促性腺激素释放激素及其类似物的研究进展

促性腺激素释放激素 (GnRH) ,是由下丘脑分泌的十肽激素 ,其受体为钙离子动员受体。GnRH脉冲式释放刺激垂体促性腺激素的合成和分泌从而调节性激素的分泌 ,是性腺轴系的原动力 ,此外对性腺还可能具有直接作用。对GnRH分子结构修饰而合成的结构类似物 ,已经在生殖内分泌疾病治疗、计划生育等方面得到应用。     

RANK/RANKL/OPG系统与人工关节无菌性松动

人工关节置换术是临床上治疗各种终末期关节疾病最常用的有效方法,但人工关节无菌性松动常影响其远期疗效。目前多数学者认为人工关节周围破骨细胞介导的骨吸收,是导致人工关节松动的主要原因。近年许多研究表明核因子-κB受体活化因子（RANK）/RANK配体（RANKL）/骨保护素（OPG）系统与人工关节无菌性松动有密切关系,在体内受多种促骨激素和细胞因子的直接或间接作用,调控RANKL-OPG比值,介导破骨细胞分化、活化和凋亡,从而影响骨代谢。该文就RANK/RANKL/OPG系统功能、磨损颗粒对其作用及其基因治疗研究进展作一综述。     

痩素对骨质疏松症效应的研究进展

瘦素作为一种内分泌激素,通过中枢和外周两种途径调节骨代谢.瘦素的中枢效应可能是通过下丘脑、交感神经系统以及β受体而最终引起骨量减少,瘦素的外周效应可能是通过骨髓基质细胞,骨化细胞和破骨细胞3个方面起作用并最终引起骨量增加.瘦素对骨代谢的整体作用可能取决于血清瘦素的水平及血脑屏障的通透性.     

Ghrelin对骨及软骨生长作用研究进展

Ghrelin是生长激素促分泌素受体的内源性配体,研究证明在体内和体外均有促进生长激素释放的作用。随着近年研究的深入,发现Ghrelin可通过体内促进生长激素分泌等内分泌途径对成骨细胞产生间接作用,也可以通过不同信号通路直接作用于细胞而促进细胞分化增殖。软骨细胞还可通过自身分泌Ghrelin而影响细胞代谢。Ghrelin可能是联系内分泌与骨骼生长的重要物质之一。该文重点介绍近年来Ghrelin对骨及软骨生长作用的研究进展。     

成骨与破骨细胞促红细胞生成素肝细胞受体B4/肝配蛋白B2双向信号通路

成骨细胞与破骨细胞以直接接触的方式共同调控骨重建平衡,这也决定了两者的不可分割性。最新研究表明前破骨细胞肝配蛋白(Ephrin)B2与成骨细胞膜上促红细胞生成素肝细胞受体(Eph)B4受体的直接接触来调控骨稳态平衡。具有EphrinB2配体的前破骨细胞可通过直接接触具有EphB4受体的前成骨细胞从而触发各自相应的下游信号转导分子。通过激活成骨细胞膜表面Eph受体而起正向作用,进一步去抑制下游信号转导分子RhoA活性促进前体细胞分化成熟。反之,EphrinB2配体的激活起到反向作用,抑制破骨相关转录因子的C-fos/NFATc1转录级联反应来抑制前破骨细胞的分化,磨损颗粒导致的骨溶解会使破骨细胞上EphrinB2配体表达明显升高,并且会促进NFATc1的高表达,可以通过这种双向信号的机制来减弱甚至是抑制磨损颗粒导致的破骨细胞的进一步分化。     

RUNX2与骨代谢的调控

目前对于骨质疏松的治疗方法包括抑制骨吸收防止骨量丢失或促进骨形成使骨量增加.RUNX2作为Runt相关基因家族成员之一,在骨代谢调控和骨形成方面起着重要的作用.RUNX2蛋白参与了多种信号转导途径,细胞外基质、骨形态发生蛋白、成纤维细胞生长因子、力学刺激、甲状旁腺激素、血管内皮生长因子等信号途径均对RUNX2的活性有一定的影响,所以RUNX2可通过与骨代谢相关的多种细胞因子相互作用而调控成骨细胞和破骨细胞的分化及活性,从而为骨质疏松的治疗提供了新的靶点.     

