血管生成在骨代谢及骨质疏松症中的作用研究进展

目前,骨质疏松症(OP)的防治主要集中于抑制骨吸收,但其局限性已显现。近年文献报道,血管生成与OP关系密切,而且发现血管生成与骨代谢间存在特定的\"耦合\"关系。血管生成,尤其是H型血管,可能通过影响骨形成、骨吸收及骨重塑进程的方式,在OP发生、发展及防治过程中发挥着重要的调节作用。本文重点梳理血管生成与骨代谢和OP之间的关系,可更全面、系统地认识OP,为其防治研究提供新的思路和理论支撑。     

Rev-erbs基因在骨代谢中的作用

骨代谢相关疾病在我国十分常见,但骨代谢的分子机制仍未完全研究清楚。近年发现Rev-erbs基因参与骨代谢过程并可能起重要作用。Rev-erbs是核受体基因,被受体激活后可以调节基因转录。多项实验结果提示该基因很可能同时参与成骨和破骨作用,对该基因的深入研究有望进一步阐明骨代谢的分子机制,为治疗临床相关疾病提供新的思路和靶点。本文对近年来Rev-erbs在骨代谢方向的相关研究进行综述,以对今后相关研究提供参考。     

神经肽与骨代谢

含神经肽的神经称为肽能神经,肽能神经在骨组织中分布广泛,以代谢活跃的部位如骨膜、骨骺、干骺端等最多,所分泌的神经肽对骨吸收和骨形成的平衡有重要的调节作用。     

骨代谢调控的垂体-骨轴机制

近年来,垂体激素包括促甲状腺激素、FSH、促肾上腺皮质激素以及催产素等,相继被发现对骨代谢具有直接的调控作用.这一发现打破了垂体激素是通过作用于靶内分泌腺间接对骨代谢进行调节的传统观念,从而提出了骨代谢调控的垂体-骨轴(pituitary-bone axis)新概念.这些突破性研究进展使人们对垂体激素的功能有了全新的了解,并且对甲亢、绝经、妊娠等引起的骨质疏松症以及糖皮质激素引起的骨坏死的发病机制有了更深的认识,为相关骨代谢疾病的防治以及新药研发提供了新的科学思路和理论基础.

Abstract：

Recent studies have shown that pituitary hormones, including thyroid stimulating hormone (TSH), follicle stimulating hormone(FSH), adrenocorticotropic hormone(ACTH), and oxytocin(OT)may actually bypass their target endocrine organs and affect the skeleton directly. Therefore, a new conception, pituitary-bone axis is proposed. This breakthrough sheds a new light on the function of pituitary hormones and the pathogenesis of osteoporosis associated with hyperthyroidism, menopause or pregnancy, and even osteonecrosis after using glucocorticoids. In addition, it is conducive to give the reference guidance for clinical treatment of metabolic bone diseases and new drug development.     

骨内细胞凋亡与骨质疏松症

骨内细胞凋亡，包括破骨细胞、成骨细胞和骨细胞的凋亡，与骨质疏松症发病机制和药物治疗有着密切的关系，本文综述了这一研究热点的最新进展。     

神经肽与骨代谢

含神经肽的神经称为肽能神经 ,肽能神经在骨组织中分布广泛 ,以代谢活跃的部位如骨膜、骨骺、干骺端等最多 ,所分泌的神经肽对骨吸收和骨形成的平衡有重要的调节作用     

雌激素α受体、β受体与骨代谢研究进展

研究结果表明雌激素在骨质疏松症中的作用是通过雌激素受体（ER）调节骨代谢实现的。1988年Komm在成骨细胞中发现了雌激素受体．1990年Penlser又在破骨细胞中发现了雌激素受体，都证明了雌激素受体对骨细胞的直接作用。1993年第一例ERKO（Estrogen Receptor Knock Out）动物模型的问世．进一步明确了雌激素受体基因在骨代谢中的重要性。本文就雌激索受体亚型在骨代谢中的不同作用做一综述。     

环氧合酶-2在骨代谢中的研究进展

环氧合酶-2(COX-2)是一种诱导酶,在正常情况下,体内仅表达微量COX-2,当机体受到致炎因子刺激时,某些细胞如单核-巨噬细胞、血管平滑肌细胞、内皮细胞等将被诱导产生大量COX-2,并催化合成大量促炎性前列腺素.以往被认为与炎症、发热和肿瘤等有密切关系,近年研究发现其在骨骼重建、骨质吸收以及成骨细胞转导等过程中扮演着重要角色.     

