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Article(id=1198652611583901873, tenantId=1146029695717560320, journalId=1189982191388893191, issueId=1198652605778985059, articleNumber=null, orderNo=null, doi=10.16438/j.0513-4870.2023-0036, pmid=null, cstr=null, oa=null, hot=null, price=null, onlineType=0, articleFormat=0, articleType=null, articleTypeStr=null, receivedDate=1673452800000, receivedDateStr=2023-01-12, revisedDate=1683216000000, revisedDateStr=2023-05-05, acceptedDate=null, acceptedDateStr=null, onlineDate=1763710652489, onlineDateStr=2025-11-21, pubDate=1691769600000, pubDateStr=2023-08-12, doiRegisterDate=null, doiRegisterDateStr=null, onlineIssueDate=1763710652489, onlineIssueDateStr=2025-11-21, onlineJustAcceptDate=null, onlineJustAcceptDateStr=null, onlineFirstDate=null, onlineFirstDateStr=null, sourceXml=null, magXml=null, createTime=1763710652489, creator=13701087609, updateTime=1763710652489, updator=13701087609, issue=Issue{id=1198652605778985059, tenantId=1146029695717560320, journalId=1189982191388893191, year='2023', volume='58', issue='8', pageStart='0', pageEnd='2540', issueExtLink='null', onlineDate='null', pubDate='1691769600000', pubDateStr='2023-08-12', beforeIssueId=null, nextIssueId=null, price=null, status=1, issueComplete=1, articleOrder=1, issueType=-1, specialIssue=null, createTime=1763710651106, creator='13701087609', updateTime=1763710739504, updator='13701087609', preIssue=null, nextIssue=null, articleTotal=null, ext={EN=IssueExt(id=1198652976601596347, tenantId=1146029695717560320, journalId=1189982191388893191, issueId=1198652605778985059, language=EN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=), CN=IssueExt(id=1198652976601596348, tenantId=1146029695717560320, journalId=1189982191388893191, issueId=1198652605778985059, language=CN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=)}, issueFiles=null, downloadFileDto=null}, startPage=2415, endPage=2423, ext={EN=ArticleExt(id=1198652611953000651, articleId=1198652611583901873, tenantId=1146029695717560320, journalId=1189982191388893191, language=EN, title=Effect of obesity induced by high-fat diet and adipose exosomes on knee post-traumatic osteoarthritis caused by destabilization of medial meniscus surgery in young mice, columnId=null, journalTitle=Acta Pharmaceutica Sinica, columnName=null, runingTitle=null, highlight=null, articleAbstract=

Obesity is an important risk factor related to osteoarthritis, but it′s role in post-traumatic osteoarthritis on young people need to further study. The internal mechanism except the mechanical loading may be associated with adipose exosomes. To examine the effect of obesity induced by high fat diet and adipose exosomes on knee post-traumatic osteoarthritis caused by destabilization of medial meniscus (DMM) surgery in young mice, 20 6-week-old C57BL/6J mice were randomly assigned to the control diet group (CD, n = 5), the DMM group (n = 5), the high fat diet group (HFD, n = 5) and the HFD plus DMM group (HFD+DMM, n = 5). The CD and DMM group were fed with a control diet, and the HFD and HFD+DMM group were fed with a high fat diet. We did the DMM surgery and the sham surgery on the mice when it was 10 weeks old. Extract obese and normal adipose exosomes, identify exosomes in vitro, and proceed fluorescence imaging in vivo using DiR staining. DMM+HFD-Exo group and DMM+CD-Exo group were injected the exosomes from the tail vain once a week (100 μL per shot with a concentration of 1 μg·μL-1). Second, 15 6-week-old C57BL/6J mice were randomly assigned to the DMM group (n = 5), the DMM plus obese adipose exosomes group (DMM+HFD-Exo, n = 5), and the DMM plus control diet adipose exosomes group (DMM+CD-Exo, n = 5). Animal welfare and experimental process are in accordance with the regulations of the Experimental Animal Ethics Committee of Nanjing University (IACUC-D2204005). All mice were sacrificed at the age of 18 weeks, the knee joints of the mice were harvested and fixed. We used micro CT to examine the samples and measured the bone volume/tissue volume, trabecular thickness, trabecular number and trabecular separation. Then the samples were decalcified and embedded in paraffin, and 4 μm thickness sections were stained with H&E and safranin O/fast green to observe the histological changes of the knee joint. The results showed compared with the control diet group, high fat diet induced obesity can aggravate the pathological changes of the post-traumatic osteoarthritis caused by DMM surgery, which shows in having a higher Mankin score. The surface of knee articular cartilage in the HFD+DMM group was rough, and the subchondral bone has an increase in bone sclerosis. Compared with the DMM group, obese adipose exosomes can exacerbate the pathological changes of the knee articular cartilage, while not influencing the subchondral bone. In conclusion, high fat diet induced obesity can aggravate the post-traumatic osteoarthritis caused by DMM surgery in young mice. The obese adipose exosomes mainly affect the surface of the knee articular cartilage.

