OPG对破骨细胞活性的影响及其信号转导机制
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摘要
骨保护素(osteoprotegerin, OPG)是肿瘤坏死因子受体超家族成员,它最主要的生物学作用是抑制体内破骨细胞(osteoclast, OC)的分化、活化,并促进其发生凋亡。临床试验及动物实验表明,重组OPG蛋白和OPG基因治疗等技术手段,对防治人及动物的骨营养不良性疾病具有一定的应用价值。但是关于OPG对OC的调控机制仍不完全清楚,对于OPG相关药物的开发及其普遍运用仍存在诸多困难。本文以原代分离鸭胚OC及诱导获取OC模型为研究对象,在体外培养过程中添加不同浓度OPG,通过形态学鉴定、细胞活性检测、实时荧光定量PCR (QRT-PCR)、蛋白免疫印迹(Western blot)等技术手段,研究OPG对OC分化、活性及凋亡中形态、功能、相关基因及关键信号蛋白的影响。本研究以期为OPG调控OC活性的机理提供理论依据。研究内容如下：
1.OPG对破骨细胞分化、活化及凋亡的影响
为了研究OPG对体外培养鸭胚OC分化、活化与凋亡的影响,收集23日龄鸭胚骨髓细胞,体外培养过程中分组加入不同浓度OPG进行处理(A组：无因子；B组：30ng/mL OPG; C组：100ng/mLOPG)。通过抗酒石酸酸性磷酸酶染色(tartrate-resistant acid phosphatase, TRAP),骨吸收陷窝分析,OC骨架(TRITC标记的鬼笔环肽,TRITC-conjugated phalloidin)及胞核(Hoechst33258)染色技术,检钡TRAP阳性细胞、OC的骨吸收活性以及OC凋亡状态。结果显示,三个实验组中TRAP阳性细胞数、OC的骨吸收活性均在OPG处理7d后达到最高水平。与对照组相比,OPG处理组OC数目及OC的骨吸收活性显著减弱(P<0.05),每个时间段骨吸收陷窝净增长面积与OC数目变化趋势一致。OPG能够抑制OC内纤维状肌动蛋白环(Filamentous-actin rings, F-actin rings)的形成,并且能够促进成熟OC内F-actin环的崩解。此外,OPG能够诱导成熟OC发生凋亡,OC的形态及核发生改变。表明OPG能够抑制OC细胞前体分化,促进成熟OC发生凋亡
2.OPG抑制破骨细胞分化成熟的机理
为了研究OPG抑制OC分化、活化的分子生物学机理,在无血清培养条件下,采用M-CSF+RANKL联合诱导RAW264.7细胞分化为OC。在培养过程中加入不同浓度OPG(0、10、20、50、100ng/mL)进行处理。通过TRAP染色,OC内F-actin环染色,骨吸收陷窝分析等技术,研究OPG对OC的分化及活化的影响。此外,通过QRT-PCR技术检测OPG对OC相关基因TRAP、RANK、MMP-9、CA Ⅱ、Cathepsin K表达量的影响。结果显示,在无血清培养条件下,M-CSF+RANKL能够诱导OC的分化与活化,并能够促进OC分化及活化中TRAP、RANK、MMP-9、CAⅡ、Cathepsin K基因的表达,而OC的分化与活化受到OPG的抑制。
3.OPG抑制破骨细胞分化成熟的MAPK信号转导机制
为了研究OPG抑制OC分化中的MAPK信号转导机制,采用M-CSF+RANKL诱导RAW264.7细胞分化形成OC,在体外培养不同时间,各组分别添加相应浓度的OPG。各时间点培养结束后收集细胞,提取总蛋白,通过Western blot法检测MAPK信号通路中关键信号蛋白的变化。结果发现,M-CSF+RANKL诱导RAW264.7细胞分化形成OC过程中p38-MAPK、JNK-MAPK、ERK-MAPK三种蛋白的磷酸化水平均上升,在诱导处理15min后p38-MAPK磷酸化水平达最大值,诱导处理30min后JNK-MAPK、ERK-MAPK磷酸化水平达最大值。不同浓度OPG均能够抑制p38-MAPK、JNK-MAPK、ERK-MAPK三种蛋白的磷酸化水平,且随OPG浓度的增加抑制作用更加明显。表明MAPK信号通路参与调控OC的分化与活化过程,且参与调控OPG抑制OC的分化与活化。
4.OPG抑制破骨细胞分化成熟的Ca2+信号转导机制
为了研究OPG抑制OC分化中的Ca2+信号转导机制,采用M-CSF+RANKL诱导RAW264.7细胞分化形成OC,在体外培养不同时间,各组分别添加相应浓度的OPG。培养结束后收集细胞,通过流式细胞术检测OC胞内[Ca2+]i,通过Western blot法检测钙/钙调蛋白依赖性蛋白激酶Ⅱ(CaMKⅡ)的磷酸化水平。结果发现,M-CSF+RANKL诱导RAW264.7细胞分化形成OC过程中OC胞内[ca2+]i极显著升高(P<0.01),CaMKIⅠ激酶磷酸化水平上升,而OPG能够降低OC胞内[Ca2+]i,并下调CaMKIⅠ激酶的磷酸化水平。表明Ca2+信号通路参与调控OC的分化与活化过程,且参与调控OPG抑制OC的分化与活化。
Osteoprotegerin (OPG) which belongs to the tumor necrosis factor (TNF) receptor superfamily. OPG is well known to negatively regulate osteoclast (OC) maturation and activation and promote the development of apoptosis of OC. Clinical trials and animal experiments indicated that it was practicable to prevent and cure human and animal bone disease by the recombinant OPG and OPG gene therapy technology. However, the mechanisms of OPG inhibitory effects to the differentiation, activation and survival of osteoclasts have not been well elucidated. There are many difficulties in drug development related OPG. Isolated primary OC and induced OC were employed in this study, different concentrations of OPG were added to the cells culture in vitro. Morphological observation, bone resorption activity assay, QRT-PCR, and Western blot were all performed to determine the morphological changes, functions, OC releated genes expression, and key signaling proteins change of OC, which were treated by OPG. The aim of this study was to determine the mechanism involved in influence of osteoprotegerin (OPG) on the OC. A series of tests were carried out:
