聚蛋白多糖酶和MMP在OA和RA關(guān)節(jié)中的表達(dá)及其意義
發(fā)布時(shí)間：2018-07-21 15:49
【摘要】： 實(shí)驗(yàn)背景和目的:關(guān)節(jié)軟骨破壞的重要病理表現(xiàn)是軟骨細(xì)胞外基質(zhì)(ECM)的減少,其中,聚蛋白多糖丟失是關(guān)節(jié)炎的主要病理表現(xiàn)之一。聚蛋白多糖可以被基質(zhì)金屬蛋白酶(MMP)和聚蛋白多糖酶(Aggrecanase)分別在核心蛋白球間區(qū)(IGD)的Asn~(341)-Phe~(342)位點(diǎn)和Glu~(373)-Ala~(374)位點(diǎn)降解,并分別產(chǎn)生FFGxx和ARGxx的新肽鏈。迄今為止被廣泛認(rèn)可的聚蛋白多糖酶有ADAMTS-4和ADAMTS-5,在MMP家族中MMP-2有廣泛的作用底物,包括聚蛋白多糖和Ⅱ型膠原,MMP-3則是MMP家族中降解聚蛋白多糖最強(qiáng)者。盡管聚蛋白多糖酶和MMP都能裂解聚蛋白多糖的核心蛋白,而在疾病狀態(tài)下哪種酶起主要作用以及聚蛋白多糖酶的上調(diào)因素仍然是近年來(lái)爭(zhēng)論的熱點(diǎn)問題。 有體外軟骨培養(yǎng)體系證實(shí)最初幾周降解聚蛋白多糖的酶是聚蛋白多糖酶,MMP在幾周后才發(fā)揮作用,聚蛋白多糖酶在軟骨降解的后期的作用尚不清楚,而且影響軟骨細(xì)胞表達(dá)聚蛋白多糖酶的因素更加復(fù)雜,甚至在體外試驗(yàn)中的研究結(jié)果也有很大差異,比如有報(bào)道用IL-1處理培養(yǎng)的正常人軟骨,不影響ADAMTS-4和ADAMTS-5的表達(dá),而另有報(bào)道人軟骨細(xì)胞經(jīng)IL-1刺激后,增加了ADAMTS-4的表達(dá),卻不影響ADAMTS-5的表達(dá)。 骨關(guān)節(jié)炎(OA)和類風(fēng)濕性關(guān)節(jié)炎(RA)都有關(guān)節(jié)軟骨破壞的病理表現(xiàn),但是二者的疾病性質(zhì)卻不相同。OA是非炎性的退行性關(guān)節(jié)炎,RA則是自身免疫性疾病,是炎性關(guān)節(jié)炎,炎癥因子,如IL-1,在其中起了重要作用。對(duì)兩種疾病的比較研究不僅可以比較聚蛋白多糖酶和MMP的作用,還對(duì)揭示人類疾病狀態(tài)下聚蛋白多糖酶的表達(dá)調(diào)節(jié)有重要意義。本文通過對(duì)ADAMTS-4、ADAMTS-5、MMP-2和MMP-3以及它們的產(chǎn)物在OA和RA病變關(guān)節(jié)的軟骨、滑膜和關(guān)節(jié)液中的表達(dá)比較,探討了聚蛋白多糖酶和MMP在人類疾病狀態(tài)下的不同作用以及可能的激活機(jī)制。 材料和方法:本研究所有標(biāo)本均取自人類膝關(guān)節(jié)股骨髁,共有OA軟骨和滑膜21例;OA關(guān)節(jié)液32例;RA軟骨9例、滑膜12例、關(guān)節(jié)液28例;正常軟骨3例。15例OA軟骨的進(jìn)行了組織塊培養(yǎng)(5天),并在第一天應(yīng)用10ug/ml的IL-1β對(duì)培養(yǎng)的軟骨塊進(jìn)行了刺激。應(yīng)用免疫組織化學(xué)方法觀察了3例正常軟骨、15例OA培養(yǎng)前后的軟骨的ADAMTS-4的表達(dá),比較了ADAMTS-4在不同軟骨的表層、中層和深層分布;應(yīng)用半定量RT-PCR方法檢測(cè)了ADAMTS-4mRNA在3例正常軟骨和15例OA培養(yǎng)前后的軟骨中的表達(dá)差異。還應(yīng)用免疫組織化學(xué)方法觀察了ADAMTS-4和ADAMTS-5在21例OA軟骨和滑膜、9例RA軟骨、12例RA滑膜中的表達(dá)比例和分布區(qū)域,并進(jìn)行了比較;應(yīng)用酶聯(lián)免疫吸附實(shí)驗(yàn)(ELISA)觀察了ADAMTS-4、ADAMTS-5、MMP-2和MMP-3以及ARGxx和FFGxx在32例OA關(guān)節(jié)液和28例RA關(guān)節(jié)液中的表達(dá),以ELISA吸光度(OD)值代表所測(cè)各項(xiàng)在關(guān)節(jié)液中的濃度,對(duì)結(jié)果進(jìn)行t檢驗(yàn)和相關(guān)性分析。 