, authors=null, authorsList=Li-tong WU, Bao-chao LI, Bo YAO, Zi-chun HUA, authorCompany=null, correspAuthors=Zi-chun HUA, authorNote=null, correspAuthorsNote=null, copyrightStatement=Copyright ©2023 Acta Pharmaceutica Sinica. All rights reserved., copyrightOwner=null, extLink=null, articleAbsUrl=null, sourceXml=null, magXml=null, pdfUrl=null, pdf=null, pdfFileSize=null, pdfExtLink=null, richHtmlUrl=null, mobilePdfUrl=null, reviewReport=null, pdfFirstPage=null, abstractGraph=null, abstractGraphContent=null, abstractVideo=null, citation=null, cebUrl=null, magXmlContent=null, mapNumber=null, fund=null), CN=ArticleExt(id=1198652615690125711, articleId=1198652611583901873, tenantId=1146029695717560320, journalId=1189982191388893191, language=CN, title=高脂饮食诱导的肥胖及其脂肪细胞外泌体对年轻小鼠创伤性膝关节炎的影响及机制研究, columnId=1190335348896011050, journalTitle=药学学报, columnName=研究论文, runingTitle=null, highlight=null, articleAbstract=

肥胖是膝关节炎的重要风险因素, 但其对于青少年创伤性骨关节炎的影响仍有待于进一步研究。除了机械负重, 其内在机制是否和脂肪组织外泌体的远程调控相关？为明确高脂饮食诱导的肥胖及其分泌的脂肪组织外泌体对年轻小鼠创伤性膝关节炎的影响作用, 本研究首先将20只6周龄C57BL/6J年轻小鼠随机分为正常饮食组(control diet, CD组)、内侧半月板失稳术(destabilization of medial meniscus, DMM) 手术组、高脂饮食组(high fat diet, HFD组) 及高脂饮食加DMM手术组(HFD+DMM组), 每组5只小鼠。CD和DMM组喂养常规饲料, HFD和HFD+DMM组喂养高脂饲料。在小鼠10周龄时进行DMM手术或假手术。提取高脂饮食组和正常饮食组小鼠脂肪组织外泌体(exosomes, Exo), 进行体外鉴定, 荧光标记活体成像。然后, 本研究将15只6周龄C57BL/6J小鼠随机分为DMM组、DMM加肥胖小鼠脂肪组织外泌体注射组(DMM+HFD-Exo组) 及DMM加正常小鼠脂肪细胞外泌体注射组(DMM+CD-Exo组), 每组5只小鼠。DMM+HFD-Exo组与DMM+CD-Exo组小鼠进行外泌体尾静脉注射, 每周一次(每次100 μL, 浓度为1 μg·μL-1)。本研究动物福利和实验过程均遵循南京大学实验动物伦理委员会的规定(批准号: IACUC-D2204005)。所有组别的小鼠于18周时终止实验, 取膝关节软骨组织进行固定, 行micro CT检测, 测量骨体积分数、骨小梁厚度、骨小梁数目和骨小梁分离度。然后再将组织标本脱钙, 制成4 μm的石蜡切片, 进行H&E及番红O固绿染色, 观察小鼠膝关节的组织形态学变化。结果显示, 与正常饮食组相比, 高脂饮食诱导的肥胖能显著加重年轻小鼠创伤性膝关节炎的病理变化, 表现为软骨Mankin评分增加, 软骨表面粗糙, 软骨下骨硬化增加; 肥胖组织外泌体能加重DMM手术诱导的软骨病理变化, 但不加重软骨下骨病变。因此, 高脂饮食诱导的肥胖可以显著加重DMM手术诱导的年轻小鼠的创伤性膝关节炎, 其机制与脂肪组织外泌体对膝关节的远程调控有部分关联。

, authors=null, authorsList=吴立桐, 李保超, 姚波, 华子春, authorCompany=null, correspAuthors=华子春, authorNote=null, correspAuthorsNote=
*华子春, Tel: 13814039758, E-mail:
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School of Life Sciences, Nanjing University, Nanjing 210023, China
4. Jiangsu Society of Biochemistry and Molecular Biology and Nanjing Genrecom Laboratories, Ltd., Nanjing 211899, China, bio=null, bioImg=null, bioContent=null, aboutCorrespAuthor=null), CN=AuthorExt(id=1198960115429766134, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1198652611583901873, authorId=1198960115194885079, language=CN, stringName=华子春, firstName=子春, middleName=null, lastName=华, prefix=null, suffix=null, authorComment=null, nameInitials=null, affiliation=null, department=null, xref=3, 4, *, address=3.南京大学生命科学学院, 江苏 南京 210023
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BMC Immunol, 2022, 23: 37., articleTitle=Blockade of exosome generation by GW4869 inhibits the education of M2 macrophages in prostate cancer, refAbstract=null), Reference(id=1198960123935814482, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1198652611583901873, doi=null, pmid=null, pmcid=null, year=2022, volume=57, issue=null, pageStart=1010, pageEnd=1016, url=http://www.yxxb.com.cn/aps/cn/article/doi/10.16438/j.0513-4870.2021-1363, language=null, rfNumber=[19], rfOrder=18, authorNames=null, journalName=Acta Pharm Sin (药学学报), refType=null, unstructuredReference=Miao YM, Zhong YL, Wei ZF Mulberry pigment inhibits Th17/Treg imbalance and improves collagen arthritis in mice[J]. 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The high fat diet (HFD) group, the control diet group (CD), the destabilization of medial meniscus (DMM) group, and the HFD plus DMM group (HFD+DMM) , figureFileSmall=zY6gzI0lvE3BUbsnC4P48A==, figureFileBig=0LVart3IXIYYZlnB4Zp2Yg==, tableContent=null), ArticleFig(id=1198960117564666075, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1198652611583901873, language=EN, label=null, caption=null, figureFileSmall=O+roiYOGfMSawVNG2h/x3g==, figureFileBig=tuFKTQnLcSvrGmoy37ZtPA==, tableContent=null), ArticleFig(id=1198960117728243952, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1198652611583901873, language=CN, label=Figure 2, caption= The second animal experimental scheme. The adipocyte exosome injection from the HFD mice and the CD mice on DMM model , figureFileSmall=O+roiYOGfMSawVNG2h/x3g==, figureFileBig=tuFKTQnLcSvrGmoy37ZtPA==, tableContent=null), ArticleFig(id=1198960117870850306, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1198652611583901873, language=EN, label=null, caption=null, figureFileSmall=qijhjA2UdwV8OiM/eTXFIA==, figureFileBig=onc+tF28Uv5f9eVB+Fa31Q==, tableContent=null), ArticleFig(id=1198960117975707916, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1198652611583901873, language=CN, label=Figure 3, caption= Changes in body weight and adipose tissue of mice in each group during the experimental period. A: Representative photos of mice treated with either CD or HFD for 12 weeks; B: The average body weight of CD and HFD mice; C: Representative photos of the adipocyte tissue of CD and HFD mice. <i>n</i> = 5, <span class="mag-xml-overline" style="border-top:1px solid black"><i>x</i></span> ± <i>s</i>. <sup>***</sup><i>P</i> < 0.001 , figureFileSmall=qijhjA2UdwV8OiM/eTXFIA==, figureFileBig=onc+tF28Uv5f9eVB+Fa31Q==, tableContent=null), ArticleFig(id=1198960118101537050, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1198652611583901873, language=EN, label=null, caption=null, figureFileSmall=ITuy8x/rf1VB3LQWch9JJw==, figureFileBig=BABk8JjMhQFWQtvsXGvm3w==, tableContent=null), ArticleFig(id=1198960118290280751, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1198652611583901873, language=CN, label=Figure 4, caption= The morphological changes of the knee joints of mice in each group (<i>n</i> = 5) , figureFileSmall=ITuy8x/rf1VB3LQWch9JJw==, figureFileBig=BABk8JjMhQFWQtvsXGvm3w==, tableContent=null), ArticleFig(id=1198960118495801651, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1198652611583901873, language=EN, label=null, caption=null, figureFileSmall=zl6Zdbb1xMDgELfAISjr3w==, figureFileBig=4F2ZxvpcFYOjprjkk/E7Og==, tableContent=null), ArticleFig(id=1198960118676156739, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1198652611583901873, language=CN, label=Figure 5, caption= The knee joint osteoarthritis (OA) is exacerbated in obese mice induced by HFD. A, B: Representative H&E staining images (A) and SO staining images (B) of the sagittal plane of the knee joint in each group. Scale bar: 100 µm; C: The modified Mankin score of the cartilage. <i>n</i> = 5, <span class="mag-xml-overline" style="border-top:1px solid black"><i>x</i></span> ± <i>s.