1. Influence of osteoprotegerin on differentiation, activation and apoptosis of osteoclasts in vitro
The aim of this study was to determine the influence of osteoprotegerin (OPG) on the differentiation, activation and apoptosis of duck embryo osteoclasts cultured in vitro. Bone marrow cells were harvested from23-day-old duck embryos and cultured in the presence of different concentrations of OPG (group A:no added factors, group B:30ng/mL OPG and group C:100ng/mL OPG). Tartrate-resistant acid phosphatase (TRAP) staining, pit formation assay, and co-staining with TRITC-conjugated phalloidin and Hoechst33258were all performed to determine the number of TRAP-positive cells, bone resorption activity and the level of apoptosis, respectively. The number of TRAP-positive cells and the net expansion of pit formations area peaked on the7th day of culture in all3groups. The number of osteoclasts and the total volume of pit formations in OPG-treated groups were significantly lower when compared to group A (P<0.05). At each time point, the net expansion of pit formations area correlated with the number of TRAP-positive cells. OPG inhibited the de novo formation of F-actin rings and promoted the disruption of existing F-actin rings in mature osteoclasts. In addition, OPG induced apoptosis in mature osteoclasts, as demonstrated by morphological changes in the nuclei. In osteoclast precursors, OPG inhibited differentiation and down regulated the formation of F-actin rings. In mature osteoclasts, OPG suppressed activation and enhanced the development of apoptosis, observed as a decrease in the number of TRAP-positive cells, the disruption of F-actin rings and morphological changes of the nuclei.
2. Mechanism involved in osteoprotegerin (OPG) affect differentiation and activation of osteoclast
The aim of this study was to determine the molecular mechanism involved in osteoprotegerin (OPG) affect differentiation and activation of osteoclast in serum-free conditions. RAW264.7cells were incubated with M-CSF+RANKL in serum-free medium for osteoclastogenesis. In the cultivation of the cells,0,10,20,50, and100ng/mL OPG were added to various groups. Osteoclast differentiation and activation were estimated via TRAP staining study, F-actin rings analysis, and bone resorption assay. Furthermore, expression levels of osteoclast related genes, such as TRAP, RANK, MMP-9, CA Ⅱ, and Cathepsin K which were influenced by OPG, were examined using real-time PCR with RAW264.7cells. In summary, these findings suggested that M-CSF+RANKL could promote the differentiation and activation of osteoclast, enhance the expression of TRAP, RANK, MMP-9, CA II, and Cathepsin K mRNA in osteoclast, whereas OPG inhibited them in serum-free conditions.
