin (+36%) was detected. Matrix degradation assays showed that plasminogen activators, by generating plasmin, participate in osteoblast-mediated degradation of the noncollagenous components of bone matrix. In addition, proliferation of primary osteoblasts derived from plasminogen activator-deficient mice was increased by 35%. Finally, osteoblast differentiation and formation of a mineralized bone matrix were enhanced in osteoblast cultures derived from tPA(-/-):uPA(-/-) mice.Conclusions: The data presented indicate the importance of the plasminogen system in degradation of the noncollagenous components of bone matrix and suggest that the accumulation of these proteins in bone matrix-as occurs during plasminogen activator deficiency-may in turn stimulate osteoblast function, resulting in increased bone formation.