技术领域technical field
本发明属于生物医药技术领域，涉及一种细胞生长因子在制药领域的新用途。The invention belongs to the technical field of biomedicine and relates to a new application of a cell growth factor in the pharmaceutical field.
背景技术Background technique
骨关节炎为一种退行性病变，系由于增龄、肥胖、劳损、创伤、关节先天性异常、关节畸形等诸多因素引起的关节软骨退化损伤、关节边缘和软骨下骨反应性增生，又称骨关节病。关节软骨损伤是骨关节炎的主要病理改变。关节软骨损伤后没有或很少有自我修复能力，这与关节软骨内无血管、神经及淋巴管支配有关。目前关节软骨损伤修复的主要治疗措施包括局部用药、软骨细胞移植、手术(关节置换)等，虽然可在一定程度上缓解症状，但由于未能充分激活关节软骨本身的修复机制，修复往往不完全，甚至可能引发周围组织发生降解，出现继发性骨关节炎。因此，关节软骨损伤修复成为骨科领域重要问题。Osteoarthritis is a degenerative disease, which is caused by many factors such as aging, obesity, strain, trauma, congenital abnormalities of joints, joint deformities and other factors. Osteoarthritis. Articular cartilage damage is the main pathological change of osteoarthritis. Articular cartilage has little or no self-repair ability after injury, which is related to the absence of blood vessels, nerves and lymphatic vessels in articular cartilage. At present, the main treatment measures for the repair of articular cartilage injury include topical medication, chondrocyte transplantation, surgery (joint replacement), etc. Although the symptoms can be relieved to a certain extent, the repair is often incomplete due to the failure to fully activate the repair mechanism of the articular cartilage itself , and may even trigger the degradation of surrounding tissues, resulting in secondary osteoarthritis. Therefore, the repair of articular cartilage damage has become an important issue in the field of orthopedics.
成纤维细胞生长因子(fibroblast growth factor，FGF)是由垂体和下丘脑分泌的多肽。FGF家族至少包括23个成员(FGF1～FGF23)，作为胞间信号分子，它们在硫酸乙酰肝素蛋白多糖协同下与成纤维细胞生长因子受体(fibroblast growth factor receptor，FGFR)结合，使受体二聚化活化，自身酪氨酸残基磷酸化，与含有SH2的信号分子结合，通过各种信号途径传递信号，参与动物发育过程中多个复杂反应，广泛地调节细胞活性，包括细胞的增殖、迁移、分化以及存活率。FGF9作为FGF家族成员之一，广泛分布于人体的脑、肾、运动神经元和发育中的骨组织中，已被证明参与了包括骨骼，睾丸，肺，心脏和眼睛在内的各种器官和组织的发育成熟过程。目前已发现FGFR家族由五个成员(FGFR1～FGFR5)组成，FGF9主要与FGFR2和FGFR3结合。在骨骼发育早期，FGF9能促进软骨细胞肥大；在骨骼发育后期，其主要调节生长板的血管化和成骨过程。FGFR2主要表达于成骨细胞系，FGF9活化FGFR2可能促进膜内成骨和提高骨密度；FGFR3主要表达于软骨细胞系，FGF9与FGFR3结合后可能抑制软骨内成骨。然而，FGF9对关节软骨损伤修复的影响和作用尚不清楚。Fibroblast growth factor (FGF) is a polypeptide secreted by the pituitary and hypothalamus. The FGF family includes at least 23 members (FGF1-FGF23), as intercellular signaling molecules, they bind to the fibroblast growth factor receptor (FGFR) under the cooperation of heparan sulfate proteoglycan, and make the receptor two Polymerization activation, phosphorylation of its own tyrosine residues, binding to signaling molecules containing SH2, transmitting signals through various signaling pathways, participating in multiple complex reactions during animal development, and extensively regulating cell activity, including cell proliferation, Migration, differentiation and survival. As a member of the FGF family, FGF9 is widely distributed in the human brain, kidney, motor neurons and developing bone tissue, and has been shown to be involved in various organs including bones, testes, lungs, heart and eyes. tissue maturation process. It has been found that the FGFR family consists of five members (FGFR1-FGFR5), and FGF9 mainly binds to FGFR2 and FGFR3. In early skeletal development, FGF9 can promote chondrocyte hypertrophy; in later skeletal development, it mainly regulates vascularization and osteogenesis of growth plate. FGFR2 is mainly expressed in osteoblast cell lines, and the activation of FGFR2 by FGF9 may promote intramembranous osteogenesis and increase bone density; FGFR3 is mainly expressed in chondrocyte cell lines, and the combination of FGF9 and FGFR3 may inhibit endochondral osteogenesis. However, the impact and role of FGF9 on the repair of articular cartilage damage is still unclear.
