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、糖尿病和脂肪营养不良，表现出改变。 骨骼和脂肪质量、脂肪分布和能量平衡。其中涉及的基本机制 人们对监管失调知之甚少。骨和脂肪组织既是内分泌器官，又是分泌因子 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 共同的间充质祖细胞。骨髓脂肪增加和骨量减少在 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通常表现为增加 骨髓脂肪。这些临床观察表明，靶向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，骨髓脂肪的起源和功能，以及它与骨骼和其他组织的关系 外周脂肪库不是很清楚。骨髓脂肪是一个独特的脂肪库，位于 骨骼和白色或棕色脂肪组织都不同。在这项研究中，我们的目标是鉴定分子 代谢性疾病骨脂共病的发病机制，尤其是新的因素 由成骨细胞和骨细胞分泌，可以调节骨髓脂肪生成，周围脂肪分布， 能量平衡与成人骨量的维持。 Runx2转录因子是间充质祖细胞向骨肉瘤细胞承诺所必需的 骨骼血统。由于成骨细胞的完全丧失，Runx2基因的全局缺失小鼠是胚胎致命的 分化和骨形成。我们最近发表了Runx2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，选择性 成熟成骨细胞和成骨细胞中Runx2的缺失抑制了出生后的骨合成并引发了快速的 出现骨质疏松症、过早衰老和死亡。Runx2活性抑制间充质细胞的趋化 到脂肪细胞谱系。成骨细胞/骨细胞中Runx2的缺失导致几乎没有内脏 肥胖，但骨髓脂肪生成急剧增加。我们进一步证明了Runx2块 通过改变能量代谢和抑制胰岛素中Akt和Erk的关键信号而促进脂肪生成 小路。根据初步数据，我们假设Runx2调控来自成熟成骨细胞的信号 骨细胞控制着骨髓脂肪生成、外周脂肪分布和能量平衡。我们会 利用新的老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Runx2的角色 成骨细胞和骨细胞在成人脂肪和骨量的相互维持中的不足。AIM 2将测试 成骨细胞/骨细胞对骨髓和外周肥胖症的需求，目标3将揭示分子 能量动态平衡的信号和机制。

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.