</i> <sup>*</sup><i>P</i> < 0.05, <sup>***</sup><i>P</i> < 0.001 , figureFileSmall=zl6Zdbb1xMDgELfAISjr3w==, figureFileBig=4F2ZxvpcFYOjprjkk/E7Og==, tableContent=null), ArticleFig(id=1198960118860706133, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1198652611583901873, language=EN, label=null, caption=null, figureFileSmall=xA93QockhlWDpxmHuXh4SA==, figureFileBig=gtetxlanIt8OCQUSgurfzQ==, tableContent=null), ArticleFig(id=1198960118978146664, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1198652611583901873, language=CN, label=Figure 6, caption= Morphological changes and quantitative analysis of the subchondral bone of the knee joint in CD, DMM, HFD, and HFD + DMM group. A: Representative reconstruction images of the micro CT analysis of trabeculae of knee joint subchondral bone in each group; B-E: The value of BV/TV, Tb.Th, Tb.N and Tb.Sp of knee joint subchondral bone. <i>n</i> = 5, <span class="mag-xml-overline" style="border-top:1px solid black"><i>x</i></span> ± <i>s.</i> <sup>*</sup><i>P</i> < 0.05, <sup>**</sup><i>P</i> < 0.01, <sup>***</sup><i>P</i> < 0.001. ns: <i>P</i> > 0.05. BV/TV: Bone volume/tissue volume; Tb.Th: Trabecular thickness; Tb.N: Trabecular number; Tb.Sp: Trabecular separation , figureFileSmall=xA93QockhlWDpxmHuXh4SA==, figureFileBig=gtetxlanIt8OCQUSgurfzQ==, tableContent=null), ArticleFig(id=1198960119070421358, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1198652611583901873, language=EN, label=null, caption=null, figureFileSmall=Lid2YxjNNbjI9a4NEyRO1w==, figureFileBig=5tqJX0VY6qEWvX3qUF1NFA==, tableContent=null), ArticleFig(id=1198960119192056186, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1198652611583901873, language=CN, label=Figure 7, caption= Characterization of CD and HFD-adpocyte derived exosomes. A: TEM analysis of CD-Exo and HFD-Exo. Scale bar: 100 nm; B: The exosome-related protein markers CD81 and TSG101 were measured by Western blot; C: Particle size and distribution of CD-Ad-Exo and HFD-Ad-Exo analyzed using nanosight tracking analysis. Ad-Exo: Adipocyte exosomes; CD81: Cluster of differentiation 81; TSG101: Tumor susceptibility gene 101 , figureFileSmall=Lid2YxjNNbjI9a4NEyRO1w==, figureFileBig=5tqJX0VY6qEWvX3qUF1NFA==, tableContent=null), ArticleFig(id=1198960119313691013, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1198652611583901873, language=EN, label=null, caption=null, figureFileSmall=1UPvZ+qdmmR9wqWahOfB+g==, figureFileBig=9/cWJQO+vmeFhQHZ6bh9Fg==, tableContent=null), ArticleFig(id=1198960119452103056, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1198652611583901873, language=CN, label=Figure 8, caption= Fluorescence imaging of DiR-labeled CD-Exo and HFD-Exo in knee joint area after 24 h of intravenous injection. A, B: Imaging of CD-Exo distribution in knee joint; C, D: Imaging of HFD-Exo distribution in knee joint , figureFileSmall=1UPvZ+qdmmR9wqWahOfB+g==, figureFileBig=9/cWJQO+vmeFhQHZ6bh9Fg==, tableContent=null), ArticleFig(id=1198960119552766364, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1198652611583901873, language=EN, label=null, caption=null, figureFileSmall=OiJK4T/ZK22USQux3Svw/Q==, figureFileBig=r++z93UTZfbb7fTkRcO/pQ==, tableContent=null), ArticleFig(id=1198960119712149938, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1198652611583901873, language=CN, label=Figure 9, caption= The knee joint OA is exacerbated by Ad-Exo from obese mice induced by HFD. A, B: Representative H&E staining images and SO staining images of the sagittal plane of the knee joint in each group. Scale bar: 100 µm; C: The modified Mankin score of the cartilage. <i>n</i> = 5, <span class="mag-xml-overline" style="border-top:1px solid black"><i>x</i></span> ± <i>s.</i> <sup>*</sup><i>P</i> < 0.05; D: The effect of GW4869 (GW) on the chondrocyte metabolic protein marker Col 2 and MMP13 <i>in vitro</i> (<i>n</i> = 5), and the protein levels of Col 2 and MMP13 in chondrocyte was detected by Western blot. Col 2: Type Ⅱ collagen; MMP13: Matrix metalloproteinases 13 , figureFileSmall=OiJK4T/ZK22USQux3Svw/Q==, figureFileBig=r++z93UTZfbb7fTkRcO/pQ==, tableContent=null), ArticleFig(id=1198960119825396157, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1198652611583901873, language=EN, label=null, caption=null, figureFileSmall=aJJUQ7FwWFrN71k1VDtEBw==, figureFileBig=LSwuIAh5ewOh7iFS3uLRmg==, tableContent=null), ArticleFig(id=1198960119984779726, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1198652611583901873, language=CN, label=Figure 10, caption= Morphological changes and quantitative analysis of the subchondral bone of the knee joint in DMM, DMM + HFD-Exo, and DMM + CD-Exo group. A: Representative reconstruction images of the micro CT analysis of trabeculae of knee joint subchondral bone in each group; B-E: The value of BV/TV, Tb.Th, Tb.N and Tb.Sp of knee joint subchondral bone. <i>n</i> = 5, <span class="mag-xml-overline" style="border-top:1px solid black"><i>x</i></span> ± <i>s</i>. <sup>*</sup><i>P</i> < 0.05 , figureFileSmall=aJJUQ7FwWFrN71k1VDtEBw==, figureFileBig=LSwuIAh5ewOh7iFS3uLRmg==, tableContent=null), ArticleFig(id=1198960120152551901, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1198652611583901873, language=EN, label=null, caption=null, figureFileSmall=null, figureFileBig=null, tableContent=
Cartilage integrity Score Chondrocyte Score Proteoglycan loss Score Tidemark integrity Score
Normal 0 Normal 0 Normal 0 Complete 0
Surface irregularity 1 Increase in whole area 1 Mild loss 1 Missing 1