甲状旁腺激素经不同信号通路调节骨代谢的研究进展

甲状旁腺激素是目前广泛应用于临床中的抗骨质疏松骨形成促进剂。然而，由于其小剂量、间歇性促进骨形成以及大剂量、连续性促进骨吸收的双向调节作用，使得甲状旁腺激素在骨质疏松症的治疗中有待进一步优化。因此，立足于甲状旁腺激素调节骨代谢的分子机制，总结甲状旁腺激素主要经如下信号通路调节骨代谢：（1）Gs/cAMP/PKA信号通路，是甲状旁腺激素调节骨组织代谢引起骨形成或骨吸收效应的主要机制。（2）G_q/11/PLC/PKC信号通路，其主要功能为抑制成骨作用。（3）nonPLC/PKC信号通路，目前认为其发挥成骨效应，但具体内容尚不完全明确。（4）β-arrestin信号通路，能通过受体脱敏及内吞机制仅产生成骨作用而无破骨的激活。对甲状旁腺激素激活的上述4条主要信号通路的内容及作用进行文献综述，以期找寻更好的骨形成促进剂。其中，SOST及Dickkopf-1单克隆抗体是新颖的靶向药物，特异性激活nonPLC/PKC信号通路或β-arrestin信号通路的甲状旁腺激素相关肽值得进一步开发和应用。     

识别促性腺激素释放激素激动剂对垂体-卵巢轴降调节抑制程度及意义

本文通过文献复习讨论促性腺激素释放激素激动剂(GnRH-a)联合促性腺激素(Gn)诱导排卵治疗方案对垂体卵巢轴的降调节作用及意义.广义的降调节作用包括:对血清促性腺激素:卵泡刺激素、黄体生成素(FSH、LH)水平、卵泡周期性发育和类固醇激素合成的影响.临床常见的垂体降调节程度包括过度抑制、部分抑制和未能达到抑制.过度抑制被认为是垂体卵巢轴完全静息状态所需要的,适用于性激素依赖性肿瘤或疾病的治疗.体外受精-胚胎移植(IVF-ET)治疗周期中仅需要达到部分垂体卵巢轴降调节,即保留进入周期募集的卵泡对促性腺激素的反应性和类固醇激素合成.未能达到抑制的垂体卵巢轴伴随着卵泡晚期早发LH峰的风险,与无降调节周期相似.GnRH-a对垂体卵巢轴的降调节作用不仅与其类型、半衰期和患者个体差异有关,并且呈现出剂量与使用时间的依赖性.大部分过度抑制效应的患者可以通过降低GnRH-a剂量逆转,恢复卵巢对外源促性腺激素的反应性.极少数妇女存在降调节的延迟反应,与LH受体变异和受体后缺陷有关.     

催产素对骨代谢调节的研究进展

催产素是一种垂体后叶激素,它的两大经典生理功能包括促进分娩期的子宫收缩与哺乳期的排乳。新近,一些研究发现了催产素对骨代谢的直接调节作用,并证明了催产素参与调节妊娠期母体的骨重建,从而充分揭示了催产素新的生理功能,同时进一步证实了学术界提出的骨代谢调控的垂体-骨轴新机制,从而为催产素及催产素类似物在骨质疏松症防治方面的应用与新药开发提供了理论根据。     

不同促性腺激素释放激素类似物对垂体反应性的作用

促性腺激素释放激素类似物分为激动剂与拮抗剂,在辅助生殖治疗中,主要用于抑制黄体生成素(LH)峰,预防卵泡早排,但两者对垂体反应性产生不同的作用。本文旨在讨论不同促性腺激素释放激素类似物对垂体反应性的影响,以及垂体外效应。     

Study of hormone replacement therapy following total thyroidectomy in thyroid cancer--with special reference to the analysis of thyroid hormone peripheral effects, using indirect calorimetry]

Peripheral effects of thyroid hormones were examined using an indirect calorimetry in 18 patients with thyroid cancer before and after total thyroidectomy. Peripheral effects of exogenous thyroid hormones in TSH-suppression therapy after thyroidectomy were also studied. The subjects were maintained without hormone replacement for 3 weeks after total thyroidectomy. The ratio of resting energy expenditure to basal energy expenditure (REE/BEE) was determined before operation, before hormone replacement, and 1 and 5 weeks after the beginning of replacement, and the values were compared with changes in the blood thyroid hormone levels. Positive correlations were observed between the changes in endogenous thyroid hormone levels before and after total thyroidectomy and those in REE/BEE (free T3 vs. REE/BEE; r = 0.756, p less than 0.01), suggesting that evaluation of REE/BEE is clinically useful as an index of peripheral effects of thyroid hormones. Five weeks after the beginning of hormone replacement, T4 and free T4 were slightly range, and no enhancement of energy metabolism was noted. From these findings, the post-operative TSH suppression therapy carried out at our department is considered to be justifiable also from the viewpoint of energy metabolism.     

