Environmental disruption of circadian rhythm predisposes mice to osteoarthritis-like changes in knee joint.
Environmental disruption of circadian rhythm predisposes mice to osteoarthritis-like changes in knee joint.
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DOI：
10.1002/jcp.24946
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发表时间：
2015-09
影响因子：
5.6
通讯作者：
Im, Hee-Jeong
中科院分区：
文献类型：
--
作者：
Kc, Ranjan;Li, Xin;Voigt, Robin M.;Ellman, Michael B.;Summa, Keith C.;Vitaterna, Martha Hotz;Keshavarizian, Ali;Turek, Fred W.;Meng, Qing-Jun;Stein, Gary S.;van Wijnen, Andre J.;Chen, Di;Forsyth, Christopher B.;Im, Hee-Jeong
昼夜节律功能障碍与许多疾病有关，但在关节软骨稳态和退行性关节疾病（包括骨关节炎（OA））中的病理生理作用仍有待于体内研究。在这里，我们测试是否环境或遗传破坏昼夜平衡易患OA样病理变化。在光：暗（LD）周期变化或昼夜节律遗传破坏后，检查雄性小鼠的昼夜运动活动。将野生型（WT）小鼠维持在恒定的12小时：12小时LD循环（12：12 LD）或暴露于每周12小时相移。或者，将雄性昼夜节律突变小鼠（ClockΔ19或Csnk 1 etau突变体）与维持恒定12：12 LD周期的年龄匹配WT同窝小鼠进行比较。在小鼠膝关节中，昼夜节律的破坏通过抑制蛋白多糖积累、上调基质降解酶和下调合成代谢介质来促进骨关节炎的变化。在机制上，这些作用涉及激活PKCδ-ERK-RUNX 2/NFκB和β-连环蛋白信号通路，刺激MMP-13和ADAMTS-5，以及抑制相移小鼠关节软骨细胞中的合成代谢介质SOX 9和TIMP-3。昼夜平衡的遗传破坏并不容易导致关节OA样病理变化。我们的研究结果，第一次，提供了令人信服的体内证据，昼夜节律的环境破坏是一个风险因素的发展OA样病变的小鼠膝关节。
Circadian rhythm dysfunction is linked to many diseases, yet pathophysiological roles in articular cartilage homeostasis and degenerative joint disease including osteoarthritis (OA) remains to be investigated in vivo. Here, we tested whether environmental or genetic disruption of circadian homeostasis predisposes to OA-like pathological changes. Male mice were examined for circadian locomotor activity upon changes in the light:dark (LD) cycle or genetic disruption of circadian rhythms. Wild-type (WT) mice were maintained on a constant 12 hour:12 hour LD cycle (12:12 LD) or exposed to weekly 12 hour phase shifts. Alternatively, male circadian mutant mice (ClockΔ19 or Csnk1etau mutants) were compared with age-matched WT littermates that were maintained on a constant 12:12 LD cycle. Disruption of circadian rhythms promoted osteoarthritic changes by suppressing proteoglycan accumulation, upregulating matrix-degrading enzymes and downregulating anabolic mediators in the mouse knee joint. Mechanistically, these effects involved activation of the PKCδ-ERK-RUNX2/NFκB and β-catenin signaling pathways, stimulation of MMP-13 and ADAMTS-5, as well as suppression of the anabolic mediators SOX9 and TIMP-3 in articular chondrocytes of phase-shifted mice. Genetic disruption of circadian homeostasis does not predispose to OA-like pathological changes in joints. Our results, for the first time, provide compelling in vivo evidence that environmental disruption of circadian rhythms is a risk factor for the development of OA-like pathological changes in the mouse knee joint.
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影响因子：
--
作者：
Gossan, Nicole;Zeef, Leo;Hensman, James;Hughes, Alun;Bateman, John F.;Rowley, Lynn;Little, Christopher B.;Piggins, Hugh D.;Rattray, Magnus;Boot-Handford, Raymond P.;Meng, Qing-Jun
通讯作者：
Meng, Qing-Jun
DOI：
10.1073/pnas.191369098
发表时间：
2001-09-25
影响因子：
11.1
作者：
Chen, L;Hahn, H;Mochly-Rosen, D
通讯作者：
Mochly-Rosen, D
影响因子：
10.3
作者：
Lopes, C;DeLyra, JL;Mariano, M
通讯作者：
Mariano, M
影响因子：
4
作者：
Ellman, M. B.;Yan, D.;Ahmadinia, K.;Chen, D.;An, H. S.;Im, H. J.
通讯作者：
Im, H. J.
影响因子：
--
作者：
Ellman, Michael B.;Kim, Jae-Sung;An, Howard S.;Kroin, Jeffrey S.;Li, Xin;Chen, Di;Yan, Dongyao;Buechter, Doug D.;Nakayama, Keiichi;Liu, Bo;Morgan, Stephanie;Im, Hee-Jeong
通讯作者：
Im, Hee-Jeong