結(jié)果:在3例正常軟骨的免疫組化切片中,只有極少數(shù)軟骨細(xì)胞中有ADAMTS-4表達(dá);OA軟骨的ADAMTS-4表達(dá)區(qū)域主要分布在軟骨表層的細(xì)胞內(nèi),中層細(xì)胞表達(dá)較少,深層軟骨細(xì)胞則幾乎沒有表達(dá);當(dāng)OA軟骨表層磨損后,ADAMTS-4陽(yáng)性細(xì)胞主要分布在中層靠近關(guān)節(jié)表面的區(qū)域,靠近深層的區(qū)域很少有陽(yáng)性細(xì)胞,深層的軟骨細(xì)胞仍然幾乎沒有ADAMTS-4的表達(dá);當(dāng)軟骨進(jìn)一步磨損,中層也消失后,深層細(xì)胞可見增生并表達(dá)ADAMTS;當(dāng)OA軟骨在經(jīng)過與IL-1β共同培養(yǎng)后,ADAMTS-4表達(dá)量增加;統(tǒng)計(jì)結(jié)果顯示培養(yǎng)前后的OA軟骨的表層和中層ADAMTS-4陽(yáng)性細(xì)胞數(shù)均顯著高于正常軟骨;OA軟骨培養(yǎng)前后相比較可見表層陽(yáng)性細(xì)胞數(shù)沒有差異,而培養(yǎng)后的OA軟骨中層陽(yáng)性細(xì)胞數(shù)明顯增多。RT-PCR的結(jié)果顯示ADAMTS-4 mRNA的表達(dá)在OA軟骨中明顯高于正常軟骨,IL-1刺激后的軟骨明顯高于OA軟骨。 所有OA和RA軟骨中均有ADAMTS-4和ADAMTS-5的表達(dá),但表達(dá)部位不同,ADAMTS-4、5在OA軟骨中主要表達(dá)在表層,RA軟骨的表層已被血管翳替代,其細(xì)胞強(qiáng)烈表達(dá)聚蛋白多糖酶,而且軟骨中層出現(xiàn)陽(yáng)性細(xì)胞的例數(shù)明顯高于OA;OA滑膜出現(xiàn)ADAMTS-4和ADAMTS-5陽(yáng)性細(xì)胞的比例分別為52%(11/21)和43%(9/21)與RA的50%(6/12)和58%(7/12)相比較沒有顯著差異。 ELISA結(jié)果顯示ADAMTS-4、ADAMTS-5、MMP-2和MMP-3以及ARGxx和FFGxx在RA關(guān)節(jié)液中的濃度均高于OA關(guān)節(jié)液,結(jié)果有顯著差異(p＜0.01)。RA和OA關(guān)節(jié)液中ARGxx的濃度明顯高于FFGxx(p＜0.01);ADAM7S-4的濃度均高于ADAMTS-5(p＜0.01);MMP-3的濃度均高于MMP-2(p＜0.01)。OA關(guān)節(jié)液中ADAMTS-4的濃度與ARGxx成正相關(guān)(r=0.38,p＜0.05);ADAMTS-5與ARGxx以及MMP-2、MMP-3與FFGxx均無(wú)明顯相關(guān)關(guān)系。RA關(guān)節(jié)液中所測(cè)各酶與其產(chǎn)物之間均無(wú)相關(guān)關(guān)系。 結(jié)論: (1)ADAMTS-4在嚴(yán)重磨損的軟骨中大量表達(dá),說(shuō)明它不僅在OA早期起著重要作用,在中晚期OA的軟骨降解中仍然有重要作用;抑制ADAMTS-4對(duì)治療中晚期OA仍然有意義; (2)聚蛋白多糖酶總是集中表達(dá)在軟骨的靠近關(guān)節(jié)面的區(qū)域,強(qiáng)烈支持OA發(fā)病機(jī)制的機(jī)械應(yīng)力學(xué)說(shuō),并且說(shuō)明機(jī)械應(yīng)力并非簡(jiǎn)單地引起的磨損,同時(shí)可能是摩擦力激活了聚蛋白多糖酶,兩者的共同作用導(dǎo)致了軟骨的逐漸變薄; (3)關(guān)節(jié)液中ARGxx多于FFGxx提示對(duì)OA和RA關(guān)節(jié)軟骨聚蛋白多糖的丟失,聚蛋白多糖酶比MMP起了更大的作用; (4)OA病變關(guān)節(jié)中軟骨細(xì)胞是聚蛋白多糖酶的主要來(lái)源,在RA病變關(guān)節(jié)中聚蛋白多糖酶主要來(lái)源于軟骨細(xì)胞和血管翳;OA和RA的滑膜均少量表達(dá)聚蛋白多糖酶; (5)IL-1β可以上調(diào)ADAMTS-4的基因表達(dá),與機(jī)械摩擦力相比兩者作用的部位是不同的,提示OA出現(xiàn)滑膜炎癥時(shí)可以加速軟骨的降解; (6)RA關(guān)節(jié)液中聚蛋白多糖酶和MMP以及其代謝產(chǎn)物均高于OA關(guān)節(jié)液,提示在人類關(guān)節(jié)炎疾病過程中炎癥因子不僅參與上調(diào)MMP,同時(shí)上調(diào)了聚蛋白多糖酶的表達(dá)。
[Abstract]:Experimental background and purpose: the important pathological manifestation of articular cartilage destruction is the reduction of the cartilage extracellular matrix (ECM), in which the loss of polyproteoglycan is one of the main pathological manifestations of arthritis. Polyproteoglycan can be Asn~ (341) of matrix