Early genetic restoration of lubricin expression in transgenic mice mitigates chondrocyte peroxynitrite release and caspase-3 activation.
Early genetic restoration of lubricin expression in transgenic mice mitigates chondrocyte peroxynitrite release and caspase-3 activation.
复制标题
转基因小鼠中润滑素表达的早期遗传恢复可减轻软骨细胞过氧亚硝酸盐的释放和 caspase-3 的激活。
DOI：
10.1016/j.joca.2017.05.012
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发表时间：
2017
影响因子：
7
通讯作者：
Jay,GD
中科院分区：
文献类型：
--
作者：
Larson,KM;Zhang,L;Badger,GJ;Jay,GD
目的探讨C57BL/ 6jprg4基因诱捕（GT）小鼠在C57BL/ 6jprg4基因诱捕酶（cree -recombinase）控制下，内源性润滑素分泌对产后短暂的润滑素缺失状态（<21 d）后关节健康恢复的作用。先前我们发现在21天重新表达的润滑素部分恢复关节润滑。设计对成年C57BL/6J小鼠的胫骨-股骨关节进行体内评价，分别观察含润滑素、缺乏润滑素和出生后缺乏润滑素直至7日龄或14日龄恢复润滑素表达的情况。在8周龄时，测量全关节摩擦系数（COF）和caspase-3激活，并对进行性循环加载后的胫骨-股骨关节进行组织学分析以确定退行性变化。测定小鼠股骨头软骨在循环加载前的过氧亚硝酸盐含量。结果在7日龄和14日龄进行基因重组的小鼠，随着关节循环时间的增加，并没有重建低COF，并且在组织病理学上与没有润滑素的窝鼠的关节没有区别。然而，在7日龄和14日龄进行重组的胫骨-股关节软骨与没有润滑油的窝鼠相比，caspase-3阳性细胞显著减少，过氧亚硝酸盐含量显著降低。结论在不完全恢复低COF的情况下，润滑素的生物学效应可能包括通过产生过氧亚硝酸盐和激活caspase-3来限制炎症。然而，完全重现低COF可能需要软骨表面未受损或没有生物污垢，这可能会干扰润滑素的活性。
ObjectiveThis study investigated the ability of endogenous lubricin secretion to restore joint health following a brief <21 day, postnatal lubricin-null state, in a C57BL/6JPrg4gene trap (GT) mouse under the control of cre-recombinase. Previously we showed that re-expression of lubricin at 21 days was partly restorative of joint lubrication.DesignThe tibio-femoral joints of adult C57BL/6J mice containing lubricin, lacking lubricin, and postnatally lacking lubricin until restoration of lubricin expression at 7 days or 14 days of age were evaluatedex vivo. At 8-weeks of age, whole joint coefficient of friction (COF), and caspase-3 activation were measured and the tibial-femoral joints histologically analyzed for degenerative changes, following progressive cyclic loading. The peroxynitrite content of femoral head cartilage from these mice prior to cyclic loading was measured.ResultsMice that underwent gene recombination at 7 and 14 days of age did not reestablish low COF as joint cycling time increased and were histopathologically indistinguishable from the joints of lubricin-null littermates. However, cartilage from tibio-femoral joints that underwent recombination at 7 and 14 days of age had significantly fewer caspase-3 positive cells and significantly reduced peroxynitrite content compared to lubricin-null littermates.ConclusionsThe biological effects of lubricin, which include limiting inflammation via peroxynitrite production and caspase-3 activation, may be achieved without completely restituting low COF. However, fully recapitulating low COF may require undamaged cartilage surfaces or absence of biofouling, which may interfere with the activity of lubricin.