3. Influences of osteoprotegerin on the differentiation, maturation of osteoclast and the involved MAPK signalling pathway
The aim of this study was to determine the MAPK signalling pathway involved in osteoprotegerin (OPG) affect differentiation and maturation of osteoclast. RAW264.7cells were incubated with M-CSF+RANKL for osteoclastogenesis. In the cultivation of the cells,0,10,20,50, and100ng/mL OPG were added to various groups at defined time points. Cells were collected and total protein were isolated, key signaling proteins involved in the MAPK signalling pathway were monitored via Western blot. Results displayed that phosphorylation of p38-MAPK, JNK-MAPK, ERK-MAPK all were enhanced in M-CSF+RANKL-induced RAW264.7cells. The phosphorylation of p38-MAPK maximized after OPG treated for15min, and the phosphorylation of JNK-MAPK, ERK-MAPK maximized after OPG treated for30min. In addition, various concentrations of OPG could suppress the phosphorylation of all the three proteins in a concentration-dependent manner. The results demonstrated that the MAPK signalling pathway involved in the differentiation and activation of osteoclast, as well as in osteoprotegerin (OPG) affect the differentiation and activation of osteoclast.
4. Influences of osteoprotegerin on the differentiation, maturation of osteoclast and the involved Ca2+signalling pathway
The aim of this study was to determine the Ca2+signalling pathway involved in osteoprotegerin (OPG) affect differentiation and maturation of osteoclast. RAW264.7cells were incubated with M-CSF+RANKL for osteoclastogenesis. In the cultivation of the cells,0,10,20,50, and100ng/mL OPG were added to various groups. Cells were collected at the end of cultivation, the concentrations of [Ca2+]i were determined by flow cytometry, and the phosphorylation of CaMKII was monitored via Western blot. Results displayed that the concentrations of [Ca2+]j were raised significantly (P<0.01), and phosphorylation of CaMKII were enhanced in M-CSF+RANKL-induced RAW264.7cells. However, the concentrations of [Ca2+]i and the phosphorylation of CaMKII were decreased by OPG. The results demonstrated that the Ca2+signalling pathway involved in the differentiation and activation of osteoclast, as well as in OPG affect the differentiation and activation of osteoclast.
1.OPG对破骨细胞分化、活化及凋亡的影响
为了研究OPG对体外培养鸭胚OC分化、活化与凋亡的影响,收集23日龄鸭胚骨髓细胞,体外培养过程中分组加入不同浓度OPG进行处理(A组：无因子；B组：30ng/mL OPG; C组：100ng/mLOPG)。通过抗酒石酸酸性磷酸酶染色(tartrate-resistant acid phosphatase, TRAP),骨吸收陷窝分析,OC骨架(TRITC标记的鬼笔环肽,TRITC-conjugated phalloidin)及胞核(Hoechst33258)染色技术,检钡TRAP阳性细胞、OC的骨吸收活性以及OC凋亡状态。结果显示,三个实验组中TRAP阳性细胞数、OC的骨吸收活性均在OPG处理7d后达到最高水平。与对照组相比,OPG处理组OC数目及OC的骨吸收活性显著减弱(P<0.05),每个时间段骨吸收陷窝净增长面积与OC数目变化趋势一致。OPG能够抑制OC内纤维状肌动蛋白环(Filamentous-actin rings, F-actin rings)的形成,并且能够促进成熟OC内F-actin环的崩解。此外,OPG能够诱导成熟OC发生凋亡,OC的形态及核发生改变。表明OPG能够抑制OC细胞前体分化,促进成熟OC发生凋亡
2.OPG抑制破骨细胞分化成熟的机理
为了研究OPG抑制OC分化、活化的分子生物学机理,在无血清培养条件下,采用M-CSF+RANKL联合诱导RAW264.7细胞分化为OC。在培养过程中加入不同浓度OPG(0、10、20、50、100ng/mL)进行处理。通过TRAP染色,OC内F-actin环染色,骨吸收陷窝分析等技术,研究OPG对OC的分化及活化的影响。此外,通过QRT-PCR技术检测OPG对OC相关基因TRAP、RANK、MMP-9、CA Ⅱ、Cathepsin K表达量的影响。结果显示,在无血清培养条件下,M-CSF+RANKL能够诱导OC的分化与活化,并能够促进OC分化及活化中TRAP、RANK、MMP-9、CAⅡ、Cathepsin K基因的表达,而OC的分化与活化受到OPG的抑制。
3.OPG抑制破骨细胞分化成熟的MAPK信号转导机制