metalloproteinases (MMP) and polyprotease (Aggrecanase) in the core protein interzone (IGD), respectively. -Phe~ (342) site and Glu~ (373) -Ala~ (374) site degrade and produce new peptide chains of FFGxx and ARGxx respectively. So far the widely recognized polyprotease has ADAMTS-4 and ADAMTS-5. MMP-2 has a wide range of substrates in MMP family, including polyproteoglycan and type II collagen, MMP-3 is the strongest proteoglycan degradation in MMP family. Although polyprotease and MMP can both cleave the core protein of polyproteoglycan, which enzyme plays a major role in the disease state and the up-regulated factor of polyprotease is still a hot issue in recent years.
In vitro cartilage culture system confirms that the enzyme that degrades polyproteoglycan in the first few weeks is polyprotease, MMP plays a role in a few Zhou Houcai. The role of polyprotease in the late stage of cartilage degradation is not clear, and the factors that affect the expression of polyprotease in cartilage cells are more complex, even in the study in vitro. There are also great differences. For example, it is reported that the normal human cartilage treated with IL-1 does not affect the expression of ADAMTS-4 and ADAMTS-5, but the expression of ADAMTS-4 is increased after IL-1 stimulation in human chondrocytes, but it does not affect the expression of ADAMTS-5.
Osteoarthritis (OA) and rheumatoid arthritis (RA) have the pathological manifestations of articular cartilage destruction, but the two diseases are not the same as non inflammatory degenerative arthritis, and RA is autoimmune disease, inflammatory arthritis, and inflammatory factors, such as IL-1, play an important role. The comparative study of the two diseases is not only possible. To compare the effects of polyprotease and MMP, it is also important to reveal the expression of polyprotease in human disease. By comparing the expression of ADAMTS-4, ADAMTS-5, MMP-2 and MMP-3 and their products in cartilage, synovium and joint fluid of the OA and RA lesions, the polyprotease and MMP are discussed in this paper. The different roles and possible activation mechanisms of human disease.
