BACKGROUND & AIMS:
Plasminogen activators (PA) are implicated in cell migration and tissue remodeling, two components of the bone resorption processes. Using mice with inactivated tissue PA (tPA), urokinase PA (uPA), or type 1 PA inhibitor (PAI-1) genes, we evaluated whether these processes, or their stimulation by parathyroid hormone (PTH) or 1,25-dihydroxyvitamin (1,25[OH]2D3) are dependent on these genes. Two culture models were used, one involving 19-day fetal calvariae, to evaluate the direct resorptive activity of osteoclasis, and the other involving 45Ca-labeled 17-day fetal metatarsals, in which this activity depends on preliminary (pre)osteoclast migration. PTH similarly increased (about 10-fold) PA activity in calvariae from wild-type tPA+/+ and uPA+/+ or deficient uPA-/- and PAI-/- mice; it affected only tPA, not uPA. In tPA-/- bones, the low PA levels, due to uPA, were not influenced by PTH. Calcitonin did not affect PA responses to PTH. No differences were observed between tPA+/+, tPA-/-, uPA+/+, and uPA-/- calvariae for any parameter related to bone resorption (development of lacunae, release of calcium and lysosomal enzymes, accumulation of collagenase, loss of hydroxyproline), indicating similar responses to PTH or calcitonin. The progressive 45Ca release was largely similar in cultures of tPA+/+, tPA-/-, uPA+/+, uPA-/-, PAI+/+, or PAI-/- metatarsals and it was similarly enhanced by PTH or 1,25(OH)2D3. However, uPA-/- metatarsals released 45Ca at a slower rate at the beginning of the cultures, suggesting an impaired recruitment of the (pre)osteoclasts, which migrate at that time from the periosteum into the calcified cartilage. Thus, it appears that the direct resorptive activity of the osteoclasts does not necessitate the presence of either tPA or uPA, but uPA is likely to facilitate the migration of the (pre)osteoclasts toward the mineralized surfaces. Although considerably enhanced by PTH, tPA does not mediate the actions of PTH (nor of 1,25[OH]2D3) evaluated in these models.
背景与目标:
纤溶酶原激活剂 (PA) 与细胞迁移和组织重塑有关,这是骨吸收过程的两个组成部分。使用具有灭活组织PA (tPA),尿激酶PA (uPA) 或1型PA抑制剂 (PAI-1) 基因的小鼠,我们评估了这些过程或甲状旁腺激素 (PTH) 或1,25-二羟基维生素 (1,25[OH]2D3) 的刺激是否依赖于这些基因。使用了两种培养模型,一种涉及19天胎儿颅骨,以评估破骨细胞的直接吸收活性,另一种涉及45ca标记的17天胎儿跖骨,其中该活性取决于破骨细胞的初步 (前) 迁移。PTH类似地增加 (约10倍) 野生型tPA +/+ 和uPA +/+ 或缺陷型uPA-/-和PAI-/-小鼠颅骨中的PA活性; 它仅影响tPA,不是uPA。在tPA-/-骨骼中,由于uPA引起的低PA水平不受PTH的影响。降钙素不影响PA对PTH的反应。tPA/,tPA-/-,uPA/,uPA-/- calvariae对于与骨吸收有关的任何参数 (腔隙的发展,钙和溶酶体酶的释放,胶原酶的积累,羟脯氨酸的损失),表明对PTH或降钙素的反应相似。tPA-/-、uPA +/+ 、uPA-/-、PAI +/+ 或PAI-/-跖骨,PTH或1,25(OH)2D3也同样增强。然而,uPA-/-跖骨在培养开始时以较慢的速度释放45Ca,这表明破骨细胞的募集受损,破骨细胞当时从骨膜迁移到钙化软骨中。因此,似乎破骨细胞的直接吸收活性并不需要tPA或uPA的存在,但是uPA可能会促进 (前) 破骨细胞向矿化表面的迁移。尽管PTH显着增强,tPA不会介导PTH的作用 (也不是1,在这些模型中评估了25[OH]2D3)。