Zinc Finger Protein 467 Is a Novel Regulator of Osteoblast and Adipocyte Commitment
Zinc Finger Protein 467 Is a Novel Regulator of Osteoblast and Adipocyte Commitment
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DOI：
10.1074/jbc.m110.178251
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发表时间：
2011-02-01
影响因子：
4.8
通讯作者：
Martin, T. John
中科院分区：
文献类型：
--
作者：
Quach, Julie M.;Walker, Emma C.;Martin, T. John
成骨细胞和脂肪细胞来源于共同的间充质祖细胞。骨质疏松症的骨丢失与从成骨细胞到脂肪细胞谱系的祖细胞分化改变有关。在分化的小鼠基质成骨细胞系Kusa 4 b10中进行cDNA微阵列和定量实时PCR（Q-PCR），以鉴定刺激成骨细胞分化的因子的基因靶点，包括甲状旁腺激素（PTH）和gp 130结合细胞因子，制瘤素M（OSM）和心肌营养素-1（CT-1）。锌指蛋白467（Zfp 467）被PTH、OSM和CT-1快速下调。Zfp 467在小鼠基质细胞中的逆转录病毒过表达和RNA干扰表明，与对照组相比，该因子刺激脂肪细胞形成并抑制成骨细胞承诺。通过Q-PCR证实了Zfp 467对脂肪细胞标志物（包括过氧化物酶体增殖物激活受体（PPAR）γ、C/EBP α、脂联素和Glycoprotein）以及晚期成骨细胞/骨细胞标志物（骨钙素和硬化素）的调节。与载体对照转导的细胞相比，胫骨内注射用逆转录病毒Zfp 467转导的颅骨细胞使C57 Bl/6小鼠中骨髓脂肪细胞的数量加倍，从而提供了Zfp 467的促脂肪形成作用的体内确认。此外，Zfp 467反式激活了一个PPAR反应元件报告构建体，并招募了一个组蛋白脱乙酰酶复合物。因此，Zfp 467是一种促进脂肪细胞分化并抑制成骨细胞分化的新型辅因子。这与骨质疏松症的治疗干预有关，包括目前可用的基于PTH的疗法，并且可能与脂肪来源的干细胞用于组织工程有关。
Osteoblasts and adipocytes are derived from common mesenchymal progenitor cells. The bone loss of osteoporosis is associated with altered progenitor differentiation from an osteoblastic to an adipocytic lineage. cDNA microarrays and quantitative real-time PCR (Q-PCR) were carried out in a differentiating mouse stromal osteoblastic cell line, Kusa 4b10, to identify gene targets of factors that stimulate osteoblast differentiation including parathyroid hormone (PTH) and gp130-binding cytokines, oncostatin M (OSM) and cardiotrophin-1 (CT-1). Zinc finger protein 467 (Zfp467) was rapidly down-regulated by PTH, OSM, and CT-1. Retroviral overexpression and RNA interference for Zfp467 in mouse stromal cells showed that this factor stimulated adipocyte formation and inhibited osteoblast commitment compared with controls. Regulation of adipocyte markers, including peroxisome proliferator-activated receptor (PPAR) gamma, C/EBP alpha, adiponectin, and resistin, and late osteoblast/osteocyte markers (osteocalcin and sclerostin) by Zfp467 was confirmed by Q-PCR. Intra-tibial injection of calvarial cells transduced with retroviral Zfp467 doubled the number of marrow adipocytes in C57Bl/6 mice compared with vector control-transduced cells, providing in vivo confirmation of a pro-adipogenic role of Zfp467. Furthermore, Zfp467 transactivated a PPAR-response element reporter construct and recruited a histone deacetylase complex. Thus Zfp467 is a novel co-factor that promotes adipocyte differentiation and suppresses osteoblast differentiation. This has relevance to therapeutic interventions in osteoporosis, including PTH-based therapies currently available, and may be of relevance for the use of adipose-derived stem cells for tissue engineering.