GLUCOCORTICOID EFFECTS ON BONE: THE ROLE OF THE OSTEOBLAST

糖皮质激素(通常被称为可的松)在几乎所有的医学领域都被用作治疗剂，在这些领域，它们被证明对无数患有类风湿性关节炎、哮喘、炎症性肠道疾病和恶性肿瘤的患者有巨大的好处。糖皮质激素对接受器官移植的患者也有挽救生命的好处。然而，众所周知，糖皮质激素也可能对骨骼、肌肉、软骨和皮肤产生有害影响，导致骨质疏松症、肌肉萎缩和皮肤损伤。事实上，可的松诱发的肌肉和骨骼疾病是糖皮质激素治疗中最常见和最严重的副作用之一，并极大地影响许多患者的生活质量和合并发病率。在本项目中，我们的目标是开发新的策略，以了解和预防考松引起的骨病。第一步是研究糖皮质激素在骨骼中的作用机制。为此，我们建立了一个模型，在该模型中，在骨形成细胞(成骨细胞)中过量产生一种可的松失活酶。以前的研究表明，这些细胞可以免受可的松的影响，而其他不产生这种酶的细胞仍然很脆弱。我们现在打算使用这个模型来研究正常和疾病条件下糖皮质激素对骨骼和肌肉的作用机制(例如，在糖皮质激素过量模型和类风湿关节炎模型中)。我们还打算研究内源性糖皮质激素如何影响骨形成细胞的发育。我们的长期目标是发现针对所需组织和细胞的药物作用的新方法，同时保护其他组织和细胞免受有害副作用。

Glucocorticoids (usually referred to as cortisone) are used as therapeutic agents in almost all fields of medicine, where they have been proven to be of great benefit to countless patients suffering from diseases such as rheumatoid arthritis, asthma, inflammatory bowel disease and malignancies. Glucocorticoids are also of live saving benefit to patients who have undergone organ transplantation. It is, however, well known that glucocorticoids may also exert deleterious effects on bone, muscle, cartilage and skin, causing osteoporosis, muscle wasting and skin damage. As a matter of fact, cortisone-induced muscle and bone disease is one of the most frequent and serious side effects associated with glucocorticoid treatment, and substantially affects quality of life and co-morbidity in many patients. In the present project, we aim to develop new strategies for the understanding and prevention of costisone-induced bone disease. The first step is to investigate the mechanisms of actions of glucocorticoids in bone. To this aim, we have generated a model in which a cortisone- inactivating enzyme is produced in excess in the bone forming cells (osteoblasts). Previous studies have shown that these cells are protected against the effects on cortisone, while other cells not producing this enzyme remained vulnerable. We now intend to use this model to study the mechanisms of glucocorticoid action on bone and muscle under normal and diseased conditions (e.g. in a model of glucocorticoid excess and in a model of rheumatoid arthritis). We also intend to study how internal glucocorticoids affect the development of bone forming cells. Our long-term aim is to uncover new ways to target drug action to the desired tissues and cells, while protecting other tissues and cells from deleterious side effects.