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而不断重塑。这种组织稳态的破坏导致了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、行动能力受限和死亡率增加。核受体PPAR3（过氧化物酶体增殖物激活受体-3）是能量代谢的重要调节因子，也是治疗不断升级的肥胖和糖尿病流行的重要治疗靶点。新出现的证据表明，PPAR3也调节骨转换。我们发现PPAR3的激活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PPAR3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PPAR3配体噻唑烷二酮（TZDs）是fda批准的治疗胰岛素抵抗和2型糖尿病的药物。最近的临床试验报道，长期使用TZDs会增加糖尿病患者的骨折发生率。因此，了解PPAR3如何调节骨代谢是至关重要的。在这项提议中，我们假设1)PPAR3在破骨细胞谱系承诺的早期和破骨细胞分化的晚期对破骨细胞的发生进行双期调控；2)这种调节受代谢环境的影响，是tzd介导的骨质流失的关键机制。在目标1中，我们将通过确定其造血起源来确定破骨细胞发育的细胞机制。在Aim 2中，我们将确定破骨细胞谱系承诺和PPAR3调控的分子机制。在Aim 3中，我们将确定TZDs在糖尿病背景下如何诱导骨质流失。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PPAR3如何通过控制破骨细胞谱系的承诺、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性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其他与骨吸收增加相关的疾病（如骨质疏松症、关节炎和癌症转移）的治疗提供基础见解。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。

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.