p38α MAPK regulates proliferation and differentiation of osteoclast progenitors and bone remodeling in an aging-dependent manner.
p38α MAPK regulates proliferation and differentiation of osteoclast progenitors and bone remodeling in an aging-dependent manner.
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DOI：
10.1038/srep45964
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发表时间：
2017-04-06
影响因子：
4.6
通讯作者：
Liu H
中科院分区：
文献类型：
--
作者：
Cong Q;Jia H;Li P;Qiu S;Yeh J;Wang Y;Zhang ZL;Ao J;Li B;Liu H
骨质量由间充质干细胞衍生的成骨细胞进行的骨形成和单核细胞衍生的破骨细胞进行的骨吸收之间的平衡决定。在此，我们通过在LysM+单核细胞中消除p38α MAPK来研究p38 MAPK在破骨细胞生成和骨吸收中的潜在作用，p38 MAPK可被生长因子和细胞因子（包括RANKL和BMP）激活。p38α缺陷促进单核细胞增殖，但以细胞密度依赖性方式调节单核细胞成骨细胞分化，增殖的p38α−/−培养物显示分化增加。虽然年轻的突变小鼠显示出骨量略有增加，但6个月大的突变小鼠出现骨质疏松症，与破骨细胞生成和骨吸收增加以及单核细胞池增加有关。此外，单核细胞特异性p38α消融导致骨形成和骨髓间充质干细胞/基质细胞数量减少，可能是由于PDGF-AA和BMP 2表达减少。破骨细胞中PDGF-AA和BMP 2的表达受p38 MAPK-Creb轴的正调控，PDGF-AA和BMP 2的启动子具有Creb结合位点。这些发现揭示了p38α MAPK调控破骨细胞生成以及协调破骨细胞和成骨细胞生成的分子机制。
Bone mass is determined by the balance between bone formation, carried out by mesenchymal stem cell-derived osteoblasts, and bone resorption, carried out by monocyte-derived osteoclasts. Here we investigated the potential roles of p38 MAPKs, which are activated by growth factors and cytokines including RANKL and BMPs, in osteoclastogenesis and bone resorption by ablating p38α MAPK in LysM+monocytes. p38α deficiency promoted monocyte proliferation but regulated monocyte osteoclastic differentiation in a cell-density dependent manner, with proliferating p38α−/− cultures showing increased differentiation. While young mutant mice showed minor increase in bone mass, 6-month-old mutant mice developed osteoporosis, associated with an increase in osteoclastogenesis and bone resorption and an increase in the pool of monocytes. Moreover, monocyte-specific p38α ablation resulted in a decrease in bone formation and the number of bone marrow mesenchymal stem/stromal cells, likely due to decreased expression of PDGF-AA and BMP2. The expression of PDGF-AA and BMP2 was positively regulated by the p38 MAPK-Creb axis in osteoclasts, with the promoters of PDGF-AA and BMP2 having Creb binding sites. These findings uncovered the molecular mechanisms by which p38α MAPK regulates osteoclastogenesis and coordinates osteoclastogenesis and osteoblastogenesis.