为了研究OPG抑制OC分化中的MAPK信号转导机制,采用M-CSF+RANKL诱导RAW264.7细胞分化形成OC,在体外培养不同时间,各组分别添加相应浓度的OPG。各时间点培养结束后收集细胞,提取总蛋白,通过Western blot法检测MAPK信号通路中关键信号蛋白的变化。结果发现,M-CSF+RANKL诱导RAW264.7细胞分化形成OC过程中p38-MAPK、JNK-MAPK、ERK-MAPK三种蛋白的磷酸化水平均上升,在诱导处理15min后p38-MAPK磷酸化水平达最大值,诱导处理30min后JNK-MAPK、ERK-MAPK磷酸化水平达最大值。不同浓度OPG均能够抑制p38-MAPK、JNK-MAPK、ERK-MAPK三种蛋白的磷酸化水平,且随OPG浓度的增加抑制作用更加明显。表明MAPK信号通路参与调控OC的分化与活化过程,且参与调控OPG抑制OC的分化与活化。
4.OPG抑制破骨细胞分化成熟的Ca2+信号转导机制
为了研究OPG抑制OC分化中的Ca2+信号转导机制,采用M-CSF+RANKL诱导RAW264.7细胞分化形成OC,在体外培养不同时间,各组分别添加相应浓度的OPG。培养结束后收集细胞,通过流式细胞术检测OC胞内[Ca2+]i,通过Western blot法检测钙/钙调蛋白依赖性蛋白激酶Ⅱ(CaMKⅡ)的磷酸化水平。结果发现,M-CSF+RANKL诱导RAW264.7细胞分化形成OC过程中OC胞内[ca2+]i极显著升高(P<0.01),CaMKIⅠ激酶磷酸化水平上升,而OPG能够降低OC胞内[Ca2+]i,并下调CaMKIⅠ激酶的磷酸化水平。表明Ca2+信号通路参与调控OC的分化与活化过程,且参与调控OPG抑制OC的分化与活化。
Osteoprotegerin (OPG) which belongs to the tumor necrosis factor (TNF) receptor superfamily. OPG is well known to negatively regulate osteoclast (OC) maturation and activation and promote the development of apoptosis of OC. Clinical trials and animal experiments indicated that it was practicable to prevent and cure human and animal bone disease by the recombinant OPG and OPG gene therapy technology. However, the mechanisms of OPG inhibitory effects to the differentiation, activation and survival of osteoclasts have not been well elucidated. There are many difficulties in drug development related OPG. Isolated primary OC and induced OC were employed in this study, different concentrations of OPG were added to the cells culture in vitro. Morphological observation, bone resorption activity assay, QRT-PCR, and Western blot were all performed to determine the morphological changes, functions, OC releated genes expression, and key signaling proteins change of OC, which were treated by OPG. The aim of this study was to determine the mechanism involved in influence of osteoprotegerin (OPG) on the OC. A series of tests were carried out:
1. Influence of osteoprotegerin on differentiation, activation and apoptosis of osteoclasts in vitro
The aim of this study was to determine the influence of osteoprotegerin (OPG) on the differentiation, activation and apoptosis of duck embryo osteoclasts cultured in vitro. Bone marrow cells were harvested from23-day-old duck embryos and cultured in the presence of different concentrations of OPG (group A:no added factors, group B:30ng/mL OPG and group C:100ng/mL OPG). Tartrate-resistant acid phosphatase (TRAP) staining, pit formation assay, and co-staining with TRITC-conjugated phalloidin and Hoechst33258were all performed to determine the number of TRAP-positive cells, bone resorption activity and the level of apoptosis, respectively. The number of TRAP-positive cells and the net expansion of pit formations area peaked on the7th day of culture in all3groups. The number of osteoclasts and the total volume of pit formations in OPG-treated groups were significantly lower when compared to group A (P<0.05). At each time point, the net expansion of pit formations area correlated with the number of TRAP-positive cells. OPG inhibited the de novo formation of F-actin rings and promoted the disruption of existing F-actin rings in mature osteoclasts. In addition, OPG induced apoptosis in mature osteoclasts, as demonstrated by morphological changes in the nuclei. In osteoclast precursors, OPG inhibited differentiation and down regulated the formation of F-actin rings. In mature osteoclasts, OPG suppressed activation and enhanced the development of apoptosis, observed as a decrease in the number of TRAP-positive cells, the disruption of F-actin rings and morphological changes of the nuclei.