Surface irregularity and pannus formation 2 Increase in local area 2 Moderate loss 2
Cracks into the transition layer 3 Decreased significantly 3 Severe loss 3
Cracks into the radiation layer 4 No staining 4
Cracks into the calcified layer 5
Complete destruction 6
), ArticleFig(id=1198960120324518382, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1198652611583901873, language=CN, label=Table 1, caption=

The modified Mankin score

, figureFileSmall=null, figureFileBig=null, tableContent=
Cartilage integrity Score Chondrocyte Score Proteoglycan loss Score Tidemark integrity Score
Normal 0 Normal 0 Normal 0 Complete 0
Surface irregularity 1 Increase in whole area 1 Mild loss 1 Missing 1
Surface irregularity and pannus formation 2 Increase in local area 2 Moderate loss 2
Cracks into the transition layer 3 Decreased significantly 3 Severe loss 3
Cracks into the radiation layer 4 No staining 4
Cracks into the calcified layer 5
Complete destruction 6
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高脂饮食诱导的肥胖及其脂肪细胞外泌体对年轻小鼠创伤性膝关节炎的影响及机制研究
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吴立桐 1 , 李保超 2 , 姚波 1 , 华子春 3, 4, *
药学学报 | 研究论文 2023,58(8): 2415-2423
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药学学报 |研究论文 2023 , 58 (8) : 2415 -2423
高脂饮食诱导的肥胖及其脂肪细胞外泌体对年轻小鼠创伤性膝关节炎的影响及机制研究
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School of Life Sciences, Nanjing University, Nanjing 210023, China
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吴立桐1, 李保超2, 姚波1, 华子春3, 4, *
作者信息
  • 1.南京外国语学校, 江苏 南京 210008
  • 2.南京大学医学院附属口腔医院, 南京市口腔医院, 江苏 南京 210019
  • 3.南京大学生命科学学院, 江苏 南京 210023
  • 4.江苏省生物化学与分子生物学学会和南京吉芮康生物科技研究院, 江苏 南京 211899
通讯作者:
*华子春, Tel: 13814039758, E-mail:
Effect of obesity induced by high-fat diet and adipose exosomes on knee post-traumatic osteoarthritis caused by destabilization of medial meniscus surgery in young mice
Li-tong WU1, Bao-chao LI2, Bo YAO1, Zi-chun HUA3, 4, *
Affiliations
  • 1. Nanjing Foreign Language School, Nanjing 210008, China
  • 2. Nanjing Stomatological Hospital, Affiliated Stomatological Hospital, Medical School, Nanjing University, Nanjing 210019, China
  • 3. School of Life Sciences, Nanjing University, Nanjing 210023, China
  • 4. Jiangsu Society of Biochemistry and Molecular Biology and Nanjing Genrecom Laboratories, Ltd., Nanjing 211899, China
出版时间: 2023-08-12 doi: 10.16438/j.0513-4870.2023-0036
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肥胖是膝关节炎的重要风险因素, 但其对于青少年创伤性骨关节炎的影响仍有待于进一步研究。除了机械负重, 其内在机制是否和脂肪组织外泌体的远程调控相关？为明确高脂饮食诱导的肥胖及其分泌的脂肪组织外泌体对年轻小鼠创伤性膝关节炎的影响作用, 本研究首先将20只6周龄C57BL/6J年轻小鼠随机分为正常饮食组(control diet, CD组)、内侧半月板失稳术(destabilization of medial meniscus, DMM) 手术组、高脂饮食组(high fat diet, HFD组) 及高脂饮食加DMM手术组(HFD+DMM组), 每组5只小鼠。CD和DMM组喂养常规饲料, HFD和HFD+DMM组喂养高脂饲料。在小鼠10周龄时进行DMM手术或假手术。提取高脂饮食组和正常饮食组小鼠脂肪组织外泌体(exosomes, Exo), 进行体外鉴定, 荧光标记活体成像。然后, 本研究将15只6周龄C57BL/6J小鼠随机分为DMM组、DMM加肥胖小鼠脂肪组织外泌体注射组(DMM+HFD-Exo组) 及DMM加正常小鼠脂肪细胞外泌体注射组(DMM+CD-Exo组), 每组5只小鼠。DMM+HFD-Exo组与DMM+CD-Exo组小鼠进行外泌体尾静脉注射, 每周一次(每次100 μL, 浓度为1 μg·μL-1)。本研究动物福利和实验过程均遵循南京大学实验动物伦理委员会的规定(批准号: IACUC-D2204005)。所有组别的小鼠于18周时终止实验, 取膝关节软骨组织进行固定, 行micro CT检测, 测量骨体积分数、骨小梁厚度、骨小梁数目和骨小梁分离度。然后再将组织标本脱钙, 制成4 μm的石蜡切片, 进行H&E及番红O固绿染色, 观察小鼠膝关节的组织形态学变化。结果显示, 与正常饮食组相比, 高脂饮食诱导的肥胖能显著加重年轻小鼠创伤性膝关节炎的病理变化, 表现为软骨Mankin评分增加, 软骨表面粗糙, 软骨下骨硬化增加; 肥胖组织外泌体能加重DMM手术诱导的软骨病理变化, 但不加重软骨下骨病变。因此, 高脂饮食诱导的肥胖可以显著加重DMM手术诱导的年轻小鼠的创伤性膝关节炎, 其机制与脂肪组织外泌体对膝关节的远程调控有部分关联。

高脂饮食  /  肥胖  /  脂肪组织  /  外泌体  /  创伤性膝关节炎

Obesity is an important risk factor related to osteoarthritis, but it′s role in post-traumatic osteoarthritis on young people need to further study. The internal mechanism except the mechanical loading may be associated with adipose exosomes. To examine the effect of obesity induced by high fat diet and adipose exosomes on knee post-traumatic osteoarthritis caused by destabilization of medial meniscus (DMM) surgery in young mice, 20 6-week-old C57BL/6J mice were randomly assigned to the control diet group (CD, n = 5), the DMM group (n = 5), the high fat diet group (HFD, n = 5) and the HFD plus DMM group (HFD+DMM, n = 5). The CD and DMM group were fed with a control diet, and the HFD and HFD+DMM group were fed with a high fat diet. We did the DMM surgery and the sham surgery on the mice when it was 10 weeks old. Extract obese and normal adipose exosomes, identify exosomes in vitro, and proceed fluorescence imaging in vivo using DiR staining. DMM+HFD-Exo group and DMM+CD-Exo group were injected the exosomes from the tail vain once a week (100 μL per shot with a concentration of 1 μg·μL-1). Second, 15 6-week-old C57BL/6J mice were randomly assigned to the DMM group (n = 5), the DMM plus obese adipose exosomes group (DMM+HFD-Exo, n = 5), and the DMM plus control diet adipose exosomes group (DMM+CD-Exo, n = 5). Animal welfare and experimental process are in accordance with the regulations of the Experimental Animal Ethics Committee of Nanjing University (IACUC-D2204005). All mice were sacrificed at the age of 18 weeks, the knee joints of the mice were harvested and fixed. We used micro CT to examine the samples and measured the bone volume/tissue volume, trabecular thickness, trabecular number and trabecular separation. Then the samples were decalcified and embedded in paraffin, and 4 μm thickness sections were stained with H&E and safranin O/fast green to observe the histological changes of the knee joint. The results showed compared with the control diet group, high fat diet induced obesity can aggravate the pathological changes of the post-traumatic osteoarthritis caused by DMM surgery, which shows in having a higher Mankin score. The surface of knee articular cartilage in the HFD+DMM group was rough, and the subchondral bone has an increase in bone sclerosis. Compared with the DMM group, obese adipose exosomes can exacerbate the pathological changes of the knee articular cartilage, while not influencing the subchondral bone. In conclusion, high fat diet induced obesity can aggravate the post-traumatic osteoarthritis caused by DMM surgery in young mice. The obese adipose exosomes mainly affect the surface of the knee articular cartilage.

