Runx2 Controlled Adipocytic Differentiation in Aging Musculoskeleton

描述(申请人提供)：体内脂肪生成的转录控制是一个复杂的过程，涉及大量基因和表型特异性以及一般调控蛋白。许多这些因子、它们的同源元件和它们的功能辅助因子都以限速浓度存在，必须组装成不同的多组分调节复合体，以选择性地激活或抑制靶基因以响应生理和发育信号。与年龄相关的变化会导致肌肉骨骼系统中肥胖的增加，并伴随着成骨细胞活性的降低，因此具有潜在的严重健康风险。脂肪生成、脂肪和葡萄糖稳态的关键调节因子已被确定，包括CAATT增强子结合蛋白(C/EBP)家族成员和过氧化物酶体增殖物激活受体(PPAR)。这些因子的零突变会导致致命性和脂肪生成的丧失。同样，Runx2/Cbfa1是胚胎发育过程中成骨细胞分化和骨形成的必备因子。去除Runx2基因会导致骨骼形成完全失败，并导致胚胎死亡。最近的发现表明，在衰老和病理条件下，骨骼中脂肪细胞和成骨细胞的数量呈负相关。然而，衰老导致脂肪生成的原因尚不清楚。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，Runx2代表了一种在功能上解决衰老受试者中以成骨为代价的脂肪生成增强的范例。我们建议的研究将通过调节Runx2蛋白的消融或表达突变的Runx2蛋白来解决这种转换所涉及的分子机制，该突变蛋白在体外和体内小鼠模型中都具有负向调节脂肪细胞分化的能力。我们假设，在老化的骨骼中，Runx2将祖细胞“启动”为成骨细胞的功能活性发生了变化，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Runx2差异/双极活性的分子机制。这些研究可能被转化为治疗先天性和退行性骨骼疾病、代谢性骨骼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.