发明内容Contents of the invention
有鉴于此，本发明的目的在于研究FGF9对关节软骨损伤修复的影响和作用，进而扩展其在制药领域中的应用。In view of this, the purpose of the present invention is to study the influence and effect of FGF9 on the repair of articular cartilage damage, and further expand its application in the pharmaceutical field.
经研究，本发明提供如下技术方案：After research, the present invention provides the following technical solutions:
FGF9在制备促进骨关节炎软骨修复的药物中的应用。Application of FGF9 in preparation of medicine for promoting cartilage repair in osteoarthritis.
进一步，所述促进骨关节炎软骨修复的药物为抑制关节软骨降解和软骨肥大化的药物。Further, the drug for promoting cartilage repair in osteoarthritis is a drug for inhibiting articular cartilage degradation and cartilage hypertrophy.
本发明的有益效果在于：本发明研究发现，FGF9在处于炎症环境的关节软骨细胞中可发挥阻滞关节软骨细胞异常分化的作用，在小鼠骨关节炎模型中能缓解关节软骨的降解，抑制关节软骨降解的关键酶MMP-13，减缓关节软骨的肥大化过程，可用于制备促进骨关节炎软骨修复的药物，在骨关节炎治疗领域具有潜在良好的应用前景。The beneficial effects of the present invention are: the present invention found that FGF9 can play a role in blocking abnormal differentiation of articular chondrocytes in articular chondrocytes in an inflammatory environment, and can relieve the degradation of articular cartilage in a mouse osteoarthritis model, inhibiting The key enzyme MMP-13 in the degradation of articular cartilage can slow down the hypertrophy process of articular cartilage, can be used to prepare drugs for promoting cartilage repair in osteoarthritis, and has a potential good application prospect in the field of osteoarthritis treatment.
附图说明Description of drawings
为了使本发明的目的、技术方案和有益效果更加清楚，本发明提供如下附图进行说明：In order to make the purpose, technical scheme and beneficial effect of the present invention clearer, the present invention provides the following drawings for illustration:
图1表示在IL-1β处理的原代关节软骨细胞中，用FGF9处理的软骨细胞比未用FGF9处理的软骨细胞MMP13和Collagen X(肥大软骨细胞的标志物)表达明显下调。**表示与空白对照组相比p<0.01。Figure 1 shows that in primary articular chondrocytes treated with IL-1β, the expressions of MMP13 and Collagen X (a marker of hypertrophic chondrocytes) were significantly down-regulated in chondrocytes treated with FGF9 than in chondrocytes not treated with FGF9. ** indicates p<0.01 compared with blank control group.
图2表示DMM手术后，关节内注射FGF9的小鼠的膝关节软骨破坏程度较未注射FGF9的小鼠明显降低。Sham control是没有行使DMM手术的左膝关节，saline为行使了DMM手术但只注射未含FGF9的溶液，FGF9为行使了DMM手术且注射含FGF9的溶液。组织切片采用藏红固绿染色。Figure 2 shows that after DMM surgery, the degree of cartilage destruction in the knee joints of mice injected with FGF9 was significantly lower than that of mice not injected with FGF9. Sham control is the left knee joint without DMM operation, saline is the DMM operation but only injecting the solution without FGF9, and FGF9 is the DMM operation and injecting the solution containing FGF9. Tissue sections were stained with saffron fast green.
图3表示DMM手术后，小鼠关节软骨的MMP13和Collagen X表达上调，而术后注射FGF9，小鼠关节软骨的MMP13和Collagen X表达又下调。Figure 3 shows that after DMM surgery, the expressions of MMP13 and Collagen X in mouse articular cartilage were up-regulated, and the expressions of MMP13 and Collagen X in mouse articular cartilage were down-regulated after injection of FGF9.
