Hedgehog信号通路与骨质疏松症

Hedgehog信号通路是一条保守而重要的信号通路,涉及到多种细胞的增殖和分化活动。近年研究发现,Hedgehog信号通路可以通过上调Runx2和Osx等主要转录因子的表达促进间充质干细胞（mesenchymalstemcells,MSCs）向成骨细胞分化,并且抑制MSCs向脂肪细胞分化。Hedgehog信号通路还可以通过调节细胞周期蛋白促进成骨细胞增殖。本文综述总结了Hedgehog信号通路调节成骨细胞增殖分化的作用机制,认为Hedgehog信号通路通过促进成骨细胞增殖分化参与调节骨代谢,为骨质疏松症的治疗提供一种新思路。     

Hedgehog信号通路在风湿病中的研究进展

刺猬(Hedgehog,Hh)信号是一条在脊椎动物胚胎发育和组织调控中起重要作用的信号通路.综述近年来相关研究发现,Hh信号通路失调与风湿病的发生发展密切相关,并在调节细胞功能、影响炎症因子、调控骨代谢等方面取得了一定成效,为该信号在风湿病基础研究及临床应用方面提供一定思路.但深入研究及临床应用仍十分有限,期待更进一步...     

SOX9家族在软骨细胞生命周期的调控作用

构成肢体的大部分骨骼是经软骨内骨化的方式发生的,从骨髓间充质干细胞分化为成熟软骨细胞的过程中,众多转录因子参与了调控,其中SOX9家族发挥着重要的调节作用.SOX9通过与DNA特定区域结合,促进问充质细胞聚集,维持软骨细胞增殖,抑制其向肥大软骨细胞分化.L-SOX5,SOX6共同参与了SOX9调控的软骨内成骨过程,起协同作用.本文就这三种SOX蛋白参与的软骨内调控WOE制及作用进行综述.     

Hedgehog信号通路调控骨形成探讨中药防治骨质疏松症的研究进展

Hedgehog信号通路是一种高度保守而重要的信号通路,参与多种细胞的增殖和分化。骨质疏松症是一种常见的以骨量减少、骨组织微结构破坏为特征,导致骨质脆性增加和易于骨折的全身性骨代谢疾病,给社会造成了巨大的负担。骨质疏松症的发生发展受多种信号通路调控。近年来,国内外研究发现,Hedgehog通路是一个很有前途的参与骨形成和骨稳态的信号通路。已有研究证实,Hedgehog信号通路可能通过增加骨形成相关因子的表达,诱导骨髓间充质干细胞成骨分化,促进成骨细胞增殖分化,对防治骨质疏松症具有重要意义。本文综述了目前Hedgehog信号通路在骨形成调节中的作用机制及中医药的干预作用,旨在为促进骨形成、防治骨质疏松症提供新的作用靶点。     

RhoA信号通路在软骨细胞生长发育中的作用

RhoA信号通路在软骨细胞中起着重要作用,它既能通过调控软骨细胞内肌动蛋白聚合状态调节软骨细胞增殖,又能参与维持软骨细胞极性、细胞形态,调节软骨细胞分化,促进软骨弹性纤维生成等过程,同时也可与其他信号通路相互作用,共同调节软骨细胞生长发育。该文就RhoA结构功能及其信号通路在软骨细胞生长发育中的作用作一综述。     

Hedgehog信号通路在肝癌发生发展中的生物学作用

原发性肝癌居所有常见恶性肿瘤第6位,死亡率高居第3位[1-3]。我国肝癌发病率为28.71/105,占所有恶性肿瘤的第4位(10.04%);死亡率居第2位(14.42%)[4]。由于肝癌发病隐匿、早期诊断困难、癌细胞生长迅速等特点,导致大多数病人确诊时已属晚期,手术切除率<30%[5]。目前临床应用的化疗、消融及肝动脉栓塞术等治疗具有一定的适应证,肿瘤残留与复发严重影响疗效。因此,深入研究肝癌发生、发展的     

Hedgehog信号通路在激素性股骨头坏死作用机制中的研究进展

糖皮质激素的不正确使用导致股骨头内骨代谢异常、脂代谢失衡、血微循环障碍是激素性股骨头坏死发生、发展的重要原因之一。Hedgehog通路作为一条高保守信号通路,在组织器官骨骼的形成发育以及疾病过程中有着重要调控作用。近年来,随着精准医学的进一步发展以及对于细胞和分子生物学的广泛深入研究,发现Hedgehog信号通路可以通过促进骨髓间充质干细胞成骨分化,抑制脂肪细胞的生成,加速血管内皮细胞的新生对激素性股骨头坏死进行有效的靶向调控。现以Hedgehog信号通路在激素性股骨头坏死病理机制中发挥的调控作用进行综述,以期为临床治疗激素性股骨头坏死提供精确的靶点。     