Thyroid-stimulating hormone, thyroid hormones, and bone loss

It has become accepted by virtue of rich anecdotal experience and clinical research that thyrotoxicosis is associated with high-turnover osteoporosis. The bone loss, primarily due to accelerated resorption that is not compensated by a coupled increase in bone formation, has been attributed solely to elevated thyroid hormone levels. Evidence using mice lacking the thyroid hormone receptors α and β establishes a role for thyroid hormones in regulating bone remodeling but does not exclude an independent action of thyroid-stimulating hormone (TSH), levels of which are low in hyperthyroid states, even when thyroid hormones are normal, as after thyroxine supplementation and in subclinical hyperthyroidism. We show that TSH directly suppresses bone remodeling and that TSH receptor null mice have profound bone loss, suggesting that reduced TSH signaling contributes to hyperthyroid osteoporosis. TSH and its receptor could become valuable drug targets in treating bone loss.     

Physiology of the pituitary, thyroid and adrenal glands

The pituitary gland is made of clusters of cells producing specific hormones that control growth (growth hormones, GH), thyroid function (TH), adrenal function (ACTH), gonadal function (FSH and LH). In addition, the neurons that join the posterior pituitary (neurohypophysis) secrete vasopressin - the antidiuretic hormone involved in maintaining water balance.The negative feedback loop is the basic mechanism to control the regulation of all endocrine glands. Hypothalamic peptides - releasing hormones (e.g. TRH, CRH) reach the hypophysis via the portal venous system and induce the secretion of specific stimulating hormones (e.g. TSH, ACTH) that drive the end-target endocrine cells to secrete hormones (e.g. thyroid hormones - T3 and T4 or adrenal hormones - cortisol, DHEAS). The plasma levels of these circulating hormones inhibit the pituitary (short feedback) or the hypothalamus (long feedback) and limit the further release of releasing- and stimulating- hormones.The effects of circulating hormones on different tissues are mediated via specific receptors on the cell membrane (e.g. vasopressin receptors), in the cytoplasm (steroid receptor for cortisol) or in the nucleus (e.g. thyroid hormone receptors). Understanding the physiological effects of peripheral hormones helps understanding the mechanisms by which clinical signs and symptoms developed in diseases characterised by excessive hormone secretion (e.g. thyrotoxicosis, Cushing syndrome, phaeochromocytomas) or lack of hormone secretion (e.g. diabetes insipidus).     

Multiple melanocortin receptors are expressed in bone cells

Melanocortin receptors belong to the seven transmembrane domain, G-protein coupled family of receptors. There are five members of this receptor family labeled MC1R-MC5R. These receptors are activated by fragments derived from a larger molecule, proopiomelanocortin (POMC) and include ACTH, alpha beta and gamma-MSH and beta-endorphin. Because of in vitro and in vivo data suggesting direct effects of these POMC molecules on bone and bone turnover, we examined bone and bone derived cells for the presence of the various members of the melanocortin receptor family. We report that the five known melanocortin receptors are expressed to varying degrees in osteoblast-like and osteoclastic cells. POMC fragments increased proliferation and expression of a variety of genes in osteoblastic cells. Furthermore, POMC mRNA was detected in osteoclastic cells. These data demonstrate that POMC-derived peptide hormones acting through high affinity melanocortin receptors have specific effects on bone cells. Thus, in addition to the indirect effects of POMC-derived hormones on bone turnover through their modulation of steroid hormone secretion, POMC fragments may have direct and specific effects on bone cell subpopulations.     

