Deficiency of ATP6V1H Causes Bone Loss by Inhibiting Bone Resorption and Bone Formation through the TGF-β1 Pathway.
Deficiency of ATP6V1H Causes Bone Loss by Inhibiting Bone Resorption and Bone Formation through the TGF-β1 Pathway.
复制标题
ATP6V1H 缺乏会通过 TGF-β 1 途径抑制骨吸收和骨形成，从而导致骨丢失
作者：
Duan X;Liu J;Zheng X;Wang Z;Zhang Y;Hao Y;Yang T;Deng H
胞浆型H +-ATP酶（V-ATP酶）是一种高度保守的古老酶，它将ATP水解的能量耦合到真核细胞的跨囊泡和质膜的质子运输中。先前报道的各种V-ATP酶亚基的突变与骨密度增加相关。我们现在表明，单倍不足的H亚基的V1域（ATP 6V1H）与骨质疏松症在人类和小鼠。对1625名汉族人的全基因组SNP阵列分析发现，ATP6V1H内的15个标签SNP中有4个（26.7%）与低脊柱骨密度显著相关。通过CRISPR/Cas9技术产生的Atp6v1h +/-敲除小鼠具有减少的骨重建和净骨基质损失。atp6v1h +/-破骨细胞显示骨形成受损和骨吸收增加。Atp6v1h +/-破骨细胞内pH升高下调TGF-β 1的活化，从而减少成骨细胞形成的诱导，但骨矿化没有改变。然而，骨形成的减少多于骨吸收。我们的数据提供了证据表明，ATP 6 V1 H功能的部分丧失导致骨质疏松症/骨量减少。我们认为破骨细胞形成缺陷通过改变骨重建触发骨形成受损。因此，ATP6V1H有可能成为骨质疏松症治疗的新靶点。
Vacuolar-type H +-ATPase (V-ATPase) is a highly conserved, ancient enzyme that couples the energy of ATP hydrolysis to proton transport across vesicular and plasma membranes of eukaryotic cells. Previously reported mutations of various V-ATPase subunits are associated with increased bone density. We now show that haploinsufficiency for the H subunit of the V1 domain (ATP6V1H) is associated with osteoporosis in humans and mice. A genome-wide SNP array analysis of 1625 Han Chinese found that 4 of 15 tag SNPs (26.7%) within ATP6V1H were significantly associated with low spine bone mineral density. Atp6v1h+/- knockout mice generated by the CRISPR/Cas9 technique had decreased bone remodeling and a net bone matrix loss. Atp6v1h+/- osteoclasts showed impaired bone formation and increased bone resorption. The increased intracellular pH of Atp6v1h+/- osteoclasts downregulated TGF-β1 activation, thereby reducing induction of osteoblast formation but the bone mineralization was not altered. However, bone formation was reduced more than bone resorption. Our data provide evidence that partial loss of ATP6V1H function results in osteoporosis/osteopenia. We propose that defective osteoclast formation triggers impaired bone formation by altering bone remodeling. In the future, ATP6V1H might, therefore, serve as a target for the therapy of osteoporosis.
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影响因子：
12.4
作者：
Rahmi G;Pidial L;Silva AK;Blondiaux E;Meresse B;Gazeau F;Autret G;Balvay D;Cuenod CA;Perretta S;Tavitian B;Wilhelm C;Cellier C;Clément O
通讯作者：
Clément O
影响因子：
30.8
作者：
Frattini, A;Orchard, PJ;Villa, A
通讯作者：
Villa, A
影响因子：
4.8
作者：
Karsdal, MA;Hjorth, P;Foged, NT
通讯作者：
Foged, NT
影响因子：
4.8
作者：
Huss, M;Ingenhorst, G;Wieczorek, H
通讯作者：
Wieczorek, H
DOI：
10.1016/j.bbrc.2010.10.117
发表时间：
2010-12-03
影响因子：
3.1
作者：
Kim T;Ha H;Kim N;Park ES;Rho J;Kim EC;Lorenzo J;Choi Y;Lee SH
通讯作者：
Lee SH