雌激素与雌激素受体骨代谢调节作用

雌激素缺乏是绝经后骨质疏松症发生的主要原因,雌激素或雌激素受体调节剂与雌激素受体结合后通过多种分子生物学机制,抑制破骨细胞骨吸收,促进成骨细胞骨形成、提高骨密度,达到治疗绝经后骨质疏松症的目的。本文综述了雌激素、选择性雌激素受体调节剂与雌激素受体相互作用对骨代谢的调节机制、雌激素治疗骨质疏松症的动物实验研究以及雌激素治疗骨质疏松症的临床研究进展,旨在为临床骨质疏松治疗策略提供科学依据。     

Endocrine role of bone in the regulation of energy metabolism

INTRODUCTION The skeleton constitutes up to ～15％ of the total human body weight and mainly consists of bone matrix and osteoblasts, osteoclasts, osteocytes and ...     

催产素及其受体调节骨代谢研究

催产素（oxytocin, OT）除具有调节分娩和母乳分泌的作用外,外周性OT和催产素受体（oxytocin receptor, OTR）,非中枢性,对骨骼也有直接的调节作用。骨髓间充质干细胞、成骨细胞（osteoblast,OB）、破骨细胞（osteoclast,OC）、骨细胞、软骨细胞、脂肪细胞均表达OT及OTR。OB在雌激素的刺激下,合成OT,并成为骨形成的旁分泌-自分泌调节剂。在雌激素的介导之下,OT/OTR与OB形成前馈环路。骨保护素(osteoclastogenesis inhibitory factor, OPG)/核因子κB受体活化因子配体（receptor activator of nuclear factor-κB ligand, RANKL）信号通路是OT及OTR发挥抗骨质疏松（osteoporosis, OP）作用的关键通路。OT通过上调骨形成蛋白,下调骨吸收标志物水平,进而提高骨髓间充质干细胞活性,促进其向OB方向而非脂肪细胞方向分化。OT通过促进OTR易位到OB的细胞核中,诱导OB的矿化。OT通过触发胞浆内Ca2+释放和一氧化氮的合成,调节OB中OPG/RANKL的比例,对破骨细胞具有双向的调节作用。此外,OT同样能够提高骨细胞和软骨细胞的活性,并在提高骨量,改善骨显微结构方面具有重要的作用。基于OT和OTR具有抗OP的良好作用,本文对近年来OT及OTR调节骨代谢的研究进行综述,以期为其临床应用与研究提供参考。     

Effect of calcitonin on bone histomorphometry and bone metabolism in rheumatoid arthritis

Summary Twenty-four women (mean age±SD 49±13 years) with classical or definite rheumatoid arthritis (disease duration 15±8 years) were treated with synthetic salmon calcitonin (SCT) nasal spray 200 IU three times a week for 3 months. Bone biopsies from the iliac crest were taken before and after SCT treatment. Histomorphometrical quantification of undecalcified bone sections was made using the manual point-counting method. SCT decreased the resorption surface of trabecular bone (ES/BS) significantly (P< 0.001). There was also a significant increase (P< 0.05) in trabecular bone volume (BV/TV) after 3 months of treatment, whereas no statistically significant changes were found in osteoid parameters. There were no significant changes in biochemical analyses of bone metabolism. We conclude that SCT might be useful in the prevention of bone loss in RA.     

降钙素基因多肽对骨代谢的影响

根据骨质疏松的发病机制不同,可分为原发性骨质疏松和继发性骨质疏松,原发性骨质疏松又可分为绝经性骨质疏松和老年性骨质疏松。骨质疏松是由多种发病因素共同作用的结果,在各型骨质疏松中,降钙素均发挥重要的调节作用。近年研究发现某些神经、血管活性肽,如降钙素基因多肽(Calcitonin gene-related peptide,CGRP）,在结构和功能上与降钙素具有一定的相似性。本文将降钙素基因多肽对骨代谢影响的相关研究进展作以下综述。     

The effect of high-dose salmon calcitonin on bone mineral metabolism in the normal rat

Summary The paucity of information on the effect of long-term high-dose salmon calcitonin administration on normal bone mineral metabolism and histology prompted an investigation of the influence of high-dose synthetic calcitonin in the rat. Serum ionized calcium, osteocalcin or BGP (bone gla protein), and immunoreactive PTH were measured serially during calcitonin administration and bone histomorphometry analyzed at 6 weeks (after sacrifice). Daily injections of salmon calcitonin, 0.4 IU/100 g (group B) and 2 IU/100 g (group C), resulted in significant hypocalcemia at 4 hours for both experimental groups (P<0.004). Serium iPTH was significantly higher over the study period for both groups administered calcitonin. Serum BGP levels were significantly lower than controls during the study in group C (P<0.002) and to a lesser extent in group B (P<0.05). In group C, bone histomorphometry revealed increased resorption (onteoclast count), decreased trabecular bone volume, and decreased double-labeled tetracycline surface (bone formation). In group B an increase in osteoclast count but no alteration in bone formation was observed. To assess the role of PTH in the above findings, high-dose calcitonin was administered to parathyroidectomized rats. All of the above changes in bone histomorphometry were not observed in this group of animals. In conclusion, high doses of calcitonin promote hypocalcemia, secondary hyperparathyroidism, and osteoclastosis in the normal rat in a dose-dependent manner with very high-dose calcitonin impairing bone formation.     

