Connection of Mineral and Energy Metabolism by the Nuclear Receptor PPAR-gamma

描述（由申请人提供）：骨是一种动态组织，通过平衡成骨细胞介导的骨形成和破骨细胞介导的骨吸收不断重塑。这种组织稳态的破坏导致几种毁灭性的人类疾病，包括骨质疏松症、关节炎和癌症的骨转移，导致严重的疼痛、骨折、危及生命的高钙血症、活动受限和死亡率增加。核受体PPAR 3（过氧化物酶体增殖物激活受体-3）是能量代谢的关键调节因子，也是治疗不断升级的肥胖症和糖尿病流行病的重要治疗靶点。新出现的证据表明，PPAR 3也调节骨转换。我们发现PPAR 3的活化促进破骨细胞分化和骨吸收。它也被证明可以抑制成骨细胞分化和骨形成。重要的是，这些发现揭示了PPAR 3在矿物质和能量代谢之间的联系中的核心作用，将骨质疏松症等骨骼疾病与以肥胖、糖尿病和动脉粥样硬化为特征的代谢综合征联系起来。合成的PPAR 3配体噻唑烷二酮（TZD）是FDA批准的用于胰岛素抵抗和2型糖尿病的药物。最近的临床试验报告说，长期使用TZD增加了糖尿病患者的骨折率。因此，了解PPAR 3如何调节骨代谢至关重要。在这个提议中，我们假设：1）PPAR 3在破骨细胞谱系定型的早期阶段和破骨细胞分化的晚期阶段对破骨细胞生成发挥双相调节作用; 2）这种调节受代谢背景的影响，并代表了TZD介导的骨丢失的关键机制。在目标1中，我们将通过鉴定破骨细胞的造血来源来确定破骨细胞发育的细胞机制。在目标2中，我们将确定破骨细胞谱系定型和PPAR 3调控的分子机制。在目标3中，我们将确定TZDs如何在糖尿病背景下诱导骨丢失。将采用多种工具，包括小鼠遗传和疾病模型、分子和细胞生物学、生物化学和小分子。这项研究将阐明PPAR 3如何通过控制破骨细胞谱系的定型、分化和功能来调节矿物质代谢，以及这种调节如何受到能量代谢的影响。它将为理解骨骼生理学及其与代谢疾病的联系开辟令人兴奋的新途径。重要的是，这些研究的结果将为糖尿病以及与骨吸收增加相关的其他疾病（如骨质疏松症、关节炎和癌症转移）的治疗提供基本见解。因此，这项研究将对更广泛的科学、临床和患者群体产生重大影响。 公共卫生相关性：最近的临床试验报告说，长期使用糖尿病药物文迪雅，一种核受体PPAR 3（过氧化物酶体增殖物激活受体-3）的激活剂，增加了糖尿病患者的骨折率。该提案研究PPAR 3和文迪雅调节骨吸收的机制，并探讨肥胖和糖尿病对这种调节的潜在影响。从这些研究中获得的见解将显著促进我们对糖尿病患者基础骨生物学和文迪雅介导的骨骼脆性的理解。

DESCRIPTION (provided by applicant): Bone is a dynamic tissue that constantly remodels by balancing osteoblast-mediated bone formation and osteoclast-mediated bone resorption. The disruption of this tissue homeostasis causes several devastating human diseases including osteoporosis, arthritis and bone metastasis of cancers, leading to severe pain, fractures, life-threatening hypercalcemia, limited mobility and increased mortality. The nuclear receptor PPAR3 (peroxisome proliferator-activated receptor-3) is a critical regulator of energy metabolism and an important therapeutic target for treating the escalating obesity and diabetes epidemic. Emerging evidence suggests that PPAR3 also modulates bone turnover. We discovered that activation of PPAR3 promotes osteoclast differentiation and bone resorption. It has also been shown to suppress osteoblast differentiation and bone formation. Importantly, these findings unravel a central role for PPAR3 in the connection between mineral and energy metabolism, linking skeletal disorders such as osteoporosis with metabolic syndrome hallmarked by obesity, diabetes and atherosclerosis. Synthetic PPAR3 ligands thiazolidinediones (TZDs) are FDA-approved drugs for insulin resistance and type 2 diabetes. Recent clinical trials have reported that long-term use of TZDs increased fracture rates among diabetic patients. Thus, it is of paramount importance to understand how PPAR3 regulates bone metabolism. In this proposal, we hypothesize that 1) PPAR3 exerts a biphasic regulation of osteoclastogenesis, at both the early stage of osteoclast lineage commitment and the late stage of osteoclast differentiation; 2) this regulation is influenced by the metabolic context and represents a critical mechanism for TZD-mediated bone loss. In Aim 1, we will determine the cellular mechanisms for osteoclast development by identifying its hematopoietic origin. In Aim 2, we will determine the molecular mechanisms for osteoclast lineage commitment and PPAR3 regulation. In Aim 3, we will determine how TZDs induce bone loss in the context of diabetes. A combination of tools will be employed, including mouse genetic and disease models, molecular and cell biology, biochemistry and small molecules. The proposed investigation will elucidate how PPAR3 regulates mineral metabolism by controlling osteoclast lineage commitment, differentiation and function, as well as how this regulation is influenced by energy metabolism. It will open exciting new paths to the understanding of skeletal physiology and its connection with metabolic diseases. Importantly, the outcome of these studies will provide fundamental insights for the treatment of diabetes, as well as other diseases associated with increased bone resorption such as osteoporosis, arthritis and cancer metastasis. Therefore, this investigation will significantly impact the broader scientific, clinical, and patient community. PUBLIC HEALTH RELEVANCE: Recent clinical trials have reported that long-term use of the diabetic drug Avandia, an activator of the nuclear receptor PPAR3 (peroxisome proliferator-activated receptor-3), increases fracture rates among diabetic patients. This proposal investigates the mechanisms by which PPAR3 and Avandia regulate bone resorption and explores the potential influence of obesity and diabetes on this regulation. Insights from these studies will significantly advance our understanding of both basic bone biology and Avandia-mediated skeletal fragility in diabetic patients.