外泌体在骨代谢中的作用

外泌体是多种细胞在生理或病理状态下主动分泌到细胞外的纳米级囊泡,富含蛋白质、核酸、脂质等生物活性物质,参与细胞间信息交流与传递.目前已有研究表明,外泌体能通过信号蛋白、miRNAs等调控成骨细胞、破骨细胞及骨髓间充质干细胞的增殖、分化,介导骨生成和骨吸收过程,在多种骨代谢疾病的发生、发展中起重要作用.     

整合素在骨质疏松症治疗中的研究进展

整合素的表达水平与破骨细胞、成骨细胞的分化、成熟及功能均有密切关系。破骨细胞表面高度表达整合素αvβ3，大多数细胞外基质蛋白通过RGD序列与αvβ3结合，促破骨细胞分化、成熟。抗αvβ3单抗、模拟RGD序列的肽类物质可竞争基质蛋白与αvβ3的结合，治疗骨质疏松；通过诱导整合素基因的表达，可促进骨形成。     

脂联素与骨代谢

脂肪细胞分泌多种生物活性分子,统称脂肪细胞因子。脂联素是新近发现的由脂肪细胞分泌的胶原样蛋白质。近年的研究表明,脂联素及其受体可在成骨细胞表达,脂联素呈剂量与时间依赖方式诱导p38丝裂原活化蛋白激酶(MAPK)及c-Jun氨基末端激酶(JNK)的活性,促进成骨细胞的增殖与分化,影响破骨细胞的分化与活性。对脂联素的深入研究有助于进一步了解肥胖与骨代谢之间的关系,为同时防治骨质疏松与动脉硬化提供新思路。     

促甲状腺激素对骨代谢的影响

随着人口老龄化,骨质疏松发病率逐年增加.近年来内分泌性骨质疏松日见增多,促甲状腺激素(TSH)及促甲状腺激素受体(TSHR)与骨量减少、骨质疏松的关系备受关注.动物实验和临床研究发现TSH对骨代谢有独立于甲状腺激素的作用.成骨细胞和破骨细胞上的TSHR起关键作用.研究发现,TSH可以抑制破骨细胞分化和细胞活化,而对成骨细胞的作用尚有争议.     

骨质疏松症治疗新进展

骨转换失衡是骨质疏松症发病的重要病理机制,骨质疏松症的治疗靶点主要集中在抑制破骨细胞活性及增强成骨细胞活性.新型骨吸收抑制剂包括核因子-kB受体活化因子配体(RANKL)的单克隆抗体、组织蛋白酶K抑制剂、新型选择性雌激素受体调节剂、口服降钙素等;新型骨形成促进剂有骨硬化素单克隆抗体、Dickkopf-1单克隆抗体、甲状旁腺激素(PTH)制剂及钙敏感受体拮抗剂等.此外,含有维生素D的复方制剂也是很有应用前景的骨质疏松治疗新药.     

骨质疏松症治疗新进展

骨转换失衡是骨质疏松症发病的重要病理机制,骨质疏松症的治疗靶点主要集中在抑制破骨细胞活性及增强成骨细胞活性。新型骨吸收抑制剂包括核因子-κB受体活化因子配体（RANKL）的单克隆抗体、组织蛋白酶K抑制剂、新型选择性雌激素受体调节剂、口服降钙素等;新型骨形成促进剂有骨硬化素单克隆抗体、Dickkopf-1单克隆抗体、甲状旁腺激素（PTH）制剂及钙敏感受体拈抗剂等。此外,含有维生素D的复方制剂也是很有应用前景的骨质疏松治疗新药。     

慢性阻塞性肺疾病患者骨代谢研究进展

COPD是一种以气流持续受限为特征的慢性呼吸系统疾病,其患病率、致残率、病死率高.骨质疏松是以骨量减少、骨结构退化和骨折风险增加的骨代谢性疾病,是COPD的重要合并症之一,但在临床中常被忽视.当COPD合并骨折时,可引起患者肺功能下降、急性加重频率及病死率增加,因此及早诊治COPD合并的骨质疏松能有效预防骨折的发生,改善患者预后.因此,早期发现、早期诊治骨质疏松,预防骨质疏松相关的骨折对于COPD患者具有重要意义.     

