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)参与细胞迁移和组织重塑,这是骨吸收过程的两个组成部分。我们使用具有灭活的组织PA(tPA),尿激酶PA(uPA)或1型PA抑制剂(PAI-1)基因的小鼠,评估了这些过程,还是甲状旁腺激素(PTH)或1,25-二羟基维生素( 1,25 [OH] 2D3)依赖于这些基因。使用了两种培养模型,一种涉及19天胎儿颅盖骨,以评估骨吸收的直接吸收活性,另一种涉及45Ca标记的17天胎儿meta骨,其中该活性取决于破骨细胞的前期迁移。在野生型tPA /和uPA /或缺乏的uPA-/-和PAI-/-小鼠的颅脑中,PTH相似地增加了PA活性(约10倍);它仅影响tPA,而不影响uPA。在tPA-/-骨骼中,由于uPA而导致的低PA水平不受PTH的影响。降钙素不影响PA对PTH的反应。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),tPA /,tPA-/-,uPA /和uPA-/-颅盖骨之间未观察到差异,表明对PTH或降钙素的反应相似。在tPA /,tPA-/-,uPA /,uPA-/-,PAI /或PAI-/-tar骨的培养物中45Ca的逐步释放在很大程度上相似,并且通过PTH或1,25(OH)2D3得以类似地增强。但是,uPA-/-meta骨在培养开始时以较慢的速率释放45Ca,这表明破骨细胞的吸收减弱,破骨细胞在那时从骨膜迁移到钙化的软骨中。因此,似乎破骨细胞的直接吸收活性并不需要存在tPA或uPA,但是uPA可能促进破骨细胞向矿化表面的迁移。尽管PTH大大增强了它的作用,但tPA并未介导在这些模型中评估的PTH的作用(也不超过1,25 [OH] 2D3)。