Runx2 Controlled Adipocytic Differentiation in Aging Musculoskeleton

描述（由申请人提供）： 体内脂肪形成的转录调控是一个复杂的过程，涉及大量的基因和表型特异性以及一般的调节蛋白。许多这些因子，它们的同源元件和它们的功能辅因子都以限速浓度存在，并且必须组装成不同的多组分调节复合物以响应生理和发育线索选择性地激活或抑制靶基因。年龄相关变化导致肌肉骨骼系统肥胖增加，同时骨形成成骨细胞活性降低，因此代表了潜在的严重健康风险。已经鉴定了脂肪生成、脂质和葡萄糖稳态的关键调节剂，包括CAATT增强子结合蛋白（C/EBP）家族和过氧化物酶体增殖物激活受体（PPAR）的成员。这些因子的突变导致致死性和脂肪形成的丧失。类似地，Runx 2/Cbfa 1是胚胎发育过程中成骨细胞分化和骨形成的必需因子。Runx 2基因缺失导致骨骼形成完全失败，并导致胚胎死亡。最近的研究表明，在衰老和病理条件下，骨中脂肪细胞和成骨细胞的数量呈反比关系。然而，目前还不清楚为什么衰老导致脂肪生成。成骨细胞和脂肪细胞起源于共同的祖细胞，其起源于骨髓中的间充质基质/干细胞。因此，Runx 2代表了功能性地解决衰老受试者中以骨生成为代价的增强的脂肪生成的范例。我们提出的研究将通过调节Runx 2蛋白的消融或突变Runx 2蛋白的表达来解决这种转换中涉及的分子机制，所述突变Runx 2蛋白在其使用离体和体内小鼠模型负调节脂肪细胞分化的能力方面受到损害。我们假设Runx 2将祖细胞“引发”成骨细胞的功能活性在老化骨骼中改变，从而有利于向脂肪细胞分化。我们的长期目标是确定在脂肪细胞和成骨分化过程中调节Runx 2的差异/双极活性的分子机制。这些研究可能会转化为先天性和退行性骨骼疾病，代谢性骨疾病和衰老的新疗法。

DESCRIPTION (provided by applicant): Transcriptional control of adipogenesis in vivo is a complex process involving a large number of genes and phenotype specific as well as general regulatory proteins. Many of these factors, their cognate elements and their functional co-factors are all present in a rate limiting concentration, and must assemble into distinct multi-component regulatory complexes to selectively activate or suppress target genes in response to physiological and developmental cues. Age related changes result in increased adiposity in the musculoskeletal system and concomitant decreased activity of bone-forming osteoblast and thus represent a potentially serious health risk. Key regulators of adipogenesis, lipid and glucose homeostasis have been identified and include members of the CAATT enhancer binding protein (C/EBP) family and peroxisome proliferator-activated receptor (PPAR). Null mutation of these factors results in lethality and loss of adipogenesis. Similarly, Runx2/Cbfa1 is an obligatory factor for osteoblast differentiation and bone formation during embryonic development. Runx2 gene ablation cause complete failure of skeleton formation and results in embryonic lethality. Recent finding indicates an inverse relationship between the numbers of adipocytes and osteoblasts in bone during aging and in pathological conditions. However it is unclear why aging leads to adipogenesis. Osteoblasts and adipocytes originate from a common progenitor which arises from mesenchymal stroma/stem cells in marrow. Thus, Runx2 represent a paradigm to functionally address the enhanced adipogenesis at the expense of osteogenesis in aging subjects. Our proposed studies will address molecular mechanisms involved in this switch by a regulated ablation of the Runx2 protein, or expression of a mutant Runx2 protein that is compromise in its ability to negatively regulate adipocytic differentiation using both ex-vivo and in vivo mouse models. We hypothesized that Runx2 functional activity to "prime" progenitor cells to osteoblasts is altered in aging skeleton thus favoring differentiation towards adipocytes. Our long term objectives are to identify molecular mechanisms regulating the differential/bi-polar activities of Runx2 during adipocytic and osteogenic differentiation. These studies may be translated to novel therapies for congenital and degenerative skeletal diseases, metabolic bone disorders and aging.