Glucose-dependent Insulinotropic Peptide & Bone Turnover

说明(申请人提供)：葡萄糖依赖的促胰岛素多肽(GIP)是一种42个氨基酸的多肽，主要由小肠的内分泌细胞合成和分泌。我们认为，GIP调节骨形成和骨吸收，以响应营养吸收。有文献记载的GIP的作用表明，GIP在将食物在肠道中的摄取和吸收与许多组织中的代谢事件联系起来方面发挥着重要作用。我们的观察结果支持GIP在调节骨细胞功能中的作用，因为GIP受体定位于成骨细胞、成骨细胞样细胞、破骨细胞和骨细胞。此外，GIP剂量依赖地增加成骨样细胞系SAOS细胞内cAMP和钙含量，刺激碱性磷酸酶活性和胶原合成，抑制破骨细胞诱导的骨吸收。基于这些体外研究结果，我们认为GIP可能在机体的营养状态和骨形成和骨吸收之间的平衡之间起到联系作用。为了进一步评估GIP是骨合成代谢的假说，我们建议在转基因小鼠过表达GIP的遗传模型和GIP受体敲除小鼠模型中，定义GIP对体内骨量和骨转换的影响。作为对这一假设的第一次检验，GIP受体基因敲除小鼠将被分析骨表型变化，具体参考骨密度和骨组织形态计量学指标。此外，将在过量表达GIP的转基因小鼠中研究GIP诱导的破骨细胞性骨吸收抑制在观察到的GIP诱导的骨量增加中的作用。这些活体方法旨在直接测试GIP是否可以调节骨形成和转换。随着基因系统的建立，我们希望确定GIP在正常骨生理中的作用。如果体内的发现支持GIP对培养的成骨细胞的深刻影响，这将建立GIP作为食物摄入和骨代谢之间的潜在联系。这反过来可能表明GIP是一种潜在的激素靶点，用于骨质疏松症等骨病理的药物干预。

DESCRIPTION (provided by applicant): Glucose-dependent Insulinotropic Peptide (GIP) is a 42 amino acid peptide synthesized and secreted largely from endocrine cells in the small intestine. We propose that GIP modulates bone formation and resorption in response to nutrient uptake. The documented actions of GIP imply an important role in coupling food intake and absorption in the intestine with metabolic events in a number of tissues. Our observations support a role for GIP in modulating bone cell function, since GIP receptors localize to osteoblasts, osteoblast-like cells, osteoclasts, and osteocytes. Furthermore, GIP dose dependently increases intracellular cAMP and calcium contents in the osteoblast-like cell line SaOS, and stimulates alkaline phosphatase activity, collagen synthesis, and inhibits osteoclast-induced bone resorption. Based on these in vitro findings, we propose that GIP may act as a link between the nutritional state of the organism and the balance between bone formation and resorption. To evaluate further the hypothesis that GIP is anabolic for bone, we propose to define the effects of GIP on bone mass and bone turnover in vivo, both in a genetic model of GIP overexpression in transgenic mice, and in GIP receptor knock-out mouse model. As a first test of the hypothesis, GIP receptor knock-out mice will be analyzed for bone phenotypic changes, with specific reference to bone density and bone histomorphometric indices. In addition, the role of GIP-induced inhibition of osteoclastic bone resorption in the observed increases in bone mass induced by GIP will be studied in transgenic mice overexpressing GIP. These in vivo approaches are designed to test directly whether GIP can modulate bone formation and turnover. With the establishment of a genetic system, we hope to define the role of GIP in normal bone physiology. Should the in vivo findings support the profound influence of GIP on cultured osteblastoid cells, this would establish GIP as a potential link between food intake and bone metabolism. This in turn may signal GIP as a potential hormone target for pharmacologic intervention in bone pathologies such as osteoporosis.