具体实施方式Detailed ways
下面将结合附图，对本发明的优选实施例进行详细的描述。实施例中未注明具体条件的实验方法，通常按照常规条件，或按照制造厂商所建议的条件。The preferred embodiments of the present invention will be described in detail below with reference to the accompanying drawings. For the experimental methods that do not specify specific conditions in the examples, usually follow the conventional conditions or the conditions suggested by the manufacturer.
一、FGF9处理对炎症环境中的关节软骨细胞的MMP13和Collagen X表达的影响1. The effect of FGF9 treatment on the expression of MMP13 and Collagen X in articular chondrocytes in an inflammatory environment
人类原代关节软骨组织标本取自行关节置换手术后切除的仍然正常的人类膝关节软骨，将其分离、消化、接种后培养至合适的细胞密度，先用10ng/ml FGF9处理30分钟(对照不处理)，再加入10ng/ml IL-1β处理24小时(FGF9仍然存在于培养基中，对照不处理)，接着采用Trizol法提取原代软骨细胞总mRNA，反转录成cDNA，最后荧光实时定量PCR检测MMP-13和Collagen X的表达。各样本目的基因的表达强度利用其对应的内参基因(GADPH)的量进行校正，每次均设3个复孔。PCR引物序列为：Human primary articular cartilage tissue specimens were taken from normal human knee articular cartilage resected after joint replacement surgery. They were separated, digested, inoculated and cultured to a suitable cell density. They were first treated with 10ng/ml FGF9 for 30 minutes (control No treatment), then add 10ng/ml IL-1β to treat for 24 hours (FGF9 still exists in the culture medium, the control is not treated), then use the Trizol method to extract the total mRNA of primary chondrocytes, reverse transcribe into cDNA, and finally fluorescein real-time The expressions of MMP-13 and Collagen X were detected by quantitative PCR. The expression intensity of the target gene in each sample was corrected by the amount of its corresponding internal reference gene (GADPH), and three replicate wells were set up each time. The PCR primer sequences are:
GADPH基因上游引物：5’-catggagaaggctggggctc-3’(SEQ ID NO.1)；GADPH gene upstream primer: 5'-catggagaaggctggggctc-3'(SEQ ID NO.1);
GADPH基因下游引物：5’-atgaggtccaccaccctgtt-3’(SEQ ID NO.2)；GADPH gene downstream primer: 5'-atgaggtccaccaccctgtt-3' (SEQ ID NO.2);
MMP-13基因上游引物：5’-cttcttcttgttgagctggactc-3’(SEQ ID NO.3)；MMP-13 gene upstream primer: 5'-cttcttcttgttgagctggactc-3' (SEQ ID NO.3);
MMP-13基因下游引物：5’-ctgtggaggtcactgtagact-3’(SEQ ID NO.4)；MMP-13 gene downstream primer: 5'-ctgtggaggtcactgtagact-3' (SEQ ID NO.4);
Collagen X基因上游引物：5’-gcagcattacgacccaagat-3’(SEQ ID NO.5)；Collagen X gene upstream primer: 5'-gcagcattacgacccaagat-3' (SEQ ID NO.5);
Collagen X基因下游引物：5’-catgattgcactccctgaag-3’(SEQ ID NO.6)；Collagen X gene downstream primer: 5'-catgattgcactccctgaag-3'(SEQ ID NO.6);
PCR扩增条件为：95℃30s；95℃5s，57℃20s，72℃15s，共40个循环；95℃30s，57℃30s，95℃30s。The PCR amplification conditions were: 95°C for 30s; 95°C for 5s, 57°C for 20s, 72°C for 15s, a total of 40 cycles; 95°C for 30s, 57°C for 30s, and 95°C for 30s.