high-fat diet  /  obesity  /  adipose tissue  /  exosome  /  post-traumatic knee osteoarthritis
吴立桐, 李保超, 姚波, 华子春. 高脂饮食诱导的肥胖及其脂肪细胞外泌体对年轻小鼠创伤性膝关节炎的影响及机制研究. 药学学报, 2023 , 58 (8) : 2415 -2423 . DOI: 10.16438/j.0513-4870.2023-0036
Li-tong WU, Bao-chao LI, Bo YAO, Zi-chun HUA. Effect of obesity induced by high-fat diet and adipose exosomes on knee post-traumatic osteoarthritis caused by destabilization of medial meniscus surgery in young mice[J]. Acta Pharmaceutica Sinica, 2023 , 58 (8) : 2415 -2423 . DOI: 10.16438/j.0513-4870.2023-0036
正文
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膝关节炎(osteoarthritis, OA) 是临床最为常见的一种疾病, 其中创伤性骨关节炎是OA中的一种亚型。创伤性骨关节炎是由创伤引起的以关节软骨的退化和继发性软骨增生骨化为主要病理变化的一种疾病, 临床主要表现为关节疼痛和活动功能障碍, 以青壮年多见, 多发于创伤后或者长期负重过度的关节如膝关节[1, 2]。肥胖是骨关节炎最主要的可控风险因素[3, 4], 据已有研究表明, 肥胖使关节处增加额外的机械压力, 肥胖者患膝关节炎几率达64.5%, 而体重正常者则为34.9%。中国疾病控制中心的数据表明, 我国6~17岁的儿童和青少年超重的肥胖率接近20%, 这表明青少年肥胖已经成为一个重要的公共健康问题。由于青少年爱好运动, 膝关节在运动中容易发生损伤。因此, 除了机械负重, 肥胖促进创伤性膝关节炎进展的其他机制研究也显得尤为重要。
肥胖状态下, 全身脂肪组织增加, 会分泌一系列的炎症因子和脂肪因子, 从而促进骨关节炎的发生和发展[5, 6]。近来, 脂肪细胞外泌体(adipocyte exosomes, Ad-Exo) 作为一种新型脂肪因子引起了学者们的关注。脂肪细胞外泌体是由脂肪细胞分泌的包含大量信息分子的囊泡, 它能够为细胞间的信号传递提供新途径, 具有存活时间长、难以降解、可远距离运输及特异性传递的特点[7, 8]。目前, 已经证实肥胖状态下脂肪细胞分泌的外泌体会出现量和质的改变, 通过血液循环运输到不同的靶器官发挥其生物学作用[9]。由此, 本课题组推测肥胖状态下脂肪细胞分泌的外泌体可能是加重创伤性膝关节炎的重要内在机制。
本研究通过高脂饮食诱导C57BL/6J雄性年轻小鼠发生肥胖, 再通过内侧半月板失稳术(destabilization of medial meniscus, DMM) 诱导创伤性膝关节炎, 结合尾静脉直接注射脂肪细胞来源的外泌体, 观察肥胖及脂肪细胞来源的外泌体对膝关节软骨及软骨下骨的形态学改变, 探究肥胖对年轻小鼠创伤性膝关节炎的影响机制, 以期为深入了解创伤性膝关节炎的发病机制提供有效的实验证据。
材料与方法
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实验动物  6周龄C57BL/6J雄性小鼠35只鼠, 购自南京大学模式实验动物所[许可证号SCXK (苏) 2018-0008], 饲养于南京大学动物实验室, 实验动物许可证号: SYXK (苏) 2019-0056, 所有实验操作均符合南京大学医学院动物实验伦理委员会(批准号: IACUC-D2204005) 的要求。
实验仪器  SkyScan1176 micro CT扫描机(德国Bruker公司); EG1150石蜡包埋机、RM223石蜡切片机(德国Leica公司); Pannoramic Scan数字切片扫描仪(匈牙利3DHIESTECH公司); XP-100PNX超速离心机(美国Beckman公司); HT7700透射电镜(日本Hitachi公司); NS300纳米粒径分析仪(英国Malvern公司); IVIS Spectrum小动物活体成像(美国PerkinElmer公司)。Tanon5200蛋白发光显影仪(上海天能公司)。
实验试剂  小鼠高脂饲料(XTHF60) 及常规饲料(SWS9102) 购自江苏协同生物公司。4%多聚甲醛(G1101-500ML) 购自武汉赛维尔生物公司。乙二胺四乙酸二钠EDTA粉末(1340) 购自广州赛国生物公司。苏木精-伊红染液(G1120) 和番红-固绿染液(G1371) 购自北京索莱宝公司。蛋白提取液(P0013B) 和SDS-PAGE蛋白上样缓冲液(P0015L) 购自上海碧云天生物公司。SDS-PAGE电泳凝胶(M00657) 购自南京金斯瑞生物公司。抗原分化簇81 (cluster of differentiation 81, CD81) 抗体(ab109201) 和肿瘤易感基因101 (tumor susceptibility gene 101, TSG101) 抗体(ab125011) 购自英国Abcam公司; 2型胶原(type Ⅱ collagen, Col 2) 抗体(28459-1-AP)、基质金属蛋白降解酶13 (matrix metalloproteinases 13, MMP13) 抗体(18165-1-AP) 和山羊抗兔IgG (SA00001-2) 购自美国Proteintech公司。Tubulin抗体(2148S) 购自美国Cell Signaling Technology公司。DiR外泌体荧光染料(UR21017) 购自上海宇玫博生物公司。白介素1β (interleukin-1β, IL-1β) 重组蛋白(SRP3083) 购自美国Sigma-Aldrich公司。GW4869 (HY-19363) 购自美国MedChemExpress公司。0.4 μm孔径Transwell细胞小室(3407) 购自美国Corning公司。
实验设计与分组
第一批实验动物分组  6周龄小鼠随机分为4组, 每组5只(图 1)。正常饮食组(control diet, CD组)、正常饮食加内侧半月板失稳手术组(DMM组)、高脂饮食组(high-fat diet, HFD组) 及高脂饮食加内侧半月板失稳手术组(HFD+DMM组)。CD和DMM组喂养基础饲料, HFD和HFD+DMM组喂养高脂饲料。使用对应饲料喂养4周后, 对DMM和HFD+DMM组小鼠右侧膝关节进行DMM手术; 对CD组和HFD组小鼠进行假手术。