Thyroid hormone regulation of Xenopus laevis metamorphosis: functions of thyroid hormone receptors and roles of extracellular matrix remodeling

The regulatory effects of the thyroid hormone on amphibian metamorphosis is mediated by thyroid hormone receptors. Using Xenopus laevis as a model system, we and others have shown that the mRNA levels of thyroid hormone receptors and 9-cis retinoic acid receptors, which form the functional heterodimers with thyroid hormone receptors, are regulated temporally in a tissue-dependent manner so that high levels of their mRNAs are present in an organ when metamorphosis is occurring. By overexpressing thyroid hormone receptors, 9-cis retinoic acid receptors, or both into developing Xenopus embryos, we have shown that both thyroid hormone receptors and 9-cis retinoic acid receptors are required for mediating the effects of thyroid hormone on embryo development and precocious but specific regulation of the genes, which are normally regulated by thyroid hormone during metamorphosis. Analyses of the developmental expression of one class of thyroid hormone response genes, which encode extracellular matrix-degrading metalloproteinases, suggest that extra cellular remodeling plays an important role during tissue remodeling, including cell death (apoptosis) and cell proliferation and differentiation. This effect of extracellular matrix on cell behavior has been supported directly by in vitro primary cell culture experiments, in which intestinal epithelial cells undergo thyroid hormone-induced apoptosis, just like that during natural metamorphosis.     

Thyroid hormone receptor β mediates thyroid hormone effects on bone remodeling and bone mass

Excess thyroid hormone (TH) in adults causes osteoporosis and increases fracture risk. However, the mechanisms by which TH affects bone turnover are not elucidated. In particular, the roles of thyroid hormone receptor (TR) isotypes in the mediation of TH effects on osteoblast‐mediated bone formation and osteoclast‐mediated bone resorption are not established. In this study we have induced experimental hypothyroidism or hyperthyroidism in adult wild‐type, TRα‐ or TRβ‐deficient mice and analyzed the effects of TH status on the structure and remodeling parameters of trabecular bone. In wild‐type mice, excess TH decreased bone volume and mineralization. High TH concentrations were associated with a high bone‐resorption activity, assessed by increased osteoclast surfaces and elevated concentrations of serum bone‐resorption markers. Serum markers of bone formation also were higher in TH‐treated mice. TRα deficiency did not prevent TH action on bone volume, bone mineralization, bone formation, or bone resorption. In contrast, TRβ deficiency blocked all the early effects of excess TH observed in wild‐type mice. However, prolonged exposure to low or high TH concentrations of TRβ‐deficient mice induced mild modifications of bone structure and remodeling parameters. Together our data suggest that TRβ receptors mediate the acute effects produced by transient changes of TH concentrations on bone remodeling, whereas TRα receptors mediate long‐term effects of chronic alterations of TH metabolism. These data shed new light on the respective roles of TRs in the control of bone metabolism by TH. © 2011 American Society for Bone and Mineral Research     

Parathyroid hormone and calcitonin modify inositol phospholipid metabolism in fetal rat limb bones

Inositol-containing phospholipids are believed to be intimately involved in the first steps of cellular signalling by certain hormones and neurotransmitters. We examined whether parathyroid hormone (PTH) and calcitonin (CT), two hormones that affect bone physiology, would elicit changes in inositol-phospholipid metabolism in cultured bone. [3H]inositol readily entered into the tissue phospholipid pool in fetal rat limb bones, and incorporated into phosphatidylinositol (92.9%), phosphatidylinositol-4-P (4.5%), and phosphatidylinositol-4,5-P2 (2.6%). PTH enhanced the incorporation of inositol into PtdIns in limb bones following 2- or 24-h hormone treatments. The effect of PTH was dose dependent (EC50 of 0.3-0.4 nM) and occurred in a concentration range similar to that for hormone-stimulated bone resorption. In contrast, 24-h treatment with CT-inhibited inositol incorporation, also in a dose-dependent manner. Two-hour CT treatment had variable effects on labeling. CT inhibited the stimulatory effect of PTH at both 2 and 24 h. The effects induced by PTH and CT were specific for PtdIns and were independent of the [3H]inositol pool size. These results indicate that inositol-phospholipid turnover can be modified during the action of these hormones on bone tissue. Although the time course of hormone-stimulated inositol incorporation observed here is slower than that found in other tissues, the change in phosphatidylinositol metabolism could mediate delayed effects of PTH or CT. Alternatively, alterations induced by PTH and CT in bone cell membranes, cell populations, or in the mineralized matrix could conceivably result in secondary changes in phosphatidylinositol metabolism.