The actions and interactions of sex steroids and growth factors/cytokines on the skeleton.
The actions and interactions of sex steroids and growth factors/cytokines on the skeleton.
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DOI：
10.1210/mend.13.6.0299
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发表时间：
1999-06
影响因子：
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通讯作者：
T. Spelsberg;M. Subramaniam;B. Riggs;S. Khosla
中科院分区：
文献类型：
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作者：
T. Spelsberg;M. Subramaniam;B. Riggs;S. Khosla
雌激素的性类固醇受体[雌激素受体（ER）]、雄激素[雄激素受体（AR）]和孕激素[孕激素受体（PR）]存在于成骨细胞（OB）和骨吸收破骨细胞（OCL）中，这些细胞是性类固醇作用的靶点，这些发现在骨生物学领域引起了极大的兴奋。随后发现，性类固醇调节OB和OCL细胞中生长因子和细胞因子的产生，这些因子介导了骨骼上的类固醇作用，这增加了该系统的兴奋和复杂性。由于这篇小型综述所要求的简洁性，我们将只使用有限数量的参考文献和综述文章来讨论该领域的选定方面。在这一领域的更多信息，读者可以参考最近的几本书和章节，这些书和章节回顾了骨生物学、骨疾病以及性类固醇在骨生物学和骨疾病中的作用（1-8）。作为这个独特系统的简要背景，骨骼维护涉及在称为骨重塑单元（BRU）的离散位点的连续重塑。如图1所示，多核骨吸收ocl首先在这些BRU部位溶解骨，产生吸收腔。虽然在特定部位启动骨吸收的机制/信号尚不清楚，但似乎通过调节OCL的分化和活性对整体骨吸收有明显的调节作用（5-8）。下面将更详细地讨论这些过程。形成骨的OBs随后被未知的信号吸收，以取代先前被吸收的骨。将这些吸收过程与维持骨量的形成相结合的主要因素的身份也将在本综述的后面讨论，并且仍然是许多争论的主题。在儿童骨骼生长期间，骨形成的增加主要涉及骨模型（在没有骨吸收的情况下表面骨的增加）。对机械应力的响应也主要利用建模。在成年早期（20-40岁），骨吸收和形成处于平衡状态，骨量得以维持。血清雌激素(E)水平的升高发生在女孩青春期开始时，伴随着生长速度的增加，并最终导致骨骺生长板的闭合和线性生长的停止(9)。E是维持成年女性骨量的主要激素，在成年男性中可能与雄激素起着类似的作用。最后，在骨质流失期间，例如女性绝经后和男女衰老期间，骨吸收超过骨形成，在某些情况下，骨质流失足以引起骨质疏松症。目前普遍认为，绝经后女性缺乏E会导致骨质疏松症，而在老年男性中，缺乏E和雄激素(a)可能导致骨质流失（1-3）。卵巢切除（OVX）动物和绝经后妇女经历骨转换增加，骨吸收增加，骨量总体减少。另一方面，E替代疗法通过抑制骨转换和骨吸收来抑制这种骨质流失，从而防止骨质疏松症的发生（1,3）。虽然，E在防止骨质流失中的完整作用机制尚不清楚，但新的研究开始阐明所涉及的分子过程。以下综述总结了性类固醇（主要是雌激素）作用中的一些重要分子事件，分子内分泌学版权©1999 by The Endocrine Society
The discoveries that sex steroid receptors for estrogen [estrogen receptor (ER)], androgen [androgen receptor (AR)], and progesterone [progesterone receptor (PR)] are present in the bone-forming osteoblasts (OB) and bone-resorbing osteoclasts (OCL), and that these cells are targets for sex steroid action, have generated much excitement in the field of bone biology. The subsequent discoveries that the sex steroids regulate the production of growth factors and cytokines in these OB and OCL cells and that these factors mediate much of the steroid action on the skeleton have added to the excitement and complexity of the system. Because of the required brevity of this minireview, we will discuss only selected aspects of this field using a limited number of references and review articles. For more information in this field, readers are referred to several recent books and chapters that review bone biology, bone diseases, and the role of sex steroids in bone biology and disease (1–8). As a brief background to this unique system, the skeletal maintenance involves a continuous remodeling at discrete sites termed bone-remodeling units (BRU). As outlined in Fig. 1, the multinucleated boneresorbing OCLs first dissolve bone at these BRU sites, resulting in resorption cavities. While the mechanism(s)/signal(s) that initiates resorption at a given site is unknown, there appears to be a marked regulation of overall bone resorption via the regulation of the OCL differentiation and activity (5–8). These processes are discussed in more detail below. The bone-forming OBs are then recruited by unknown signals, to replace the previously resorbed bone. The identities of the primary factors that couple these processes of resorption to formation to maintain bone mass are also addressed later in this review and are still the subject of much debate. During periods of skeletal growth in children, the increase in bone formation largely involves bone modeling (accretion of bone at surfaces in the absence of bone resorption). The response to mechanical stresses also utilizes mostly modeling. During early adulthood (20–40 yr), bone resorption and formation are in balance and bone mass is maintained. The increased serum estrogen (E) level, which occurs at the onset of puberty in girls, is accompanied by an increase in growth velocity and, ultimately, in the closure of the epiphyseal growth plate and the cessation of linear growth (9). E is the primary hormone responsible for maintaining bone mass in adult women and may serve a similar role along with androgen, in adult men. Finally, during periods of bone loss, such as in postmenopause in women and aging in both genders, bone resorption outpaces bone formation and, in some cases, the bone loss is sufficient to cause osteoporosis. It is currently accepted that in postmenopausal females, a deficiency of E results in osteoporosis, whereas in aging males, the deficiency of E and androgens (A) may lead to bone loss (1–3). Ovariectomized (OVX) animals and postmenopausal women experience increased bone turnover, increased bone resorption, and an overall decrease in bone mass. On the other hand, E replacement therapy inhibits this bone loss by inhibiting bone turnover and bone resorption, which prevents the development of osteoporosis (1, 3). Although, the complete mechanisms of action of E in this protection against bone loss are still unclear, new studies are beginning to elucidate the molecular processes involved. The following review summarizes some of the important molecular events in the actions of sex steroids, primarily estrogens, which 0888-8809/99/$3.00/0 Molecular Endocrinology Copyright © 1999 by The Endocrine Society