第二批实验动物分组  6周龄小鼠随机分为3组, 每组5只(图 2)。内侧半月板失稳手术组(DMM组)、DMM加肥胖小鼠脂肪组织外泌体注射组(DMM+HFD-Exo组) 和DMM加正常小鼠脂肪细胞外泌体注射组(DMM+CD-Exo组)。在小鼠10周龄时进行DMM手术或假手术。DMM+HFD-Exo组与DMM+CD-Exo组小鼠进行外泌体尾静脉注射, 注射浓度为1 μg·μL-1[10], 每次注射100 μL, 每周一次。
所有动物于18周时终止实验, 收取膝关节样本, 进行micro CT扫描, 进行组织化学染色。
DMM手术  在手术当天给小鼠称量体重, 用4%异氟烷和0.8 L·min-1氧气进行麻醉诱导, 麻醉完成后将小鼠移至手术台, 手术前及手术时, 以面罩吸入2%异氟烷和0.8 L·min-1氧气进行麻醉的维持。右膝关节处备皮、消毒, 在显微镜下在髌骨内侧切开皮肤、皮下组织和关节囊后, 将髌骨向外侧拨开, 暴露内侧半月板韧带, 然后剪断前交叉韧带, 使内侧的半月板游离, 造成膝关节不稳定。分层缝合深部筋膜、皮下组织及皮肤。假手术组在暴露半月板后不做处理, 分层缝合伤口。
脂肪组织外泌体提取  按步骤分离Ad-Exo[9]。分离正常小鼠和肥胖小鼠的腹股沟脂肪组织, 放置于PBS中洗涤3次, 将脂肪组织剪碎直至乳糜状, 放入事先配好的完全培养基(MEM-α培养基+10%胎牛血清+1%双抗), 预培养1 h; 然后用MEM-α培养基清洗脂肪组织并离心。将沉淀物在无外泌体的培养基(MEM-α培养基+10%无外泌体胎牛血清+1%双抗) 中培养16 h。用70 μm筛网过滤并收集上清液, 按照顺序: 300 ×g离心10 min; 2 000 ×g离心10 min; 10 000 ×g离心30 min, 每次均收集上清液。然后120 000 ×g离心70 min, 丢弃上清液后加入PBS重悬, 再次以120 000 ×g离心70 min后丢弃上清。再次用200 μL PBS重悬, 得到正常和肥胖脂肪组织外泌体(CD-Exo和HFD-Exo), 保存于-80 ℃冰箱。
Ad-Exo鉴定
透射电镜检测Ad-Exo形态  外泌体定量后稀释为1 μg·μL-1, 吸取15 μL外泌体放于铜网上静置1 min。使用滤纸将铜网上的剩余样本吸干, 然后吸取15 μL 2%醋酸双氧铀染色液在室温条件下染色1 min并晾干, 再将染色完成的样品放置于灯下烤10 min, 观察并拍照。
纳米粒子跟踪分析技术(nanosight tracking analysis, NTA) 检测外泌体粒径大小和浓度  用去离子水清洗样本池, 以聚苯乙烯微球(110 nm) 校准仪器, 再将样品用PBS缓冲液稀释1 000倍后上机进行检测。
Western blot (WB) 检测Ad-Exo相关标记物  采用BCA (bicinchoninic acid) 法对Ad-Exo样品进行蛋白定量, 100 ℃水浴5 min, 配置电泳凝胶, 上样20 μg蛋白量, 恒压电泳分离蛋白, 转膜, 5%牛奶封闭1 h, 一抗CD81、TSG101, 4 ℃孵育过夜, 用TBST洗膜3次, 每次10 min, 二抗室温孵育1 h, 再次用TBST洗膜3次, 每次10 min, 发光显影后使用Image J软件对蛋白条带进行定量分析。
Ad-Exo荧光标记  配置1 μmol·L-1 DiR染料工作液, 在200 μL Ad-Exo中加入50 μL DiR染料工作液, 随后立即将离心管盖紧, 并涡旋混匀, 然后放置于室温静置30 min。向孵育完成的Ad-Exo溶液中加入20 mL PBS缓冲液稀释, 然后按照Ad-Exo提取方法重新分离Ad-Exo, 以去除多余的染料。用200 μL PBS缓冲液重悬离心多次后获得的沉淀物, 即为染色后的Ad-Exo。
Ad-Exo尾静脉注射  将小鼠固定后将尾部充分暴露, 用酒精棉球反复擦拭尾部使尾静脉暴露, 沿着与尾静脉平行的方向进针至少3 mm, 入针的阻力减轻后再注射。
体外外泌体分泌抑制实验  在ADTC5软骨细胞培养基中加入10 ng·mL-1浓度IL-1β来模拟OA炎症的微环境。然后将小鼠脂肪组织剪碎至靡状后通过Transwell细胞小室与软骨细胞共同培养24 h。治疗组在脂肪组织与软骨细胞共同培养之前, 用10 μmol·L-1 GW4869对脂肪组织进行预处理12 h抑制脂肪组织分泌外泌体。同上, 用WB进行检测软骨细胞合成代谢分子Col 2和软骨细胞分解代谢分子MMP13的表达变化。
活体成像分析  使用DiR染色的外泌体进行尾静脉注射24 h后, 使用748 nm波长发射激光对小动物进行荧光成像, 检测注射物在膝关节软骨的分布情况。
标本取材及处理  两组实验的小鼠于18周龄时用乙醚麻醉后使其颈椎脱臼, 在膝关节上、下方1 cm处剪断股骨和胫骨, 剔除关节周围的多余组织如肌肉、韧带等, 注意不能损伤软骨表面, 完成后将整个关节在4%多聚甲醛中浸泡固定。
膝关节的软骨下骨形态检测  膝关节在4%多聚甲醛中固定24 h后, 进行micro CT检测, 以9 μm有效像素获得各组膝关节软骨下骨图像, 再进行三维重建。在膝关节软骨中选取3块0.5×0.5×0.5 mm3大小的立方体, 分析各组的骨体积分数(bone volume/tissue volume, BV/TV)、骨小梁数目(trabecular number, TB.N)、骨小梁厚度(trabecular thickness, Tb.Th) 及骨小梁分离度(trabecular separation, Tb. Sp) 等参数变化。
软骨组织形态学观察  膝关节在室温下用10% EDTA脱钙液脱钙4周, 每3天更换一次脱钙液, 若针头能轻松刺入骨骼中则视为脱钙完全。完成脱钙后, 用梯度乙醇脱水, 二甲苯透明后, 浸蜡包埋, 连续做4 μm切片。切片分别行苏木精-伊红染色(hematoxylin-eosin staining, H&E)、番红O固绿染色。
H&E染色  将切片依次放入: 二甲苯中脱蜡2次, 每次10 min; 乙醇梯度水化每次30 s后, 用清水冲洗, 再放入苏木精中着色5 min; 用流水洗去多余染液后用0.5% 盐酸进行乙醇分色; 流水冲洗2 min; 氨水返蓝5 min; 流水冲洗2 min; 浸入伊红染色液3 min; 流水冲洗1 min; 体积分数75%乙醇分色2次, 每次10 s; 95%乙醇脱水2次, 每次10 s; 100%乙醇脱水2次, 每次30 s; 二甲苯透明2次, 每次60 s; 最后用中性树胶进行封固。
