Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX 75390-9041, USA.
Mol Cell Biol. 2011 Dec;31(23):4692-705. doi: 10.1128/MCB.05979-11. Epub 2011 Sep 26.
Osteoclasts are bone-resorbing cells essential for skeletal development, homeostasis, and regeneration. They derive from hematopoietic progenitors in the monocyte/macrophage lineage and differentiate in response to RANKL. However, the precise nature of osteoclast progenitors is a longstanding and important question. Using inducible peroxisome proliferator-activated receptor γ (PPARγ)-tTA TRE-GFP (green fluorescent protein) reporter mice, we show that osteoclast progenitors reside specifically in the PPARγ-expressing hematopoietic bone marrow population and identify the quiescent PPARγ(+) cells as osteoclast progenitors. Importantly, two PPARγ-tTA TRE-Cre-controlled genetic models provide compelling functional evidence. First, Notch activation in PPARγ(+) cells causes high bone mass due to impaired osteoclast precursor proliferation. Second, selective ablation of PPARγ(+) cells by diphtheria toxin also causes high bone mass due to decreased osteoclast numbers. Furthermore, PPARγ(+) cells respond to both pathological and pharmacological resorption-enhancing stimuli. Mechanistically, PPARγ promotes osteoclast progenitors by activating GATA2 transcription. These findings not only identify the long-sought-after osteoclast progenitors but also establish unprecedented tools for their visualization, isolation, characterization, and genetic manipulation.
破骨细胞是骨骼发育、稳态和再生所必需的骨吸收细胞。它们来源于单核细胞/巨噬细胞谱系中的造血祖细胞，并响应 RANKL 分化。然而，破骨细胞祖细胞的确切性质是一个长期存在的重要问题。使用诱导型过氧化物酶体增殖物激活受体 γ（PPARγ）-tTA TRE-GFP（绿色荧光蛋白）报告小鼠，我们表明破骨细胞祖细胞特异性存在于表达 PPARγ 的造血骨髓群体中，并将静止的 PPARγ(+) 细胞鉴定为破骨细胞祖细胞。重要的是，两个 PPARγ-tTA TRE-Cre 控制的遗传模型提供了令人信服的功能证据。首先，PPARγ(+) 细胞中的 Notch 激活导致破骨前体细胞增殖受损，从而导致骨量增加。其次，通过白喉毒素选择性消融 PPARγ(+) 细胞也会因破骨细胞数量减少而导致骨量增加。此外，PPARγ(+) 细胞对病理性和药理学增强吸收的刺激有反应。从机制上讲，PPARγ 通过激活 GATA2 转录来促进破骨细胞祖细胞。这些发现不仅确定了长期以来寻求的破骨细胞祖细胞，而且还建立了用于其可视化、分离、表征和遗传操作的前所未有的工具。
