TGFβ-induced degradation of TRAF3 in mesenchymal progenitor cells causes age-related osteoporosis
TGFβ-induced degradation of TRAF3 in mesenchymal progenitor cells causes age-related osteoporosis
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DOI：
10.1038/s41467-019-10677-0
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发表时间：
2019-06-26
影响因子：
16.6
通讯作者：
Boyce, Brendan F.
中科院分区：
文献类型：
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作者：
Li, Jinbo;Ayoub, Akram;Boyce, Brendan F.
炎症通过促进骨破坏和抑制骨形成诱导骨质疏松症。TRAF 3通过抑制破骨细胞前体中RANKL诱导的NF-κ B信号传导来限制骨破坏。然而，TRAF 3在间充质祖细胞（MPCs）中的作用尚不清楚。MPCs中TRAF 3缺失的小鼠由于骨形成减少和骨破坏增加而发生早发性骨质疏松症。在年轻小鼠中，TRAF 3阻止MPC中的β-连环蛋白降解并维持成骨细胞形成。然而，当TGF β 1从吸收骨中释放时，鼠和人骨样品中的TRAF 3蛋白水平在老化过程中降低。TGF β 1通过GSK-3 β介导的β-连环蛋白降解诱导鼠MPC中TRAF 3降解并抑制成骨细胞形成。因此，TRAF 3正调控MPC分化成成骨细胞。MPCs中的TRAF 3缺失激活NF-κ B RelA和RelB，促进RANKL表达并增强骨破坏。我们的结论是，在衰老过程中，TRAF 3的药理学稳定可以通过抑制骨破坏和促进骨形成来治疗/预防年龄相关性骨质疏松症。
Inflammaging induces osteoporosis by promoting bone destruction and inhibiting bone formation. TRAF3 limits bone destruction by inhibiting RANKL-induced NF-kappa B signaling in osteoclast precursors. However, the role of TRAF3 in mesenchymal progenitor cells (MPCs) is unknown. Mice with TRAF3 deleted in MPCs develop early onset osteoporosis due to reduced bone formation and enhanced bone destruction. In young mice TRAF3 prevents beta-catenin degradation in MPCs and maintains osteoblast formation. However, TRAF3 protein levels decrease in murine and human bone samples during aging when TGF beta 1 is released from resorbing bone. TGF beta 1 induces degradation of TRAF3 in murine MPCs and inhibits osteoblast formation through GSK-3 beta-mediated degradation of beta-catenin. Thus, TRAF3 positively regulates MPC differentiation into osteoblasts. TRAF3 deletion in MPCs activated NF-kappa B RelA and RelB to promote RANKL expression and enhance bone destruction. We conclude that pharmacologic stabilization of TRAF3 during aging could treat/prevent age-related osteoporosis by inhibiting bone destruction and promoting bone formation.