Materials and methods: all specimens of this study were taken from the human knee joint femoral condyle, including 21 cases of OA cartilage and synovial membrane, 32 cases of OA joint fluid, 9 cases of RA cartilage, 12 cases of synovial membrane, 28 cases of articular fluid and 3 cases of OA cartilage of normal cartilage for 5 days (5 days), and the first day the 10ug/ml IL-1 beta was used to stimulate the cultured cartilaginous block. Immunohistochemistry was used to observe the expression of ADAMTS-4 in 3 normal cartilages and 15 cases of OA before and after culture. The distribution of ADAMTS-4 in the surface, middle and deep layers of different cartilage was compared. The differential expression of ADAMTS-4mRNA in 3 normal cartilages and 15 cases of OA before and after cultured OA was detected by semi quantitative RT-PCR. The expression of ADAMTS-4 and ADAMTS-5 in 21 cases of OA cartilage and synovium, 9 cases of RA cartilage and 12 cases of RA synovium were observed and compared. The expression of ADAMTS-4, ADAMTS-5, MMP-2 and MMP-3, and ARGxx and FFGxx in 32 cases of articular fluid and 28 joint fluid were observed by enzyme linked immunosorbent assay (ELISA). The absorbance (OD) value of ELISA represented the concentration of the tested substances in the joint fluid, and the results were tested by T and correlation analysis.
Results: in the immunohistochemical sections of 3 cases of normal cartilage, only a few chondrocytes were expressed in ADAMTS-4; the ADAMTS-4 expression area of OA cartilage mainly distributed in the cells of the cartilage surface, the expression of the medium layer cells was less, and the deep cartilage cells were almost not expressed. When the surface of the OA soft bone was worn, the ADAMTS-4 positive cells were mainly distributed in the cells. In the area near the surface of the joint, there are few positive cells near the deep layer, and the deep cartilage cells still have almost no expression of ADAMTS-4. When the cartilage is further worn and the middle layer is disappearing, the deep cells can be seen to proliferate and express ADAMTS; when the OA cartilage is co cultured with IL-1 beta, the expression of ADAMTS-4 is increased; the statistical results are increased. The number of ADAMTS-4 positive cells in the surface and middle layer of OA cartilage before and after culture was significantly higher than that of normal cartilage. There was no difference in the number of positive cells before and after OA cartilage culture, while the number of positive cells in the middle layer of OA cartilage increased obviously after the culture, and the result of.RT-PCR showed that the expression of ADAMTS-4 mRNA in OA cartilage was obviously higher than that of normal cartilage. Cartilage, after IL-1 stimulation, was significantly higher than that of OA cartilage.
The expression of ADAMTS-4 and ADAMTS-5 in all OA and RA cartilage, but the expression site is different, ADAMTS-4,5 is mainly expressed in the surface of OA cartilage, the surface of RA cartilage is replaced by pannus, and the cells strongly express polyprotease, and the number of positive cells in the middle cartilage layer is obviously higher than that of OA; OA synovium appears ADAMTS-4 and ADAMTS-5. The proportion of positive cells was 52% (11/21) and 43% (9/21) respectively, and there was no significant difference compared with 50% (6/12) and 58% (7/12) of RA.
ELISA results showed that the concentration of ADAMTS-4, ADAMTS-5, MMP-2 and MMP-3 as well as ARGxx and FFGxx in RA joint solution was higher than that of OA joint solution. The results showed significant difference (P < 0.01).RA and OA joint concentration was higher than that of 0.01. The concentration of ADAMTS-4 in the liquid is positively correlated with ARGxx (r=0.38, P < 0.05); ADAMTS-5 and ARGxx and MMP-2, MMP-3 and FFGxx have no significant correlation. There is no correlation between the enzymes measured in.RA joint fluid and their products.
Conclusion:
(1) the expression of ADAMTS-4 in severely worn cartilage indicates that it not only plays an important role in the early stage of OA, but also plays an important role in the degradation of cartilage in the middle and late stages of OA, and the inhibition of ADAMTS-4 is still significant for the treatment of OA in the middle and late stages.
(2) polyprotease is always concentrated in the area near the articular surface of the cartilage, strongly supports the mechanical stress of the pathogenesis of OA, and shows that the mechanical stress is not simply caused by the wear and tear, and it may be that the friction force activates the polyprotease, and the co action of the two causes the gradual thinning of the cartilage.
(3) ARGxx in the synovial fluid is more than FFGxx, suggesting that the loss of polyproteoglycan in articular cartilage of OA and RA is more significant than that of MMP.