Bone structure and metabolism in a rodent model of male senile osteoporosis

Osteoporosis is a common and severe condition in elderly men, which is poorly characterized. In order to identify the hallmarks of age-related bone loss in the male mammalian skeleton, we studied several aspects of bone structure and metabolism in 23-month-old male Sprague-Dawley rats and compared them to 5-month-old animals. Cancellous bone mineral density, bone volume and trabecular number were markedly reduced in the proximal tibia of aged rats when compared to the young rats. An increase in bone matrix material density indicating a reduced deposition of new bone matrix was seen. Also, serum levels of osteocalcin, a marker of bone formation, were reduced in old males. The decreased bone formation could in part be linked to the decreased serum insulin-like growth factor 1 (IGF-1) levels which were observed in these animals. Serum levels of RatLaps (c-terminal telopeptide of type I collagen) were increased. Interestingly, an ex vivo osteoclast generation assay revealed that bone marrow from aged rats formed fewer osteoclasts than that from young rats. Consistent with this observation, serum levels of soluble RANKL, a critical osteoblast derived factor for osteoclastogenesis, were decreased in aged rats and RANKL mRNA expression was slightly reduced in bone marrow cells. Elevated leptin and adiponectin levels present in these animals could have contributed further to impaired osteoclastogenesis. We conclude that aged male rodents are characterized by a severely diminished cancellous bone network and a bone turnover situation in which bone formation is decreased to such an extent that it is outweighed by bone resorption, despite a blunted osteoclast generation potential of the bone marrow.     

Effect of parathyroidectomy on osteoporosis and bone metabolism

The presentation of patients with hyperparathyroidism has changed over the past decades with the routine use of multichannel serum electrolyte analyzers. Serum calcium abnormalities rather than overt symptoms prompt the evaluation for suspected hyperparathyroidism. It is rare to see a patient with cystic bone changes; instead it is more common to have subtle bone loss identified in the evaluation of bone mineral density. Parathyroidectomy is recommended in patients with osteoporosis. Since the effect of parathyroid hormone on bone is complex, the changes in bone metabolism following parathyroidectomy and the effect of parathyroidectomy on fracture risk are important factors to consider. Studies have yielded conflicting results regarding the questions of bone density and fracture risk, limited by small sample size and short follow-up periods. Recent investigations describe a subset of patients with bone disease that may benefit from early surgical intervention.     

二肽基肽酶4抑制剂对骨代谢影响的研究进展

DM患者患骨质疏松症的患病风险较高。二肽基肽酶4(DPP-4)广泛表达于全身组织器官。DPP-4抑制剂通过诱导间充质干细胞分化、减少AGEs聚集、增加IGF-1自分泌、抑制炎症因子表达、延长GLP-1及葡萄糖依赖性促胰岛素分泌多肽半衰期、促进APN分泌、改善维生素D水平、降低硬骨素水平等途径,对骨代谢产生一定影响。本文对DPP-4抑制剂对骨代谢的研究进展进行综述,旨在为临床治疗DM合并骨质疏松症提供依据。     

The role of extracellular modulators of canonical Wnt signaling in bone metabolism and diseases

Objectives

The Wnt signaling pathway is a key pathway in various processes, including bone metabolism. In this review, current knowledge of all extracellular modulators of the canonical Wnt signaling in bone metabolism is summarized and discussed.

Methods

The PubMed database was searched using the following keywords: canonical Wnt signaling, β-catenin bone metabolism, BMD, osteoblast, osteoporosis, Wnt, LRPs, Frizzleds, sFRPs, sclerostin or SOST, dickkopfs, Wif1, R-spondins, glypicans, SOST-dc1 and kremen, all separately as well as in different combinations.

Results

Canonical Wnt signaling is considered to be one of the major pathways regulating bone formation. Consequently, a large number of studies were performed to elucidate the role of numerous proteins in canonical Wnt signaling and bone metabolism. These studies led to the identification of novel modulators of the pathway like the R-spondin and glypican protein families. Furthermore novel insights are gained in the regulatory role of the different Wnt proteins. Finally, due to its function in bone formation, the pathway is an interesting target for the development of therapeutics for osteoporosis and other bone diseases. In this review, we discuss the promising results of the Wnt modulators sclerostin, Dkk1 and sFRP1 as targets for osteoporosis treatment.

Conclusion

The increasing number of studies into the exact function of all proteins in the canonical Wnt pathway in general and in bone metabolism already led to novel insights in the regulation of the canonical Wnt pathway. In this review we covered the current knowledge of all extracellular modulators of canonical Wnt signaling.