GLUCOCORTICOID EFFECTS ON BONE: THE ROLE OF THE OSTEOBLAST

糖皮质激素（通常称为可的松）在几乎所有的医学领域都被用作治疗剂，其中它们已被证明对无数患有诸如类风湿性关节炎、哮喘、炎性肠病和恶性肿瘤的患者具有极大的益处。糖皮质激素对接受器官移植的患者也有挽救生命的益处。然而，众所周知，糖皮质激素也可能对骨、肌肉、软骨和皮肤产生有害作用，导致骨质疏松症、肌肉萎缩和皮肤损伤。事实上，可的松诱导的肌肉和骨骼疾病是与糖皮质激素治疗相关的最常见和最严重的副作用之一，并且在许多患者中显著影响生活质量和共病。在本项目中，我们的目标是开发新的策略，以了解和预防考地松诱导的骨疾病。第一步是研究糖皮质激素在骨中的作用机制。为此目的，我们已经产生了一种模型，其中可的松失活酶在骨形成细胞（成骨细胞）中过量产生。以前的研究表明，这些细胞受到保护，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在正常和患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性关节炎模型中）。我们还打算研究内部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将药物作用靶向所需组织和细胞的新方法，同时保护其他组织和细胞免受有害副作用的影响。

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.