Hedgehog信号通路在肾间质纤维化中作用的研究进展

肾间质纤维化是慢性肾脏病进展的共同通路。Hedgehog信号通路的激活在其中的作用和在胚胎肾脏发育中的作用似乎一样重要。近年研究发现,异常活化的Hedgehog信号通路与肾间质纤维化发生、发展有着密切联系,降低Hedgehog信号的活化可能是治疗肾间质纤维化的新策略,有望降低慢性肾脏疾病的进展。本文综述Hedgehog信号通路的组成成份和调节,并着重讨论其在肾脏纤维化中的作用。     

Hedgehog信号通路在缺氧肠上皮屏障功能调控的作用

目的 探讨Hedgehog(Hh)信号通路在缺氧肠上皮屏障功能调控的作用.方法 大鼠小肠上皮细胞系IEC-6细胞分为3组:常氧组(21％氧浓度)、缺氧组(2％氧浓度)、缺氧+环巴胺组(用5 mmol/L的环巴胺预处理30 min后,再给予2％氧浓度进行缺氧处理).RT-PCR检测Hh信号通路IHH、PTCH、GLI-1 mRNA的表达变化,电阻测定仪检测跨上皮电阻(TER),Western blot检测IHH、紧密连接蛋白经典表达分子胞质附着蛋白(ZO-1)、咬合蛋白(Occludin)、闭合蛋白(Claudin-1)的表达情况.组间比较采取单因素方差分析,两两比较采用LSD-t检验.结果 RT-PCR检测结果表明:常氧组Hh信号通路IHH、PTCH、GLI-1 mRNA的相对表达量分别为0.056±0.009、0.459±0.087、0.142±0.023;缺氧组分别为0.303±0.052、0.678±0.073、0.483±0.061,两组比较,差异有统计学意义(t=-14.05,-11.85,-6.52,P＜0.05).Western blot检测结果显示:常氧组和缺氧组的IHH相对蛋白表达量分别为0.39±0.06和0.91±0.15,两组比较,差异有统计学意义(t=-8.08,P＜0.05).常氧组、缺氧组和缺氧+环巴胺组的TER分别为(134±5) Ohm/cm2、(100±6)Ohm/cm2、(118±5)Ohm/cm2,3组比较,差异有统计学意义(F=1.04,P＜0.05).与常氧组比较,缺氧组下降约27.7％(t=7.84,P＜0.05);与缺氧组比较,缺氧+环巴胺组回升约16.4％,但仍低于常氧组(t=4.23,P＜0.05).常氧组胞质附着蛋白-1、咬合蛋白、闭合蛋白-1的表达分别为1.18±0.24、0.80 ±0.13、0.90±0.09,缺氧组分别为0.58±0.08、0.32±0.05、0.50±0.09,缺氧+环巴胺组分别为0.92 ±0.21、0.43 ±0.10、0.82±0.11,3组比较,差异有统计学意义(F=4.95,2.88,10.09,P＜0.05).缺氧组较常氧组分别降低48.7％、40.0％、55.6％(t=12.86,9.35,18.90,P＜0.05);缺氧+环巴胺组较缺氧组分别提高59.9％、35.2％、65.1％(=5.63,2.92,6.66,P＜0.05).结论 缺氧条件可刺激激活Hh信号通路,从而引起紧密连接蛋白表达降低,导致肠上皮屏障功能损害.     

Expression of Indian Hedgehog During Fracture Healing in Adult Rat Femora

Indian hedgehog (Ihh) has recently been shown to be expressed in prehypertrophic and hypertrophic chondrocytes during embryonic development, and it has been implicated in the regulation of terminal differentiation of chondrocytes. In this paper we examined the expression of Ihh during fracture healing in an adult rat model. A transverse diaphyseal fracture was made in the right femur, and the expression of Ihh in the fracture callus was examined at 1, 2, and 3 weeks after fracture. Northern blot analysis demonstrated the expression of Ihh mRNA in these tissues. Immunohistological analysis detected hedgehog protein in prehypertrophic chondrocytes in the fracture callus at 1 week after fracture. From 2 weeks and on, positive staining was observed in hypertrophic chondrocytes as well. At 3 weeks, some of the osteoblasts close to the endochondral ossification front were also stained positive for hedgehog protein. Our data indicate that Ihh is expressed in chondrocytes and osteoblasts during the process of fracture healing in adult rat femora, suggesting that Ihh, a regulator of endochondral ossification in embryonic development, may also play a role in the regulation of bone formation during fracture repair in adult animals. Received: 29 March 1999 / Accepted: 30 September 1999     