(4) the chondrocytes in the OA lesions are the main source of polyprotease. In the RA lesion, polyprotease is mainly derived from the chondrocytes and pannus, and the synovial membrane of OA and RA expresses a small amount of polyprotease.
(5) IL-1 beta can up regulate the gene expression of ADAMTS-4, which is different from the mechanical friction, suggesting that the degradation of cartilage can be accelerated when OA occurs in synovitis.
(6) both polyprotease and MMP and their metabolites in RA joint fluid are higher than those of OA joint fluid. It is suggested that in the process of human arthritis, inflammatory factors not only participate in the up regulation of MMP, but also up the expression of polyprotease.
【學(xué)位授予單位】：山東大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2008
【分類號(hào)】：R341
本文編號(hào)：2136008
[Abstract]:Experimental background and purpose: the important pathological manifestation of articular cartilage destruction is the reduction of the cartilage extracellular matrix (ECM), in which the loss of polyproteoglycan is one of the main pathological manifestations of arthritis. Polyproteoglycan can be Asn~ (341) of matrix metalloproteinases (MMP) and polyprotease (Aggrecanase) in the core protein interzone (IGD), respectively. -Phe~ (342) site and Glu~ (373) -Ala~ (374) site degrade and produce new peptide chains of FFGxx and ARGxx respectively. So far the widely recognized polyprotease has ADAMTS-4 and ADAMTS-5. MMP-2 has a wide range of substrates in MMP family, including polyproteoglycan and type II collagen, MMP-3 is the strongest proteoglycan degradation in MMP family. Although polyprotease and MMP can both cleave the core protein of polyproteoglycan, which enzyme plays a major role in the disease state and the up-regulated factor of polyprotease is still a hot issue in recent years.
In vitro cartilage culture system confirms that the enzyme that degrades polyproteoglycan in the first few weeks is polyprotease, MMP plays a role in a few Zhou Houcai. The role of polyprotease in the late stage of cartilage degradation is not clear, and the factors that affect the expression of polyprotease in cartilage cells are more complex, even in the study in vitro. There are also great differences. For example, it is reported that the normal human cartilage treated with IL-1 does not affect the expression of ADAMTS-4 and ADAMTS-5, but the expression of ADAMTS-4 is increased after IL-1 stimulation in human chondrocytes, but it does not affect the expression of ADAMTS-5.
Osteoarthritis (OA) and rheumatoid arthritis (RA) have the pathological manifestations of articular cartilage destruction, but the two diseases are not the same as non inflammatory degenerative arthritis, and RA is autoimmune disease, inflammatory arthritis, and inflammatory factors, such as IL-1, play an important role. The comparative study of the two diseases is not only possible. To compare the effects of polyprotease and MMP, it is also important to reveal the expression of polyprotease in human disease. By comparing the expression of ADAMTS-4, ADAMTS-5, MMP-2 and MMP-3 and their products in cartilage, synovium and joint fluid of the OA and RA lesions, the polyprotease and MMP are discussed in this paper. The different roles and possible activation mechanisms of human disease.
Materials and methods: all specimens of this study were taken from the human knee joint femoral condyle, including 21 cases of OA cartilage and synovial membrane, 32 cases of OA joint fluid, 9 cases of RA cartilage, 12 cases of synovial membrane, 28 cases of articular fluid and 3 cases of OA cartilage of normal cartilage for 5 days (5 days), and the first day the 10ug/ml IL-1 beta was used to stimulate the cultured cartilaginous block. Immunohistochemistry was used to observe the expression of ADAMTS-4 in 3 normal cartilages and 15 cases of OA before and after culture. The distribution of ADAMTS-4 in the surface, middle and deep layers of different cartilage was compared. The differential expression of ADAMTS-4mRNA in 3 normal cartilages and 15 cases of OA before and after cultured OA was detected by semi quantitative RT-PCR. The expression of ADAMTS-4 and ADAMTS-5 in 21 cases of OA cartilage and synovium, 9 cases of RA cartilage and 12 cases of RA synovium were observed and compared. The expression of ADAMTS-4, ADAMTS-5, MMP-2 and MMP-3, and ARGxx and FFGxx in 32 cases of articular fluid and 28 joint fluid were observed by enzyme linked immunosorbent assay (ELISA). The absorbance (OD) value of ELISA represented the concentration of the tested substances in the joint fluid, and the results were tested by T and correlation analysis.