瘦素在骨与软骨代谢中的作用

肥胖对机体健康的不良影响已得到越来越多的重视,但人们在研究和防治肥胖的同时,也发现肥胖对骨骼有保护作用:肥胖者很少患有骨质疏松症,髋部骨折的发生率也较低[1]。体重或体重指数(BMI)与骨密度(BMD)的相关性已经得到公认,许多研究进一步证明体重的重要组成部分———体脂量(     

The role of apolipoprotein E in bone metabolism

Apolipoprotein E (apoE) is a major structural apolipoprotein of several lipoprotein classes. Over the last 13 years, numerous studies have focused on the question whether human apoE affects bone phenotypes and, more recently, whether apoE regulates bone metabolism in mice. Here, we first provide a brief background introduction into the structure, established physiological and pathophysiological functions of apoE, and will then discuss the new aspects of the emerging role of apoE in bone.     

The role of bone marrow and visceral fat on bone metabolism

The protective effect of total fat mass on bone mineral density (BMD) has been challenged with studies showing no or negative association after adjusting for weight. Subsequently, more studies have evaluated the relationship of regional adiposity with BMD, and findings were inconsistent for central obesity. Advancements in imaging techniques enable us to directly and noninvasively study the role of adiposity on skeletal health. Visceral adiposity measured by computed tomography (CT) has consistently been shown to have negative effects on bone. Availability of magnetic resonance spectroscopy (MRS) also allows us to noninvasively quantify bone marrow fat (BMF), which has been known to be associated with osteoporosis from histomorphometric studies. Using MRS along with dual energy x-ray absorptiometry, studies have reported a detrimental role of BMF on BMD. With the increase in aging and obesity of the population, it is important to continue this effort in identifying the contribution of adipose tissues to bone quality and fracture.     

云克对绝经后骨质疏松骨代谢调节的作用

目的评价云克对骨代谢调节的作用。方法选择明确诊断的绝经后骨质疏松患者113例,监测云克治疗前及治疗后9个月血清骨特异性碱性磷酸酶（BALP）、骨钙素（BGP）、肿瘤坏死因子（TNF-α）、白细胞介素1（IL-1）、白细胞介素6（IL-6）、雌二醇（E2）及骨密度（BMD）的变化。结果治疗前绝经后骨质疏松患者BMD及E2明显降低（P〈0.01）。IL-1、IL-6、BALP、BGP明显升高（P〈0.01）。TNF-α高于正常对照组（P〈0.05）。治疗后9个月,IL-1、IL-6、BALP、BGP较治疗前明显下降（P〈0.01）,BMD增加（P〈0.05）,E2无明显变化。结论云克对骨生成区具有明显的导向性,进入骨组织参与骨代谢调节,具有抑制破骨细胞活性,抑制骨丢失,增加BMD的作用。     

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.     

The regulation of osteoblast function and bone mineralisation by extracellular nucleotides: The role of p2x receptors

Extracellular nucleotides, signalling through P2 receptors, regulate the function of both osteoblasts and osteoclasts. Osteoblasts are known to express multiple P2 receptor subtypes (P2X2,5,7 and P2Y(1),(2,4,6)), levels of which change during differentiation. ATP and UTP potently inhibit bone mineralisation in vitro, an effect mediated, at least in part, via the P2Y(2) receptor. We report here that primary rat osteoblasts express additional, functional P2 receptors (P2X1, P2X3, P2X4, P2X6, P2Y(12), P2Y(13) and P2Y(14)). Receptor expression changed with cellular differentiation: e.g., P2X4 receptor mRNA levels were 5-fold higher in mature, bone-forming osteoblasts, relative to immature, proliferating cells. The rank order of expression of P2 receptor mRNAs in mature osteoblasts was P2X4>P2Y(1)>P2X2>P2Y(6)>P2X1>P2Y(2)>P2Y(4)>P2X6>P2X5>P2X7>P2X3>P2Y(14)>P2Y(13)>P2Y(12). Increased intracellular Ca(2+) levels following stimulation with P2X-selective agonists indicated the presence of functional receptors. To investigate whether P2X receptors might also regulate bone formation, osteoblasts were cultured for 14days with P2X receptor agonists. The P2X1 and P2X3 receptor agonists, α,β-meATP and β,γ-meATP inhibited bone mineralisation by 70% and 90%, respectively at 1μM, with complete abolition at ≥25μM; collagen production was unaffected. Bz-ATP, a P2X7 receptor agonist, reduced bone mineralisation by 70% and 99% at 10μM and 100μM, respectively. Osteoblast alkaline phosphatase activity was similarly inhibited by these agonists, whilst ecto-nucleotide pyrophosphatase/phosphodiesterase activity was increased. The effects of α,β-meATP and Bz-ATP were attenuated by antagonists selective for the P2X1 and P2X7 receptors, respectively. Our results show that normal osteoblasts express functional P2X receptors and that the P2X1 and P2X7 receptors negatively regulate bone mineralisation.     