Action of Estradiol on Epiphyseal Growth Plate Chondrocytes

Estrogen plays an important role in the human growth plate by accelerating growth and promoting epiphyseal fusion in both sexes. Nevertheless, the precise mechanisms responsible for these effects are poorly understood. In the present study, we examined the role of 17-estradiol (E2) on cell proliferation and viability, type X collagen synthesis, alkaline phosphatase activity, and matrix calcification in primary cultures of resting, proliferating, and prehypertrophic chondrocytes derived from explants of the bovine fetal epiphyseal growth plate. Growth plate chondrocytes were isolated and separated into maturationally distinct subpopulations, which were cultured for 7–21 days to high density in either (1) serum-free medium, (2) 1 nM thyroid hormone (T₃), (3) E2 concentrations ranging from 10^–13 M to 10^–7 M, or (4) a combination of T₃ and E2. To compare E2 effects in both sexes, chondrocytes were harvested from 8 fetuses of both sexes. After hormone treatment, cell cultures were analyzed for cell number and viability, collagen type X, alkaline phosphatase (ALP), and matrix calcification. Neither DNA content nor cell viability were affected by the duration or type of hormone treatment. By itself, E2 stimulated maturation of all subpopulations only in pharmacologic doses (10^–7 M). Physiologic E2 concentrations were no different than negative controls treated with ITS (insulin, transferrin, and selenite). Regardless of E2 concentrations, the addition of E2 to 1 nM T₃ did not appreciably affect the response to T₃ alone, which stimulates maturation of the phenotype. All effects were comparable in both male and female chondrocytes, in all cell subpopulations (maturation stages) and fetuses of varying gestational age. These findings indicate that at physiologic concentrations, the effects of E2 on fetal bovine growth plate chondrocyte appear to be indirect and independent of T₃, suggesting that, in vivo, E2 acts in concert with other factors or hormones to induce fusion of the growth plate.     

缺血再灌注对大鼠部分肝切除术后肝脏Hedgehog信号的影响

目的 观察缺血再灌注对大鼠部分肝切除术后肝脏Hedgehog (Hh)信号的影响.方法 切除肝脏左叶和中叶以建立SD大鼠部分肝切除模型.18只雄性SD大鼠随机均分为3组:假手术组(A)、部分肝切除术组(B)、部分肝切除术+缺血再灌注组(C).A、B和C组于术后48 h取血液和肝组织,检测血浆谷丙转氨酶(ALT)和肝组织细胞核抗原(Ki-67)、Sonic hedgehog(Shh),Indian hedgehog(Ihh)和脑胶质瘤相关的致癌基因2(Gli-2)的表达.结果 C组ALT浓度高于A和B组(P＜0.01),B组ALT浓度高于A组(P＞0.05).苏木素-伊红(HE)染色显示B组可见较多肝细胞脂肪变性和少数处于不同分裂期的肝细胞;C组可见较多肝细胞脂肪变性和多数处于不同分裂期的肝细胞.B、C组Ki-67、Shh和Ihh、Gli-2表达高于A组(P＜0.01),C组高于B组(P＜0.05).结论 大鼠部分肝切除术后Hh信号通路可能被激活,从而促进肝脏再生修复.肝脏缺血再灌注可能促进部分肝切除术后Hh信号通路的激活.     

兔髂骨骺板软骨细胞体外构建骺板样软骨组织

目的　利用组织工程学技术体外构建骺板样软骨组织。方法　从 4～ 5周龄兔髂骨骺板软骨处获取软骨细胞 ,在离心管内轻微离心后 ,体外培养。行组织学观察。结果　培养至第 7天时 ,细胞呈现定向分化 ,形态与体内骺板软骨细胞相类似 :肥大软骨细胞体积较大、呈圆形或椭圆形 ;增殖、成熟软骨细胞体积小 ,呈圆形或扁圆形 ;细胞周围充满大量的细胞外基质。这些不同分化阶段的细胞形成了分化区带 ,肥大软骨细胞位于上侧 ,增殖、成熟细胞位于中间 ,其次是散在静止软骨细胞。培养第 14天 ,分化区带更加明显 ,增殖、成熟细胞和肥大软骨细胞呈现纵向定向排列。培养第 2 1天 ,组织表面出现膜样的结构。结论　体外构建的骺板样软骨组织与天然骺板的组织学形态极为相似。从髂骨处骺板处获取肥大软骨细胞进行体外构建骺板软骨材料 ,更具有临床实用性     

