Function of HDAC7 in Osteoblasts

描述（由申请人提供）：许多颅面、牙科和骨科疾病需要更好的治疗方法来促进骨骼生长和再生。为了提高我们在临床上操纵成骨细胞形成骨的能力，将需要对控制其生理的分子机制有更深入的了解。我已经确定组蛋白去乙酰化酶7 （HDAC7）是成骨细胞分化的重要调节因子，对发展新的骨修复疗法具有潜在的意义。HDAC7是成骨细胞中的一种转录抑制因子。抑制HDAC7表达加速bmp2刺激的成骨细胞分化，提示HDAC7负向调控成骨细胞分化。因此，HDAC7功能的拮抗有望引发骨合成代谢反应。用含有BMP2的成骨细胞前体治疗可导致HDAC7从细胞核输出，可能解除了靶基因的抑制作用。我的主要假设是，HDAC7被Runx2和其他转录因子招募到成骨细胞分化所需基因的启动子，在那里它与其他调节因子相关联，带来转录抑制。我进一步假设HDAC7的核输出对于允许成骨细胞基因表达和细胞分化是必要的。我已经开发出过表达HDAC7的成骨细胞样细胞，这将使我能够通过两个具体目标来验证这些假设：1)定义过表达和构成核HDAC7对成骨细胞的影响；2)在成骨细胞中鉴定hdac7相关蛋白。这些目标的完成将提高我们对HDAC7在骨生理学中的作用的理解，并作为可能的治疗靶点和BMP2在颅面、骨科和牙科应用中的中介。

DESCRIPTION (provided by applicant): Better therapies to promote bone growth and regeneration are needed for many craniofacial, dental and orthopedic conditions. To improve our ability to clinically manipulate the formation of bone by osteoblasts will require a deeper understanding of the molecular mechanisms that govern their physiology. I have identified histone deacetylase 7 (HDAC7) as an important regulator of osteoblast differentiation that has potential implications for the development of new bone restorative therapies. HDAC7 is a transcriptional repressor in osteoblasts. Suppression of HDAC7 expression accelerated BMP2-stimulated osteoblast differentiation, suggesting that HDAC7 negatively regulates osteoblast differentiation. Therefore, antagonism of HDAC7 function would be anticipated to elicit a bone-anabolic response. Treatment with osteoblast precursors with BMP2 leads to export of HDAC7 from the nucleus, presumably relieving target genes from its repressive effects. My central hypothesis is that HDAC7 is recruited to the promoter of genes required for osteoblast differentiation by Runx2 and other transcription factors, where it associates with other regulators to bring about transcriptional repression. I further hypothesize that nuclear export of HDAC7 is necessary to allow osteoblast gene expression and cellular differentiation. I have developed HDAC7-overexpressing osteoblast-like cells that will enable me to test these hypotheses by two specific aims: 1) Define the effects of overexpressed and constitutively-nuclear HDAC7 on osteoblasts; and 2) Identify HDAC7-associated proteins in osteoblasts. Completion of these aims will improve our understanding of HDAC7's role in bone physiology and as a possible therapeutic target and as a mediator of BMP2 in craniofacial, orthopedic and dental applications. PUBLIC HEALTH RELEVANCE: Improved therapies are needed to facilitate treatment of the diseases and injuries that involve damage or malformation to bone of the craniofacial region. My previous work suggests that Histone Deacetylase 7 (HDAC7) inhibits differentiation of osteoblasts and revealed that HDAC7 is a target of bone morphogenic protein 2, which is currently used clinically to stimulate localized bone growth. This grant proposal will determine the functional role of HDAC7 and identify novel factors that cooperate with HDAC7 during skeletal growth. These results are important steps towards development of new therapeutic strategies for promoting bone growth and healing.