Acute effects of nasal salmon calcitonin on calcium and bone metabolism

Summary Effects of a single dose of 200 IU of nasal salmon calcitonin (SCT) on calcium metabolism and biochemical markers of bone turnover were investigated in 12 healthy male volunteers in a randomized, placebo-controlled, crossover design. The nasal spray was given in the morning, and subsequently blood and urine samples were collected for 26 hours. There was a significant decrease in serum ionized calcium with a nadir 4 hours after administration of nasal SCT accompanied by a significant increase in serum parathyroid hormone (P = 0.01) and serum calcitriol (P = 0.04). Nasal SCT did not reduce urinary hydroxyproline/creatinine. Urinary deoxypyridinoline/creatinine was lowered significantly 2 hours after administration of nasal SCT and throughout the first 24 hours, but remained unchanged for the last 2 hours. On a 24-hour basis, urinary deoxypyridinoline/creatinine decreased from 14.1 (3.5) nmol/mmol to 11.7 (3.2) nmol/mmol after nasal SCT (P = 0.04). Nasal SCT did not change the serum levels of alkaline phosphatase, osteocalcin, and the carboxyterminal propeptide of type 1 procollagen. The results indicate that nasal SCT given as a single dose provokes a modest decrease in bone resorption lasting several hours, but leaves bone formation unaffected.     

核受体信号在脂类代谢中的调控作用

核受体是配体依赖性转录因子超家族,对脂类代谢基因有重要的转录调控作用,与许多代谢性疾病密切相关,近年来,国内外对核受体在脂类代谢中调控作用的广泛研究,有助于进一步加深对胆固醇结石病等与脂类代谢相关疾病的发病机制认识.     

Fluoride,parathyroid hormone and calcitonin: Inter-relationships in bone calcium metabolism

The influence of fluoride, parathyroid hormone and calcitonin on bone calcium metabolism was investigated in a bone culture system using half-calvaria of five-day old mice. Fluoride levels in the ash of half-calvaria of 0.007% (low fluoride group), 0.041% (moderate fluoride group), and 0.107% (high fluoride group) were achieved by varying the maternal and neonatal intake of fluoride. Fluoride inhibited the loss of calcium from bones cultured in control medium and parathyroid hormone-containing media, and promoted the uptake of calcium by bones cultured in medium containing calcitonin. Dead bones of the moderate and high fluoride groups took up more calcium from the culture medium than bones of the low fluoride group. Fluoride appears to exert its effect on bone calcium metabolism predominantly via a reduction in mineral solubility.Supported by Grant No. DE-01850, National Institute of Dental Research, Bethesda, Maryland.     

AMPK信号通路对骨代谢的调节作用

最近越来越多的证据显示骨质疏松症可能与肥胖症类似,也与能量代谢紊乱相关。而腺苷酸活化蛋白激酶(AMPK)是维持细胞能量平衡以及调节多种代谢相关激素的重要分子,AMPK激活后可以开启分解代谢通路以产生更多的ATP,同时会关闭合成代谢通路以减少ATP的消耗。已知AMPK不仅能被脂肪细胞分泌的脂联素和瘦素激活,还能被抗糖尿病类药物二甲双胍和噻唑烷二酮类激活,而这些脂肪因子和药物都能影响骨代谢,同时最近的研究也表明AMPK信号通路对骨代谢有调节作用。体外激活AMPK可以影响成骨,基因敲除AMPKα或β亚基会使小鼠骨量降低,骨形成和骨吸收同时增加但伴有骨重建的负平衡,但是其中涉及的具体机制并不明确。本文就AMPK的结构和功能、在骨组织细胞中的作用、与成骨成脂分化平衡的关系作一综述,并分析AMPK通路作为骨质疏松症潜在治疗靶点的可能性。     

Runx2基因对骨代谢调控的研究进展

人体骨代谢是一个复杂的过程,是破骨细胞（ osteoclast ,OC）吸收旧骨和成骨细胞（ osteoblast ,OB）形成新骨的动态平衡的过程。 Runx2（core binding factor alphal 1,核心结合因子a1）是调控成骨细胞和破骨细胞的分化促进骨形成的关键调控因子,通过调控成骨细胞特异性细胞外基质蛋白基因的表达和成骨细胞周期参与成骨细胞的分化过程,促进骨形成和抑制骨吸收。本文就Runx2在骨代谢中的作用作一综述。