Indian hedgehog在软骨细胞力学信号转导作用的研究进展

软骨细胞力学是近几年生物力学发展的新领域,是细胞工程和组织工程学的基础,细胞的形态、结构、功能及其新陈代谢、分化都与力学有着密切的关系。力学对维持软骨细胞生物学功能必不可少,机械应力联合其他化学分子共同调节关节软骨的生理和病理变化[1]。软骨细胞通过细胞骨架、细胞外基质、离子通道、细胞膜受体等来感受力学信号,并且结合基因表达来调控自身的代谢活动[2]。近年来研究发现Indian hedgehog为力学敏感性的基因[3]。本文主要对软骨细胞力学生物学转导机制以及与Indian hedgehog信号通路进行综述。     

汉防己甲素对马兜铃酸A诱导的人近端肾小管上皮细胞转分化的干预作用

目的：探讨汉防己甲素（tetrandrine,rret）对马兜铃酸A（aristoloehic acid Ⅰ,AAⅠ）诱导的人近端肾小管上皮细胞（HK-2）转分化的拮抗效应。方法：将正常培养的HK-2随机分组：正常组、模型组、汉防己甲素高浓度组、汉防己甲素中浓度组、汉防己甲素低浓度组、泼尼松龙对照组（糖皮质激素组）。48h后观察各组细胞形态的变化,逆转录-聚合酶链式反应方法检测各组E—cadherin、TGF-β1、α-SMA mRNA表达水平,双抗体夹心酶联免疫吸附法测定各组细胞培养液中TGF-β1浓度,流式细胞技术测定各组E—cadherin阳性表达细胞的百分率。结果：汉防己甲素干预组及泼尼松龙对照组E—cadherin mRNA表达水平明显高于模型组（P〈0．05）,相反,其TGF-β1、α-SMA mRNA表达水平明显低于模型组（P〈0．05）;汉防己甲素干预组及泼尼松龙对照组TGF-β1浓度亦明显低于模型组（P〈0．05）;汉防己甲素干预组（中、低浓度）E—cadherin阳性表达细胞的百分率明显高于模型组（P〈0．05）,但汉防己甲素高浓度组和泼尼松龙对照组E—cadherin阳性表达细胞的百分率较之模型组增高不明显（P〉0．05）。结论：一定浓度（10μg／ml）的AAⅠ能诱导体外培养的HK-2转分化,适当浓度的Tet对AAi诱导的HK-2转分化具有明显的拮抗作用;AAI亦能上调TGF-β1的表达,而适当浓度的Tet能拮抗AAI引起的TGF-β1的高表达。     

Hedgehog signaling displays a biphasic expression pattern during intestinal injury and repair

Background/Purpose

Gastrointestinal injury is common clinically. The exact mechanism by which gastrointestinal repair occurs has yet to be well defined. Hedgehog (Hh) signaling is known to be involved in gastrointestinal development and repair of tissues such as skin and heart. The present study aimed to investigate the role of Hh in the repair of the small intestine.

Methods

i) To study acute intestinal injury, we optimized a mouse model of 5-flurouracil (5-FU) induced injury of the small intestine. Ileal tissues were evaluated for injury and repair markers at day 0, 2, 5, and 9. ii) Immunohistochemistry (Sonic hedgehog, Shh), in situ hybridization (Shh), and Ptch/LacZ transgenic mice were carried out to localize hedgehog expression. A33CrPr × ShhTg knock-in mice were bred to study the effect of Shh over-expression. qPCR of Shh, Ihh, Ptch, Bmp4 was carried out to quantify hedgehog signaling. iii) 5FU treated mice were then treated with a hedgehog inhibitor or saline (control) and the effects of Shh inhibition including apoptosis, proliferation, and mitosis were then compared.

Results

i) Immunohistochemistry and in situ hybridization of Shh, qPCR of hedgehog signaling pathway genes, and Ptch/LacZ staining results consistently showed down-regulation during the injury phase (P < 0.05) followed by up-regulation during the repair phase (P < 0.005). ii) Hh signaling inhibition following 5-FU induced injury augmented apoptotic activity (P < 0.05), suppressed mitotic activity (P < 0.005) in intestinal crypts, and reduced Paneth cell hyperplasia (P < 0.005). iii) Shh over-expression in conditionally knock-mice led to increased mitotic, Paneth, and goblet cells.

Conclusion

Hedgehog signaling pathway displays a biphasic expression pattern during the injury/repair of small intestine. It may play an important regulatory role in intestinal repair.     

铁介导骨代谢异常中“刺猬信号通路” 可能的作用

近年来有许多研究提示：铁代谢与骨质疏松症关系密切,铁过载可能引起骨代谢异常。在铁代 谢与骨代谢异常的相关机制中,许多研究认为刺猬信号通路（hedgehog信号通路,Hh信号通路）在 “铁介导骨代谢异常”中起着重要作用,本文将相关研究文献进行梳理综述。