Osteoblasts Role in Dysfunction of Body Adiposity and Bone Metabolism

摘要：患有代谢性疾病的患者，如肥胖症、糖尿病和脂肪代谢障碍， 骨和脂肪量、脂肪分布和能量稳态。其中涉及的潜在机制 人们对失调的了解很少。骨骼和脂肪组织都是内分泌器官， 调节能量代谢。骨合成成骨细胞和脂肪形成脂肪细胞来源于 普通的间充质祖细胞骨髓脂肪增加，骨量减少， 骨质疏松症糖尿病和衰老骨折风险最高的骨质疏松性骨骼总是表现出增加的 骨髓脂肪这些临床观察表明，针对骨髓脂肪可能是治疗这些疾病的一种方法。 每年有200万美国成年人因骨质疏松症和低骨量而发生骨折。 然而，骨髓脂肪的来源和功能，以及它与骨和其他组织的关系， 外周脂肪库不是很清楚。骨髓脂肪是一种独特的脂肪储存库， 与白色或棕色脂肪组织不同。在这项研究中，我们的目标是确定分子 骨与脂肪共病的代谢性疾病的潜在机制，特别是新的因素 由成骨细胞和骨细胞分泌，可以调节骨髓脂肪生成，外周脂肪分布， 能量平衡和维持成人骨量。 Runx 2转录因子对于间充质祖细胞向成纤维细胞的定向分化是必需的。 骨骼谱系Runx 2基因的全局无效小鼠由于成骨细胞的完全丧失而具有胚胎致死性 分化和骨形成。我们最近发表了Runx 2对软骨细胞也是必不可少的， 增殖、肥大成熟和软骨内骨化。我们的初步数据显示， 成熟成骨细胞和骨细胞中Runx 2的缺乏抑制了出生后骨合成，并引发了骨合成的快速增加。 骨质疏松症的发生、过早衰老和死亡。Runx 2活性抑制间充质细胞的定型 到脂肪细胞谱系。成骨细胞/骨细胞中Runx 2的缺失导致内脏神经元几乎不存在。 但骨髓脂肪生成显著增加。我们进一步证明，Runx 2块 通过改变能量代谢和通过抑制胰岛素中Akt和Erk的关键信号传导， 途径。基于初步数据，我们假设Runx 2调节成熟成骨细胞的信号， 骨细胞控制骨髓脂肪生成、外周脂肪分布和能量稳态。我们将 利用新的小鼠模型来测试我们的假设在三个特定的目标。目标1将研究Runx 2的作用 缺乏成骨细胞和骨细胞在相互维持成人脂肪和骨量。目标2将测试 骨髓和外周肥胖对成骨细胞/骨细胞需求，Aim 3将揭示其分子机制 能量平衡的信号和机制。

ABSTRACT: Patients with metabolic diseases, such as obesity, diabetes, and lipodystrophy exhibit altered bone and fat mass, fat distribution, and energy homeostasis. The underlying mechanisms involved in these dysregulations are poorly understood. Bone and fat tissue are both endocrine organs and secrete factors that regulate energy metabolism. Bone synthesizing osteoblasts and fat forming adipocytes are derived from common mesenchymal progenitors. Increased bone marrow fat and decreased bone mass is noted in osteoporosis, diabetes, and aging. Osteoporotic bones at highest risk for a fracture always exhibit increased marrow fat. These clinical observations suggest that targeting bone marrow fat may be a treatment for these diseases and for 2-million fractures in US adults that occur yearly due to osteoporosis and low bone mass. However, the origin and function of the bone marrow fat, as well as its relationship to the bone and other peripheral fat depots are not very clear. The bone marrow fat is a unique fat depot that is located adjacent to the bone and is different from either white or brown adipose tissue. In this study, we aim to identify molecular mechanisms underlying the metabolic diseases with comorbidity of the bone and fat, especially novel factors secreted by the osteoblast and osteocytes that can regulate marrow adipogenesis, peripheral fat distribution, energy homeostasis and maintenance of adult bone mass. The Runx2 transcription factor is essential for the commitment of mesenchymal progenitors to the cells of skeletal lineage. Global null mice of the Runx2 gene are embryonic lethal due to complete loss of osteoblast differentiation and bone formation. We have recently published that Runx2 is also essential for chondrocyte proliferation, hypertrophic maturation, and endochondral ossification. Our preliminary data show that selective deficiency of Runx2 in mature osteoblasts and osteocytes inhibits postnatal bone synthesis and trigger a rapid onset of osteoporosis, premature aging, and death. Runx2 activity inhibits commitment of mesenchymal cells to the adipocyte lineage. Deletion of Runx2 in osteoblasts/osteocytes results in the near absence of visceral adiposity but a dramatic increase in marrow adipogenesis. We further demonstrate that Runx2 blocks adipogenesis by altering energy metabolism and by inhibiting critical signaling from Akt and Erk in the insulin pathways. Based on the preliminary data we hypothesize that Runx2 regulated signals from mature osteoblast and osteocytes control marrow adipogenesis, peripheral fat distribution, and energy homeostasis. We will utilize novel mouse models to test our hypotheses in three specific aims. Aim 1 will examine the role of Runx2 deficient osteoblasts and osteocytes in the reciprocal maintenance of adult fat and bone mass. Aim 2 will test the requirement of osteoblast/osteocyte for marrow and peripheral adiposity, and Aim 3 will uncover molecular signals and mechanisms for energy homeostasis.