Results: in the immunohistochemical sections of 3 cases of normal cartilage, only a few chondrocytes were expressed in ADAMTS-4; the ADAMTS-4 expression area of OA cartilage mainly distributed in the cells of the cartilage surface, the expression of the medium layer cells was less, and the deep cartilage cells were almost not expressed. When the surface of the OA soft bone was worn, the ADAMTS-4 positive cells were mainly distributed in the cells. In the area near the surface of the joint, there are few positive cells near the deep layer, and the deep cartilage cells still have almost no expression of ADAMTS-4. When the cartilage is further worn and the middle layer is disappearing, the deep cells can be seen to proliferate and express ADAMTS; when the OA cartilage is co cultured with IL-1 beta, the expression of ADAMTS-4 is increased; the statistical results are increased. The number of ADAMTS-4 positive cells in the surface and middle layer of OA cartilage before and after culture was significantly higher than that of normal cartilage. There was no difference in the number of positive cells before and after OA cartilage culture, while the number of positive cells in the middle layer of OA cartilage increased obviously after the culture, and the result of.RT-PCR showed that the expression of ADAMTS-4 mRNA in OA cartilage was obviously higher than that of normal cartilage. Cartilage, after IL-1 stimulation, was significantly higher than that of OA cartilage.
The expression of ADAMTS-4 and ADAMTS-5 in all OA and RA cartilage, but the expression site is different, ADAMTS-4,5 is mainly expressed in the surface of OA cartilage, the surface of RA cartilage is replaced by pannus, and the cells strongly express polyprotease, and the number of positive cells in the middle cartilage layer is obviously higher than that of OA; OA synovium appears ADAMTS-4 and ADAMTS-5. The proportion of positive cells was 52% (11/21) and 43% (9/21) respectively, and there was no significant difference compared with 50% (6/12) and 58% (7/12) of RA.
ELISA results showed that the concentration of ADAMTS-4, ADAMTS-5, MMP-2 and MMP-3 as well as ARGxx and FFGxx in RA joint solution was higher than that of OA joint solution. The results showed significant difference (P < 0.01).RA and OA joint concentration was higher than that of 0.01. The concentration of ADAMTS-4 in the liquid is positively correlated with ARGxx (r=0.38, P < 0.05); ADAMTS-5 and ARGxx and MMP-2, MMP-3 and FFGxx have no significant correlation. There is no correlation between the enzymes measured in.RA joint fluid and their products.
Conclusion:
(1) the expression of ADAMTS-4 in severely worn cartilage indicates that it not only plays an important role in the early stage of OA, but also plays an important role in the degradation of cartilage in the middle and late stages of OA, and the inhibition of ADAMTS-4 is still significant for the treatment of OA in the middle and late stages.
(2) polyprotease is always concentrated in the area near the articular surface of the cartilage, strongly supports the mechanical stress of the pathogenesis of OA, and shows that the mechanical stress is not simply caused by the wear and tear, and it may be that the friction force activates the polyprotease, and the co action of the two causes the gradual thinning of the cartilage.
(3) ARGxx in the synovial fluid is more than FFGxx, suggesting that the loss of polyproteoglycan in articular cartilage of OA and RA is more significant than that of MMP.
(4) the chondrocytes in the OA lesions are the main source of polyprotease. In the RA lesion, polyprotease is mainly derived from the chondrocytes and pannus, and the synovial membrane of OA and RA expresses a small amount of polyprotease.
(5) IL-1 beta can up regulate the gene expression of ADAMTS-4, which is different from the mechanical friction, suggesting that the degradation of cartilage can be accelerated when OA occurs in synovitis.
(6) both polyprotease and MMP and their metabolites in RA joint fluid are higher than those of OA joint fluid. It is suggested that in the process of human arthritis, inflammatory factors not only participate in the up regulation of MMP, but also up the expression of polyprotease.
【學(xué)位授予單位】：山東大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2008
【分類號(hào)】：R341
【參考文獻(xiàn)】
相關(guān)期刊論文 前2條
1 管劍龍,施桂英;基質(zhì)金屬蛋白酶與骨關(guān)節(jié)炎[J];中華風(fēng)濕病學(xué)雜志;2000年01期
2 婁思權(quán);骨關(guān)節(jié)炎的病理與發(fā)病因素[J];中華骨科雜志;1996年01期
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