Chondroprotection by urocortin involves blockade of the mechanosensitive ion channel Piezo1.
Chondroprotection by urocortin involves blockade of the mechanosensitive ion channel Piezo1.
复制标题
尿路素的软骨保护涉及机械敏感离子通道压电的阻塞。
DOI：
10.1038/s41598-017-04367-4
复制
发表时间：
2017-07-11
影响因子：
4.6
通讯作者：
Townsend PA
中科院分区：
文献类型：
--
作者：
Lawrence KM;Jones RC;Jackson TR;Baylie RL;Abbott B;Bruhn-Olszewska B;Board TN;Locke IC;Richardson SM;Townsend PA
骨关节炎（OA）的特征在于关节软骨的进行性破坏和软骨细胞死亡。在这里，我们显示了内源性肽尿皮质素1（UCN 1）和两种受体亚型，CRF-R1和CRF-R2，在原代人关节软骨细胞（AC）的表达，并证明其作为自分泌/旁分泌促生存因子的作用。这种作用只能使用CRF-R1选择性拮抗剂CP-154526去除，表明Ucn 1在促进软骨细胞存活时通过CRF-R1起作用。这种细胞死亡的特征在于p53表达的增加以及半胱天冬酶9和3的裂解。CRF-R1与CP-154526的拮抗作用导致细胞内钙（Ca 2+）随时间推移蓄积和细胞死亡。这些影响可以用非选择性阳离子通道阻断剂钆（Gd 3+）来防止。因此，非选择性阳离子通道的开放导致细胞死亡，Ucn 1将该通道保持在闭合构象。该通道被鉴定为机械敏感通道Piezo 1。我们继续确定Ucn 1的这种通道抑制最初是由环磷酸腺苷（cAMP）的增加和随后的磷脂酶A2（PLA 2）失活介导的，已知其代谢物可以调节离子通道。这些新途径的知识可能为干预措施提供机会，这些干预措施可能会阻止OA的进展。
Osteoarthritis (OA) is characterised by progressive destruction of articular cartilage and chondrocyte cell death. Here, we show the expression of the endogenous peptide urocortin1 (Ucn1) and two receptor subtypes, CRF-R1 and CRF-R2, in primary human articular chondrocytes (AC) and demonstrate its role as an autocrine/paracrine pro-survival factor. This effect could only be removed using the CRF-R1 selective antagonist CP-154526, suggesting Ucn1 acts through CRF-R1 when promoting chondrocyte survival. This cell death was characterised by an increase in p53 expression, and cleavage of caspase 9 and 3. Antagonism of CRF-R1 with CP-154526 caused an accumulation of intracellular calcium (Ca2+) over time and cell death. These effects could be prevented with the non-selective cation channel blocker Gadolinium (Gd3+). Therefore, opening of a non-selective cation channel causes cell death and Ucn1 maintains this channel in a closed conformation. This channel was identified to be the mechanosensitive channel Piezo1. We go on to determine that this channel inhibition by Ucn1 is mediated initially by an increase in cyclic adenosine monophosphate (cAMP) and a subsequent inactivation of phospholipase A2 (PLA2), whose metabolites are known to modulate ion channels. Knowledge of these novel pathways may present opportunities for interventions that could abrogate the progression of OA.
登录
查看更多内容
DOI：
10.1084/jem.182.6.2097
发表时间：
1995-12-01
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Amin AR;Di Cesare PE;Vyas P;Attur M;Tzeng E;Billiar TR;Stuchin SA;Abramson SB
通讯作者：
Abramson SB
影响因子：
1.1
作者：
Chowdhury, T. T.;Akanji, O. O.;Lee, D. A.
通讯作者：
Lee, D. A.
影响因子：
10.8
作者：
Huang, Y;Chan, FL;Yao, XQ
通讯作者：
Yao, XQ
影响因子：
2.7
作者：
Finger, F;Schörle, C;Aigner, T
通讯作者：
Aigner, T
DOI：
10.1006/bbrc.1999.1446
发表时间：
1999-11-11
影响因子：
3.1
作者：
Asker, C;Wiman, KG;Selivanova, G
通讯作者：
Selivanova, G