A dysfunctional TRPV4-GSK3β pathway prevents osteoarthritic chondrocytes from sensing changes in extracellular matrix viscoelasticity.
A dysfunctional TRPV4-GSK3β pathway prevents osteoarthritic chondrocytes from sensing changes in extracellular matrix viscoelasticity.
复制标题
DOI：
10.1038/s41551-021-00691-3
复制
发表时间：
2021-12
影响因子：
28.1
通讯作者：
Bhutani N
中科院分区：
文献类型：
--
作者：
Agarwal P;Lee HP;Smeriglio P;Grandi F;Goodman S;Chaudhuri O;Bhutani N
承重软骨细胞外基质的组成和粘弹性的变化影响软骨细胞的增殖和表型，并与骨关节炎有关。然而，潜在的分子机制是未知的。在这里，我们表明，藻酸盐水凝胶的粘弹性调节健康人软骨细胞的细胞体积（更快的应力松弛允许细胞扩张和更慢的应力松弛限制它），但在骨关节炎软骨细胞。健康软骨细胞中的细胞体积调节与合成代谢基因表达、多种促炎细胞因子分泌和离子通道蛋白TRPV 4（瞬时受体电位阳离子通道亚家族V成员4）调节的细胞内钙调节的变化相关，TRPV 4控制GSK 3 β（糖原合成酶激酶3 β）的磷酸化，GSK 3 β是一种在骨关节炎中具有多效性作用的酶。但是，骨关节炎软骨细胞中TRPV 4-GSK 3 β通路的功能障碍使细胞无法对粘弹性的环境变化做出反应。我们的研究结果为恢复骨关节炎中软骨细胞的稳态提供了策略。
Changes in the composition and viscoelasticity of the extracellular matrix in load-bearing cartilage influence the proliferation and phenotypes of chondrocytes, and are associated with osteoarthritis. However, the underlying molecular mechanism is unknown. Here, we show that the viscoelasticity of alginate hydrogels regulates cellular volume in healthy human chondrocytes (with faster stress relaxation allowing cell expansion and slower stress relaxation restricting it) but not in osteoarthritic chondrocytes. Cellular-volume regulation in healthy chondrocytes was associated with changes in anabolic gene expression, in the secretion of multiple pro-inflammatory cytokines, and in the modulation of intracellular calcium regulated by the ion-channel protein TRPV4 (transient receptor potential cation channel subfamily V member 4), which controls the phosphorylation of GSK3β (glycogen synthase kinase 3 beta), an enzyme with pleiotropic effects in osteoarthritis. But a dysfunctional TRPV4-GSK3β pathway in osteoarthritic chondrocytes rendered the cells unable to respond to environmental changes in viscoelasticity. Our findings suggest strategies for restoring chondrocyte homeostasis in osteoarthritis.
登录
查看更多内容
影响因子：
4.9
作者：
Cook AD;Pobjoy J;Steidl S;Dürr M;Braine EL;Turner AL;Lacey DC;Hamilton JA
通讯作者：
Hamilton JA
影响因子：
16.6
作者：
Chaudhuri O;Gu L;Darnell M;Klumpers D;Bencherif SA;Weaver JC;Huebsch N;Mooney DJ
通讯作者：
Mooney DJ
影响因子：
41.2
作者：
Chaudhuri O;Gu L;Klumpers D;Darnell M;Bencherif SA;Weaver JC;Huebsch N;Lee HP;Lippens E;Duda GN;Mooney DJ
通讯作者：
Mooney DJ
影响因子：
12.7
作者：
Chen D;Shen J;Zhao W;Wang T;Han L;Hamilton JL;Im HJ
通讯作者：
Im HJ
影响因子：
2.4
作者：
Alexopoulos, LG;Williams, GM;Guilak, F
通讯作者：
Guilak, F