番红O固绿染色  55 ℃烘片30 min, 在经历脱蜡、脱二甲苯、水化后, 用苏木精染色3 min, 用水冲洗5 min, 用1%盐酸乙醇分化30 s, 用水冲洗5 min, 放入氨水中反蓝30 s, 用水冲洗5 min, 放入快绿中1 min, 1%乙酸30 s, 番红O溶液中60 min, 体积分数为95%乙醇2次, 每次1 min, 体积分数为100%乙醇2次, 每次1 min, 二甲苯2次, 每次1 min, 最后用中性树胶封固。
膝关节软骨退变评价  根据改良的Mankin评分标准(表 1), 由两名实验者用双盲法对各组H&E染色及番红O固绿染色切片进行评分, 两名实验者评分的平均值为最终评分, 评分越高则表明膝关节软骨退变程度越高。
统计学分析  所有测量都重复3次, 实验数据采用SPSS21.0进行统计分析, 正态分布的数据经方差齐性检验后都以平均值±标准差表示。独立样本t检验用于比较两组数据之间差异, 单因素方差分析(one-way ANOVA) 用于比较多组数据之间差异。P < 0.05时认为差异有显著性意义。
结果
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1 高脂饮食对年轻小鼠体重及脂肪组织的影响
如图 3所示, 18周时高脂饮食能明显诱导年轻小鼠肥胖。正常小鼠体重为30.81 ± 1.43 g (n = 5), 肥胖小鼠体重为45.80 ± 5.66 g (n = 5), 肥胖的体重增长约为50% (图 3A、B), 差异具有统计学意义(P < 0.001)。肥胖小鼠的脂肪组织相较于正常小鼠的肥胖组织约增大200% (图 3C)。
2 高脂饮食对创伤性膝关节软骨形态学的影响
如图 4所示, CD组膝关节软骨表面光滑明亮; DMM组膝关节表面出现不平滑的凹点; HFD组小鼠膝关节表面光滑, 但是出现轻微水肿; HFD+DMM组小鼠膝关节表面明显粗糙不平, 颜色发白(n = 5); 表明高脂饮食诱导的肥胖能够加重DMM带来的关节损伤。
3 高脂饮食对创伤性膝关节软骨改良Mankin评分结果比较
如图 5所示, 图A为H&E染色切片, 图B为番红O固绿染色切片。造模后8周, CD组软骨表面光滑, 组织结构完整。DMM组软骨表面轻微蛋白聚糖丢失, 软骨表面较为光滑。HFD组软骨较为光滑, 未见明显的蛋白聚糖丢失。HFD+DMM组软骨表面蛋白聚糖丢失, 表现为番红O失染, 软骨表面较为粗糙, 软骨细胞死亡。图C为各实验组(n = 5) 改良Mankin评分的平均结果, CD组为0.8 ± 0.83, DMM组为8.0 ± 1.0, HFD组为2.8 ± 0.84, HFD+DMM组为12.6 ± 1.14。结果显示, 高脂饮食可以提高创伤性膝关节炎的Mankin评分, 差异具有统计学意义(P < 0.05)。
4 高脂饮食对创伤性膝关节软骨的micro CT分析
如图 6所示, 选取膝关节软骨下骨区域(图 6A), 并对各组小鼠的骨小梁参数进行定量分析(图 6B~E)。单纯HFD组小鼠相比CD组骨小梁厚度增加(P < 0.05), 骨小梁数目减少(P < 0.05), 但骨体积分数没有显著变化(P > 0.05)。DMM组小鼠骨组织相比CD组出现骨体积分数和骨小梁厚度升高(P < 0.001), 表明DMM手术成功诱导了骨关节炎模型的软骨下骨改建。当同时存在HFD和DMM刺激时, 小鼠膝关节软骨下骨变化更加显著。相比于DMM组, HFD+DMM组的骨体积分数显著升高(P < 0.05)。这些结果说明, 肥胖能够加剧骨关节炎中软骨下骨的病变。
5 肥胖脂肪组织外泌体对创伤性膝关节软骨形态学的影响
5.1 肥胖和正常脂肪组织来源外泌体的提取与鉴定
如图 7所示, 电镜下观察外泌体颗粒, 呈椭圆形(图 7A), 大小不一, 正常饮食和高脂饮食小鼠的脂肪组织来源的外泌体直径均主要集中在30~200 nm, Western blot可见外泌体高表达特异性标记物CD81、TSG101 (图 7B), NTA显示高脂饮食小鼠的Ad-Exo含量高于正常饮食小鼠的Ad-Exo (图 7C)。
5.2 肥胖和正常脂肪细胞外泌体在膝关节的代谢情况
DiR染料标记后的外泌体对小鼠尾静脉注射24 h后, 外泌体能够富集于膝关节区域, 且高脂饮食脂肪组织来源的外泌体的分布强度要高于正常饮食脂肪组织来源的外泌体的分布强度(图 8)。
5.3 肥胖脂肪组织外泌体对创伤性膝关节软骨的组织病理学变化以及改良Mankin评分结果比较
如图 9A、B所示, 造模后8周, DMM组软骨表面依然表现为轻微的蛋白聚糖丢失。DMM+HFD-Exo组软骨表面蛋白聚糖丢失, 表现为番红O失染, 软骨表面较为粗糙, 软骨细胞死亡。DMM+CD-Exo组相较于DMM组表现为染色强度增加。各实验组改良Mankin评分的平均结果如下(图 9C), DMM、DMM+HFD-Exo和DMM+CD-Exo组分别为7.8 ± 0.83、10.8 ± 1.79和8.2 ± 0.84。结果显示, HFD-Exo可以提高创伤性膝骨性关节炎的Mankin评分, 差异具有统计学意义(P < 0.05)。
为进一步探究外泌体抑制剂的作用, 本研究在体外采用IL-1β模拟体内炎症的微环境处理ADTC5软骨细胞系24 h后, 发现软骨细胞合成代谢分子Col 2表达下调, 软骨细胞分解代谢分子MMP13表达上调。HFD脂肪组织处理的结果与上述结果类似, 采用外泌体抑制剂GW4869可以有效缓解上述变化(图 9D)。
5.4 肥胖脂肪组织外泌体对创伤性膝关节软骨的micro CT分析
如图 10所示, 选取膝关节软骨下骨区域(图 10A), 并对各组小鼠的骨小梁参数进行定量分析(图 10B~E)。相较于DMM组, DMM+HFD-Exo组的骨体积分数轻微升高, DMM+CD-Exo组骨体积分数没有明显变化, 差异无统计学意义(P > 0.05)。此外, DMM+HFD-Exo组小鼠相比DMM组骨小梁数目增加(P < 0.05), 骨小梁分离度降低(P < 0.05)。
讨论