结果如图1所示，在未用FGF9处理的关节软骨细胞中，经IL-1β处理的细胞比未经IL-1β处理的细胞其MMP13和Collagen X表达上调，提示经IL-1β处理的关节软骨细胞处于一个炎症环境之中，从而模拟了骨关节炎的软骨细胞环境。而在用IL-1β处理的关节软骨细胞中，经FGF9处理的细胞比未经FGF9处理的细胞其MMP13和Collagen X表达明显下调。提示FGF9在处于炎症环境的关节软骨细胞中起阻滞关节软骨细胞异常分化的作用。The results are shown in Figure 1, in articular chondrocytes not treated with FGF9, the expression of MMP13 and Collagen X in IL-1β-treated cells was up-regulated compared with that in non-IL-1β-treated cells, suggesting that IL-1β-treated articular chondrocytes Chondrocytes are in an inflammatory environment that mimics the chondrocyte environment of osteoarthritis. In the articular chondrocytes treated with IL-1β, the expressions of MMP13 and Collagen X in the cells treated with FGF9 were significantly down-regulated compared with the cells not treated with FGF9. It is suggested that FGF9 plays a role in blocking the abnormal differentiation of articular chondrocytes in the inflammatory environment.
二、FGF9处理对小鼠骨关节炎模型的影响2. Effect of FGF9 treatment on mouse osteoarthritis model
1、DMM模型建立1. DMM model establishment
内侧半月板胫骨韧带切断后将导致内侧半月板(Destabilization of the medial meniscus，DMM)的不稳定。采用显微外科技术实施DMM手术构建小鼠膝关节炎模型。手术主要步骤如下：将小鼠固定、消毒后，用显微刀片切开髌骨韧带内侧，暴露关节腔，钝性分离股骨髁间的脂肪垫，暴露髁间区域，用显微刀片挑断内侧半月板胫骨韧带，缝合组织与皮肤。术中注意避免损伤关节软骨，术后不固定手术肢体，笼内自由活动，腹腔注射青霉素预防感染。对照组小鼠不做处理。The medial meniscus (Destabilization of the medial meniscus, DMM) will be unstable after the tibial ligament is severed. A mouse model of knee arthritis was established by microsurgical technique using DMM. The main steps of the operation are as follows: After the mouse was fixed and disinfected, the medial patellar ligament was incised with a microblade to expose the joint cavity, the fat pad between the femoral condyles was bluntly separated to expose the intercondylar area, and the medial half moon was picked off with a microblade Plate tibial ligament, suture tissue and skin. During the operation, care should be taken to avoid damage to the articular cartilage. After the operation, the operated limbs were not fixed, and they could move freely in the cage. Penicillin was injected intraperitoneally to prevent infection. The mice in the control group were not treated.
2、FGF9处理2. FGF9 treatment
手术2周后，麻醉小鼠行FGF9关节腔内注射实验。注射分两步：先把FGF9溶液(2.5μg粉剂溶解在5μl生理盐水中)或者生理盐水(对照，5μl)与纤维蛋白原溶液混合(3μg/μl)后注射在关节腔中；接着注射1μl凝血酶(0.2unit)使纤维蛋白原转变为纤维蛋白。于手术第5周时处死小鼠，取小鼠膝关节进行组织切片。Two weeks after the operation, the mice were anesthetized for intra-articular injection of FGF9. Injection is divided into two steps: first, FGF9 solution (2.5 μg powder dissolved in 5 μl normal saline) or normal saline (control, 5 μl) is mixed with fibrinogen solution (3 μg/μl) and then injected into the joint cavity; then 1 μl blood coagulation is injected Enzyme (0.2 unit) converts fibrinogen to fibrin. The mice were sacrificed at the 5th week of operation, and the knee joints of the mice were taken for tissue sections.
3、藏红固绿染色观测膝关节软骨情况3. Observation of knee articular cartilage by saffron fast green staining
取小鼠膝关节组织切片，采用藏红固绿染色，显微镜下观察软骨组织学特征并进行评价。The mouse knee joint tissue sections were taken, stained with saffron fast green, and the histological characteristics of the cartilage were observed and evaluated under a microscope.
