Chagin Andrei S, Vuppalapati Karuna K, Kobayashi Tatsuya, Guo Jun, Hirai Takao, Chen Min, Offermanns Stefan, Weinstein Lee S, Kronenberg Henry M
1] Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm 17177, Sweden [2] Endocrine Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114-2696, USA.
Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm 17177, Sweden.
Nat Commun. 2014 Apr 30;5:3673. doi: 10.1038/ncomms4673.
Round chondrocytes in the resting zone of the growth plate provide precursors for columnar chondrocytes and have stem-like properties. Here we demonstrate that these stem-like chondrocytes undergo apoptosis in the absence of the receptor (PPR) for parathyroid hormone-related protein. We examine the possible roles of heterotrimeric G-proteins activated by the PPR. Inactivation of the G-protein stimulatory α-subunit (G(s)α) leads to accelerated differentiation of columnar chondrocytes, as seen in the PPR knockout, but a remnant of growth cartilage remains, in contrast to disappearance of the growth cartilage in the PPR knockout. Stem-like chondrocytes lose their quiescence and proliferate upon G(s)α ablation. Inactivation of G(s)α in mice with a mutant PPR that cannot activate G proteins, Gq and G11, leads to a PPR knockout-like phenotype. Thus, G(s)α is the major mediator of the anti-differentiation action of the PPR, while activation of both G(s)α and Gq/11α is required for quiescence of stem-like chondrocytes.
生长板静止区的圆形软骨细胞为柱状软骨细胞提供前体细胞，并具有干细胞样特性。在此我们证明，在缺乏甲状旁腺激素相关蛋白受体（PPR）的情况下，这些干细胞样软骨细胞会发生凋亡。我们研究了由PPR激活的异源三聚体G蛋白的可能作用。G蛋白刺激性α亚基（G(s)α）的失活导致柱状软骨细胞加速分化，这与PPR基因敲除小鼠的情况相似，但与PPR基因敲除小鼠中生长软骨消失不同的是，仍有残余的生长软骨存在。干细胞样软骨细胞在G(s)α缺失后失去静止状态并开始增殖。在具有无法激活G蛋白Gq和G11的突变型PPR的小鼠中，G(s)α的失活会导致类似PPR基因敲除的表型。因此，G(s)α是PPR抗分化作用的主要介质，而干细胞样软骨细胞的静止需要G(s)α和Gq/11α两者的激活。