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随着社会发展, 人们生活的水平在不断上升, 生活习惯和饮食结构也在改变。人们摄入糖类与脂质的不断增多而人们的运动量却在减少, 导致青少年肥胖率不断提高。大量研究表明[11-13], 肥胖可以通过增加机械负荷、刺激炎症因子如TNF-α和IL-1β加重骨关节病的发生。DMM手术是研究创伤性骨关节炎最常用的模型之一。本研究通过12周高脂饮食成功建立动物肥胖模型。与正常饮食对照组相比, 高脂饮食组的膝关节仅有轻微的病理学改变。DMM手术成功造成了年轻小鼠膝关节的病理变化, 包括胫骨内侧软骨表面出现磨损, 软骨细胞死亡, 番红O大范围失染; 而肥胖能够明显加重这些病理变化。Micro CT表明, DMM手术对胫骨软骨下骨造成的骨体积分数增高现象也会被高脂饮食诱导的肥胖所加重, 提示发生了软骨下骨的骨硬化, 这是骨关节炎重要的影像学指征。这些发现与其他研究如肥胖对老年膝关节炎的影响基本一致[14, 15], 提示青少年肥胖会加重创伤性骨关节炎。因此, 应积极预防青少年肥胖, 防止其对创伤性膝关节炎的不利影响。
肥胖与OA这两大健康问题普遍存在于世界范围内, 肥胖在OA发展中的作用已经被许多研究结果证实, 肥胖除了能增加个体的负重关节负荷以外, 还能够通过干扰机体代谢的稳态来诱导和加重OA[6, 16]。肥胖状态下全身白色脂肪增加, 脂肪组织对膝关节远程调控是如何实现的, 目前尚不清楚。外泌体是广泛存在于体液的、由细胞分泌的胞外囊泡, 直径在30~160 nm, 有传递信号分子、介导细胞与细胞之间的信号交流的功能[10, 17]。本研究通过荧光染色标记发现高脂饮食脂肪组织分泌的外泌体能更多地聚集于膝关节处, 这和Flaherty等[9]在2019年报道的研究结果是一致的, 他们发现健康小鼠的脂肪组织每天大约可以分泌1%的外泌体, 而肥胖小鼠分泌的量是健康小鼠的2倍。尾静脉注射高脂饮食脂肪组织分泌的外泌体同样能够增加创伤性膝骨性关节炎的病理变化, 但其病理变化集中在软骨区域, 而软骨下骨未见明显变化。体外实验也表明, HFD诱导的肥胖脂肪组织可以分泌外泌体降低软骨细胞的合成代谢, 同时促进软骨细胞的分解代谢。本研究结果证实了脂肪组织外泌体对膝关节有远程调控作用, 部分解释了肥胖加重创伤性膝骨性关节炎的机制。本研究结果表明, 外泌体能够通过自身携带的生物活性物质在物理层面上或功能层面上破坏软骨基质的信号传递, 其病理变化集中在软骨层, 这也说明肥胖加重的创伤性膝骨性关节炎部分由肥胖组织外泌体导致, 部分要归因于其他因素, 如机械负荷加重导致的软骨下骨变化。此外, 外泌体抑制剂GW4869在体外可以有效地缓解软骨的降解变化[18], 提示未来可以采用抑制外泌体分泌的方法来治疗肥胖相关的膝关节炎。
本研究还存在一定的局限和不足, 如本研究仅选择了DMM手术8周后的一个时间点, 未能全面、连续地反映创伤性膝关节炎的整个病变进程; 其次, 小鼠和人体之间无疑存在一定的差异, 动物模型研究的结果尚需在临床患者水平进行进一步验证; 再次, 在今后研究中可以在功能学加入药效学指标进行有效性证明[19], 同时也可对软骨从MRI等指标做半定量分析; 最后, 外泌体抑制剂GW4869体内抑制效果和对膝关节炎病理变化的作用有待于进一步实验。
综上, 12周高脂饮食可以诱导C57BL/6J年轻小鼠肥胖, 能显著加重DMM手术干预导致的创伤性膝骨性关节炎的病理变化, 其机制和脂肪组织外泌体对膝关节的远程调控有部分关联。
作者贡献: 吴立桐和李保超负责整体实验、数据分析及论文撰写; 姚波和华子春负责研究设计、论文审阅及研究经费支持。
利益冲突: 本文所有作者均声明不存在任何利益冲突。
基金
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  • 中国科协中学生英才计划生物项目(2022年度)
  • 国家自然科学基金资助项目(82130106)
  • 江苏省卫健委重点项目(ZD2022025)
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参考文献 引证文献
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2023年第58卷第8期
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doi: 10.16438/j.0513-4870.2023-0036
  • 接收时间：2023-01-12
  • 首发时间：2025-11-21
  • 出版时间：2023-08-12
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  • 收稿日期：2023-01-12
  • 修回日期：2023-05-05
基金
中国科协中学生英才计划生物项目(2022年度)
国家自然科学基金资助项目(82130106)
江苏省卫健委重点项目(ZD2022025)
作者信息
    1.南京外国语学校, 江苏 南京 210008
    2.南京大学医学院附属口腔医院, 南京市口腔医院, 江苏 南京 210019
    3.南京大学生命科学学院, 江苏 南京 210023
    4.江苏省生物化学与分子生物学学会和南京吉芮康生物科技研究院, 江苏 南京 211899

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*华子春, Tel: 13814039758, E-mail:
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Number of
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Number of
species		 占总种数比例
Percentage of
total species (%)		 属
Genus		 种数
Number of
species		 占总种数比例
Percentage of total
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鹅膏菌科Amanitaceae 2 11 5.26 鹅膏菌属 Amanita 10 4.78
小菇科 Mycenaceae 2 12 5.74 丝盖伞属 Inocybe 5 2.39
多孔菌科 Polyporaceae 8 14 6.70 蜡蘑属 Laccaria 5 2.39
红菇科 Russulaceae 3 23 11.00 小皮伞属 Marasmius 6 2.87
小菇属 Mycena 11 5.26
光柄菇属 Pluteus 5 2.39
红菇属 Russula 17 8.13
栓菌属 Trametes 5 2.39
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