结果如图2所示，相比行使了DMM手术但只注射未含FGF9溶液的小鼠，DMM手术后注射了FGF9的小鼠的膝关节软骨破坏程度明显降低，提示FGF9可以使骨关节炎模型小鼠的软骨降解过程延迟。The results are shown in Figure 2. Compared with mice that underwent DMM surgery but were only injected with FGF9-free solutions, the degree of cartilage damage in the knee joints of mice injected with FGF9 after DMM surgery was significantly reduced, suggesting that FGF9 can make osteoarthritis models The cartilage degradation process was delayed in mice.
4、免疫组化检测关节软骨MMP13和Collagen X表达情况4. Immunohistochemical detection of expression of MMP13 and Collagen X in articular cartilage
取小鼠膝关节组织切片，用二甲苯脱蜡，梯度浓度的酒精复水，3％H2O2消除内源性过氧化氢酶的活性，胰酶孵育修复抗原，山羊血清封闭，然后用兔MMP13多克隆抗体(1:50稀释；ProteinTech公司)或兔Collagen X多克隆抗体(1:20稀释；Calbiochem Merck公司)孵育过夜，磷酸盐缓冲液洗净切片，再用辣根过氧化物酶标记的二抗孵育，最后用二氨基联苯胺显色，甲基绿复染，观察MMP13和Collagen X在小鼠关节软骨的表达情况。Take mouse knee tissue sections, dewax with xylene, rehydrate with graded alcohol, 3% H2 O2 to eliminate endogenous catalase activity, trypsin incubation to repair antigen, goat serum to block, and then use Rabbit MMP13 polyclonal antibody (1:50 dilution; ProteinTech Company) or rabbit Collagen X polyclonal antibody (1:20 dilution; Calbiochem Merck Company) was incubated overnight, the sections were washed with phosphate buffer, and then horseradish peroxidase Incubate with labeled secondary antibody, develop color with diaminobenzidine, and counterstain with methyl green to observe the expression of MMP13 and Collagen X in mouse articular cartilage.
结果如图3所示，DMM手术后小鼠关节软骨的MMP13和Collagen X表达上调，说明在关节炎进程中关节软骨降解增加并发生过度软骨肥大化，而术后注射FGF9，MMP13和Collagen X的表达又下调，提示FGF9对关节软骨降解和软骨肥大化具有抑制作用。The results are shown in Figure 3. The expressions of MMP13 and Collagen X in the articular cartilage of mice after DMM surgery were up-regulated, indicating that the degradation of articular cartilage increased and excessive cartilage hypertrophy occurred in the process of arthritis. The expression was down-regulated again, suggesting that FGF9 has an inhibitory effect on articular cartilage degradation and cartilage hypertrophy.
最后说明的是，以上优选实施例仅用以说明本发明的技术方案而非限制，尽管通过上述优选实施例已经对本发明进行了详细的描述，但本领域技术人员应当理解，可以在形式上和细节上对其作出各种各样的改变，而不偏离本发明权利要求书所限定的范围。Finally, it should be noted that the above preferred embodiments are only used to illustrate the technical solutions of the present invention and not to limit them. Although the present invention has been described in detail through the above preferred embodiments, those skilled in the art should understand that it can be described in terms of form and Various changes may be made in the details without departing from the scope of the invention defined by the claims.
| Application Number | Priority Date | Filing Date | Title |
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| CN201410341118.0ACN104162148A (en) | 2014-07-17 | 2014-07-17 | Application of FGF (fibroblast growth factor) 9 in preparation of osteoarthritis cartilage repair promotion medicine |
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| CN201410341118.0ACN104162148A (en) | 2014-07-17 | 2014-07-17 | Application of FGF (fibroblast growth factor) 9 in preparation of osteoarthritis cartilage repair promotion medicine |
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| CN104162148Atrue CN104162148A (en) | 2014-11-26 |
| Application Number | Title | Priority Date | Filing Date |
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| CN201410341118.0APendingCN104162148A (en) | 2014-07-17 | 2014-07-17 | Application of FGF (fibroblast growth factor) 9 in preparation of osteoarthritis cartilage repair promotion medicine |
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| Date | Code | Title | Description |
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| C06 | Publication | ||
| PB01 | Publication | ||
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| C12 | Rejection of a patent application after its publication | ||
| RJ01 | Rejection of invention patent application after publication | Application publication date:20141126 |