PGC-1α Controls Skeletal Stem Cell Fate and Bone-Fat Balance in Osteoporosis and Skeletal Aging by Inducing TAZ.
PGC-1α Controls Skeletal Stem Cell Fate and Bone-Fat Balance in Osteoporosis and Skeletal Aging by Inducing TAZ.
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DOI：
10.1016/j.stem.2018.06.009
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发表时间：
2018-08-02
期刊：
影响因子：
23.9
通讯作者：
Wang CY
中科院分区：
文献类型：
--
作者：
Yu B;Huo L;Liu Y;Deng P;Szymanski J;Li J;Luo X;Hong C;Lin J;Wang CY
骨干细胞（ssc）的异常谱系规范有助于骨质疏松症和骨骼老化中骨量减少和骨髓脂肪组织（MAT）增加。虽然已经确定了成骨细胞和脂肪形成谱系的主要调节因子，但对与MAT积累和骨质疏松性骨质流失相关的因素知之甚少。在这里，我们发现过氧化物酶体增殖因子激活受体𝛄共激活因子1-α (PGC-1α)是细胞命运决定的关键开关，其表达随着人类和小鼠ssc的衰老而降低。PGC-1α的缺失促进了小鼠ssc的成脂分化，以牺牲成骨细胞分化为代价。SSCs中PGC-1α的缺失会破坏骨形成，间接促进骨吸收，同时增加MAT的积累。相反，PGC-1α的诱导可减轻骨质疏松症的骨质流失和MAT的积累。机制上，PGC-1α通过诱导TAZ维持骨和脂肪平衡。我们的研究结果表明，PGC-1α是治疗骨质疏松症和骨骼衰老的潜在重要治疗靶点。Yu等人的研究表明，代谢调节因子PGC-1α调节骨质疏松症的骨脂平衡。SSCs中PGC-1α的缺失会破坏骨形成并促进MAT的积累。机制上，PGC-1α通过诱导TAZ表达直接控制SSC命运的决定。诱导PGC-1α可减轻骨质疏松症的骨质流失和MAT积累。
Aberrant lineage specification of skeletal stem cells (SSCs) contributes to reduced bone mass and increased marrow adipose tissue (MAT) in osteoporosis and skeletal aging. Although master regulators of osteoblastic and adipogenic lineages have been identified, little is known about factors that are associated with MAT accumulation and osteoporotic bone loss. Here, we identify peroxisome-proliferator-activated receptor 𝛄 coactivator 1-α (PGC-1α) as a critical switch of cell fate decisions whose expression decreases with aging in human and mouse SSCs. Loss of PGC-1α promoted adipogenic differentiation of murine SSCs at the expense of osteoblastic differentiation. Deletion of PGC-1α in SSCs impaired bone formation and indirectly promoted bone resorption while enhancing MAT accumulation. Conversely, induction of PGC-1α attenuated osteoporotic bone loss and MAT accumulation. Mechanistically, PGC-1α maintains bone and fat balance by inducing TAZ. Our results suggest that PGC-1α is a potentially important therapeutic target in the treatment of osteoporosis and skeletal aging. Yu et al. show that the metabolic regulator PGC-1α regulates bone-fat balance in osteoporosis. Loss of PGC-1α in SSCs impaired bone formation and promoted MAT accumulation. Mechanistically, PGC-1α directly controlled SSC fate decision by inducing TAZ expression. Induction of PGC-1α could attenuate bone loss and MAT accumulation in osteoporosis.
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