A novel inhibitor of osteoclast generation

我们发现，瘦素是一种由脂肪细胞产生的调节食欲和新陈代谢的新激素，是一种强大的破骨细胞形成抑制因子。破骨细胞是存在于骨骼中的大型细胞，负责骨吸收，因此这些细胞有助于常见的骨骼疾病，如骨质疏松症、Paget病和骨癌。骨质疏松症导致巨大的疼痛和残疾，仅它一项就花费了澳大利亚纳税人每年超过4亿美元。超重的人往往血液中的瘦素水平更高，骨骼也更致密，这表明血液中的瘦素可能与骨密度或强度有关。此外，瘦素是在骨髓中产生的，而骨髓是产生破骨细胞的地方。破骨细胞是由存在于骨髓和血液中的白细胞形成的。最近的发现发现了一系列在破骨细胞形成中起关键作用的新因子。其中一种因子被称为骨保护素，是破骨细胞形成的抑制因子。缺乏骨保护素的突变小鼠破骨细胞数量大大增加，并出现严重的骨质疏松，而骨保护素过多的突变小鼠的骨骼密度比正常大得多。这些因子的出现现在允许在实验室中产生人类破骨细胞，这使得进一步研究这一过程是如何调控的。我们已经发现，瘦素增加了白细胞产生的护骨素的数量，我们认为这是瘦素抑制破骨细胞生成的主要方式。在这个项目中，我们打算进一步研究瘦素如何以及为什么能够影响破骨细胞的生成和功能，因为瘦素可能是治疗骨质疏松症和其他骨骼疾病的合适药物。

We have found that leptin, a new hormone produced by fat cells which regulates appetite and metabolism, is a powerful inhibitor of osteoclast formation. Osteoclasts are large cells present in bone which are responsible for bone resorption and therefore these cells contribute to common bone conditions such as osteoporosis, Paget's disease and bone cancer. Osteoporosis causes a great deal of pain and disability and it alone costs the Australian taxpayers more than $400 million per year. Persons who are overweight tend to have higher circulating blood levels of leptin and also tend to have denser bones, which suggests that there might be a relationship between blood leptin and bone density or strength. Furthermore, leptin is produced in the bone marrow which is where osteoclasts are produced. Osteoclasts are formed from white blood cells which are present in the bone marrow and the blood. Very recent discoveries have identified a family of new factors which play a key role in the formation of osteoclasts. One of these factors has been called osteoprotegerin and is an inhibitor of osteoclast formation. Mutant mice lacking osteoprotegerin have greatly increased numbers of osteoclasts and severe osteoporosis whereas mutants with too much osteoprotegerin have bones which are much denser than normal. The availability of these factors now allows the generation of human osteoclasts in the laboratory which enables the further study of how the process is regulated. We have found that leptin increases the amount of osteoprotegerin produced by white blood cells and we believe that this is the major way that leptin inhibits osteoclast generation. In this project, we intend to further investigate how and why leptin is able to influence the generation and function of osteoclasts as leptin may be a suitable treatment for osteoporosis and other bone diseases.