Control of osteoblastic bone formation involves the cumulative action of numerous transcription factors, including both activating and repressive functions that are important during specific stages of differentiation. The nuclear receptor retinoic acid receptor-related orphan receptor β (Rorβ) has been recently shown to suppress the osteogenic phenotype in cultured osteoblasts, and is highly upregulated in bone marrow-derived osteogenic precursors isolated from aged osteoporotic mice, suggesting Rorβ is an important regulator of osteoblast function. However the specific gene expression patterns elicited by Rorβ are unknown. Using microarray analysis, we identified 281 genes regulated by Rorβ in an MC3T3-E1 mouse osteoblast cell model (MC3T3-Rorβ-GFP). Pathway analysis revealed alterations in genes involved in MAPK signaling, genes involved in extracellular matrix (ECM) regulation, and cytokine-receptor interactions. Whereas the identified Rorβ-regulated ECM genes normally decline during osteoblastic differentiation, they were highly upregulated in this non-mineralizing MC3T3-Rorβ-GFP model system, suggesting that Rorβ may exert its anti-osteogenic effects through ECM disruption. Consistent with these in vitro findings, the expression of both RORβ and a subset of RORβ-regulated genes were increased in bone biopsies from postmenopausal women (73±7 years old) compared to premenopausal women (30±5 years old), suggesting a role for RORβ in human age-related bone loss. Collectively, these data demonstrate that Rorβ regulates known osteogenic pathways, and may represent a novel therapeutic target for age-associated bone loss.

译文

控制成骨细胞骨形成涉及许多转录因子的累积作用,包括在分化的特定阶段重要的激活和抑制功能。最近,核受体视黄酸受体相关孤儿受体 β (ror β) 已被证明可以抑制培养的成骨细胞的成骨表型,并且在从老年骨质疏松小鼠分离的骨髓来源的成骨前体中高度上调,表明ror β 是重要的成骨细胞功能调节剂。然而,ror β 引起的特定基因表达模式尚不清楚。使用微阵列分析,我们在MC3T3-E1小鼠成骨细胞模型 (MC3T3-Rorβ-GFP) 中鉴定出281个受ror β 调节的基因。通路分析揭示了参与MAPK信号传导的基因,参与细胞外基质 (ECM) 调控的基因以及细胞因子-受体相互作用的改变。尽管鉴定出的ror β 调控的ECM基因在成骨细胞分化过程中通常会下降,但在这种非矿化的MC3T3-Rorβ-GFP模型系统中它们被高度上调,这表明ror β 可能通过ECM破坏发挥其抗成骨作用。与这些体外发现一致,与绝经前妇女 (30 ± 5岁) 相比,绝经后妇女 (73 ± 7岁) 的骨活检中ror β 和ror β 调控基因的子集的表达均增加,表明ror β 在人类与年龄相关的骨丢失中的作用。总的来说,这些数据表明ror β 调节已知的成骨途径,并可能代表与年龄相关的骨丢失的新治疗靶标。

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