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The Molecular and Epigenetic Regulation of Osteoblast and Osteoclast Differentiation and the Implications in Osteoporosis.

机译：成骨细胞和破骨细胞分化的分子和表观遗传调控及其在骨质疏松症中的意义。

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摘要

The human skeleton undergoes continuous bone remodeling, a process relying on orchestrated balance between the actions of osteoblasts and osteoclasts. Complex molecular signaling networks govern the differentiation and functions of mesenchymal stem cell (MSC)-derived osteoblasts and monocyte macrophage-derived osteoclasts, as local factors, immune cytokines and systemic hormones exert their regulatory effects. Moreover, the lineage decisions of MSCs to choose osteogenesis over adipogenesis is critical for maintenance of bone mass. MSC cell fate is determined by epigenetic regulations of various lineage-specific genes and genes promoting 'stemness'. In most bone pathologies especially osteoporosis, the balance in bone remodeling and in MSC lineage decisions become disrupted. To explore the molecular regulation of bone cells, we evaluated the effect of Wnt4 on bone loss associated with osteoporosis and skeletal aging. We generated transgenic mice overexpressing Wnt4 in osteoblasts, and discovered that Wnt4 signaling could attenuate bone loss and suppress inflammation in models of osteoporosis, inflammatory and age-related bone loss. Mechanistically, non-canonical Wnt4 signaling could attenuate Nf-kappab signaling by competitive sequestering of transforming growth factor associated kinase 1 (Tak1) in bone marrow macrophages. Furthermore, Wnt4 recombinant protein injection effectively prevented and reversed bone loss induced by estrogen-deficiency. Hence, non-canonical Wnt4 signaling could not only promote bone formation, but also inhibit bone resorption and inflammation in marrow microenvironment by a novel crosstalk with NF-kappaB signaling. To explore the epigenetic regulation of MSC differentiation towards osteoblasts, we discovered two novel histone demethylases KDM4B and KDM6B, which promoted osteogenesis and inhibited adipogenesis of human MSCs. Mechanistically, KDM4B and KDM6B epigenetically activated different osteogenic transcription factors by removing gene silencing marks H3K9me3 and H3K27me3 respectively. Furthermore, H3K27me3- and H3K9me3- positive MSCs in osteoporotic and aged mouse bone marrow become elevated, along with a reduction in KDM4B and KDM6B. These findings supported that these histone demethylases play a critical role in MSC cell fate decisions, and may become potential therapeutic targets for treatment of osteoporosis.
机译：人体骨骼经历连续的骨骼重塑，该过程依赖于成骨细胞和破骨细胞作用之间协调的平衡。复杂的分子信号网络控制着间充质干细胞（MSC）来源的成骨细胞和单核巨噬细胞来源的破骨细胞的分化和功能，因为局部因素，免疫细胞因子和全身激素发挥了调节作用。此外，MSC选择成骨而不是脂肪形成的血统决定对于维持骨量至关重要。 MSC细胞的命运取决于各种谱系特异性基因和促进“干性”的基因的表观遗传学规定。在大多数骨病理学中，特别是在骨质疏松症中，骨重塑和MSC血统决定的平衡被破坏了。为了探索骨细胞的分子调控，我们评估了Wnt4对与骨质疏松症和骨骼老化相关的骨质流失的影响。我们在成骨细胞中生成了过表达Wnt4的转基因小鼠，并发现Wnt4信号传导可以减轻骨质疏松症，炎症和年龄相关性骨质疏松模型中的骨质流失并抑制炎症。从机制上讲，非典型的Wnt4信号传导可以通过竞争性螯合骨髓巨噬细胞中的转化生长因子相关激酶1（Tak1）来减弱Nf-kappab信号传导。此外，Wnt4重组蛋白注射液可有效预防和逆转雌激素缺乏引起的骨质流失。因此，非经典的Wnt4信号传导不仅可以促进骨骼形成，而且还可以通过与NF-κB信号传导的新型串扰抑制骨髓微环境中的骨吸收和炎症。为了探索MSC向成骨细胞分化的表观遗传学调控，我们发现了两种新型的组蛋白脱甲基酶KDM4B和KDM6B，它们促进了成骨细胞生成并抑制了人类MSC的成脂作用。从机制上讲，KDM4B和KDM6B通过分别去除基因沉默标记H3K9me3和H3K27me3在表观遗传学上激活了不同的成骨转录因子。此外，骨质疏松症和老年小鼠骨髓中的H3K27me3-和H3K9me3-阳性MSC升高，同时KDM4B和KDM6B减少。这些发现支持这些组蛋白脱甲基酶在MSC细胞命运决定中起关键作用，并可能成为治疗骨质疏松症的潜在治疗靶标。

著录项

  • 作者

    Yu, Bo.;

  • 作者单位

    University of California, Los Angeles.;

  • 授予单位 University of California, Los Angeles.;
  • 学科 Molecular biology.;Cellular biology.
  • 学位 Ph.D.
  • 年度 2015
  • 页码 142 p.
  • 总页数 142
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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