2. Mechanism involved in osteoprotegerin (OPG) affect differentiation and activation of osteoclast
The aim of this study was to determine the molecular mechanism involved in osteoprotegerin (OPG) affect differentiation and activation of osteoclast in serum-free conditions. RAW264.7cells were incubated with M-CSF+RANKL in serum-free medium for osteoclastogenesis. In the cultivation of the cells,0,10,20,50, and100ng/mL OPG were added to various groups. Osteoclast differentiation and activation were estimated via TRAP staining study, F-actin rings analysis, and bone resorption assay. Furthermore, expression levels of osteoclast related genes, such as TRAP, RANK, MMP-9, CA Ⅱ, and Cathepsin K which were influenced by OPG, were examined using real-time PCR with RAW264.7cells. In summary, these findings suggested that M-CSF+RANKL could promote the differentiation and activation of osteoclast, enhance the expression of TRAP, RANK, MMP-9, CA II, and Cathepsin K mRNA in osteoclast, whereas OPG inhibited them in serum-free conditions.
3. Influences of osteoprotegerin on the differentiation, maturation of osteoclast and the involved MAPK signalling pathway
The aim of this study was to determine the MAPK signalling pathway involved in osteoprotegerin (OPG) affect differentiation and maturation of osteoclast. RAW264.7cells were incubated with M-CSF+RANKL for osteoclastogenesis. In the cultivation of the cells,0,10,20,50, and100ng/mL OPG were added to various groups at defined time points. Cells were collected and total protein were isolated, key signaling proteins involved in the MAPK signalling pathway were monitored via Western blot. Results displayed that phosphorylation of p38-MAPK, JNK-MAPK, ERK-MAPK all were enhanced in M-CSF+RANKL-induced RAW264.7cells. The phosphorylation of p38-MAPK maximized after OPG treated for15min, and the phosphorylation of JNK-MAPK, ERK-MAPK maximized after OPG treated for30min. In addition, various concentrations of OPG could suppress the phosphorylation of all the three proteins in a concentration-dependent manner. The results demonstrated that the MAPK signalling pathway involved in the differentiation and activation of osteoclast, as well as in osteoprotegerin (OPG) affect the differentiation and activation of osteoclast.
4. Influences of osteoprotegerin on the differentiation, maturation of osteoclast and the involved Ca2+signalling pathway
The aim of this study was to determine the Ca2+signalling pathway involved in osteoprotegerin (OPG) affect differentiation and maturation of osteoclast. RAW264.7cells were incubated with M-CSF+RANKL for osteoclastogenesis. In the cultivation of the cells,0,10,20,50, and100ng/mL OPG were added to various groups. Cells were collected at the end of cultivation, the concentrations of [Ca2+]i were determined by flow cytometry, and the phosphorylation of CaMKII was monitored via Western blot. Results displayed that the concentrations of [Ca2+]j were raised significantly (P<0.01), and phosphorylation of CaMKII were enhanced in M-CSF+RANKL-induced RAW264.7cells. However, the concentrations of [Ca2+]i and the phosphorylation of CaMKII were decreased by OPG. The results demonstrated that the Ca2+signalling pathway involved in the differentiation and activation of osteoclast, as well as in OPG affect the differentiation and activation of osteoclast.
引文
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