Aberrant Fluid Shear Stress Contributes to Articular Cartilage Pathogenesis via Epigenetic Regulation of ZBTB20 by H3K4me3
Yu Jin,* Zhenxia Li,* Yanran Wu, Hairui Li, Zhen Liu, Lu Liu, Ningjuan Ouyang, Ting Zhou, Bing Fang, Lunguo Xia Department of Orthodontics, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine; College of Stomatology, Shanghai Jiao Tong University; Natio...
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Dove Medical Press
2021
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oai:doaj.org-article:55785ee77a3a4b0e9eedf9ea28556add2021-11-21T19:08:51ZAberrant Fluid Shear Stress Contributes to Articular Cartilage Pathogenesis via Epigenetic Regulation of ZBTB20 by H3K4me31178-7031https://doaj.org/article/55785ee77a3a4b0e9eedf9ea28556add2021-11-01T00:00:00Zhttps://www.dovepress.com/aberrant-fluid-shear-stress-contributes-to-articular-cartilage-pathoge-peer-reviewed-fulltext-article-JIRhttps://doaj.org/toc/1178-7031Yu Jin,* Zhenxia Li,* Yanran Wu, Hairui Li, Zhen Liu, Lu Liu, Ningjuan Ouyang, Ting Zhou, Bing Fang, Lunguo Xia Department of Orthodontics, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine; College of Stomatology, Shanghai Jiao Tong University; National Center for Stomatology; National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology, Shanghai, 200011, People’s Republic of China*These authors contributed equally to this workCorrespondence: Lunguo Xia; Bing FangDepartment of Orthodontics, Shanghai Ninth People’s Hospital, College of Stomatology, Shanghai Jiao Tong University School of Medicine, 500 Quxi Road, Shanghai, 200011, People’s Republic of ChinaTel +86 21 23271699Email xialunguo@hotmail.com; fangbing@sjtu.edu.cnPurpose: Osteoarthritis (OA) is a common disease for human beings, characterized by severe inflammation, cartilage degradation, and subchondral bone destruction. However, current therapies are limited to relieving pain or joint replacement and no effective treatment methods have been discovered to improve degenerative changes. Currently, a variety of evidences have indicated that aberrant mechanical stimuli is closely associated with articular joint pathogenesis, while the detailed underlying mechanism remains unelucidated. In the present study, we determined to investigate the impact of excessive high fluid shear stress (FSS) on primary chondrocytes and the underlying epigenetic mechanisms.Materials and Methods: Phalloidin staining and EdU staining were used to evaluate cell morphology and viability. The mRNA level and protein level of genes were determined by qPCR, Western blot assay, and immunofluorescence staining. Mechanistic investigation was performed through RNA-sequencing and CUT&Tag sequencing. In vivo, we adopted unilateral anterior crossbites (UAC) mice model to investigate the expression of H3K4me3 and ZBTB20 in aberrant force-related cartilage pathogenesis.Results: The results demonstrated that FSS greatly disrupts cell morphology and significantly decreased chondrocyte viability. Aberrant FSS induces remarkable inflammatory mediators production, leading to cartilage degeneration and degradation. In depth mechanistic study showed that FSS results in more than 10-fold upregulation of H3K4me3, and the modulatory effect of H3K4me3 on cartilage was obtained by directly targeting ZBTB20. Furthermore, Wnt signaling was strongly activated in high FSS-induced OA pathogenesis, and the negative impact of ZBTB20 on chondrocytes was also achieved through activating Wnt signaling pathway. Moreover, pharmacological inhibition of H3K4me3 activation by MM-102 or treatment with Wnt pathway inhibitor LF3 could effectively alleviate the destructive effect of FSS on chondrocytes. In vivo UAC mice model validated the dysregulation of H3K4me3 and ZBTB20 in aberrant force-induced cartilage pathogenesis.Conclusion: Through the combination of in vitro FSS model and in vivo UAC model, KMT2B-H3K4me3-ZBTB20 axis was first identified in aberrant FSS-induced cartilage pathogenesis, which may provide evidences for epigenetic-based therapy in the future.Keywords: osteoarthritis, fluid shear stress, H3K4me3, epigenetic, cartilage degenerationJin YLi ZWu YLi HLiu ZLiu LOuyang NZhou TFang BXia LDove Medical Pressarticleosteoarthritisfluid shear stressh3k4me3epigeneticcartilage degenerationPathologyRB1-214Therapeutics. PharmacologyRM1-950ENJournal of Inflammation Research, Vol Volume 14, Pp 6067-6083 (2021) |
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DOAJ |
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DOAJ |
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EN |
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osteoarthritis fluid shear stress h3k4me3 epigenetic cartilage degeneration Pathology RB1-214 Therapeutics. Pharmacology RM1-950 |
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osteoarthritis fluid shear stress h3k4me3 epigenetic cartilage degeneration Pathology RB1-214 Therapeutics. Pharmacology RM1-950 Jin Y Li Z Wu Y Li H Liu Z Liu L Ouyang N Zhou T Fang B Xia L Aberrant Fluid Shear Stress Contributes to Articular Cartilage Pathogenesis via Epigenetic Regulation of ZBTB20 by H3K4me3 |
| description |
Yu Jin,* Zhenxia Li,* Yanran Wu, Hairui Li, Zhen Liu, Lu Liu, Ningjuan Ouyang, Ting Zhou, Bing Fang, Lunguo Xia Department of Orthodontics, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine; College of Stomatology, Shanghai Jiao Tong University; National Center for Stomatology; National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology, Shanghai, 200011, People’s Republic of China*These authors contributed equally to this workCorrespondence: Lunguo Xia; Bing FangDepartment of Orthodontics, Shanghai Ninth People’s Hospital, College of Stomatology, Shanghai Jiao Tong University School of Medicine, 500 Quxi Road, Shanghai, 200011, People’s Republic of ChinaTel +86 21 23271699Email xialunguo@hotmail.com; fangbing@sjtu.edu.cnPurpose: Osteoarthritis (OA) is a common disease for human beings, characterized by severe inflammation, cartilage degradation, and subchondral bone destruction. However, current therapies are limited to relieving pain or joint replacement and no effective treatment methods have been discovered to improve degenerative changes. Currently, a variety of evidences have indicated that aberrant mechanical stimuli is closely associated with articular joint pathogenesis, while the detailed underlying mechanism remains unelucidated. In the present study, we determined to investigate the impact of excessive high fluid shear stress (FSS) on primary chondrocytes and the underlying epigenetic mechanisms.Materials and Methods: Phalloidin staining and EdU staining were used to evaluate cell morphology and viability. The mRNA level and protein level of genes were determined by qPCR, Western blot assay, and immunofluorescence staining. Mechanistic investigation was performed through RNA-sequencing and CUT&Tag sequencing. In vivo, we adopted unilateral anterior crossbites (UAC) mice model to investigate the expression of H3K4me3 and ZBTB20 in aberrant force-related cartilage pathogenesis.Results: The results demonstrated that FSS greatly disrupts cell morphology and significantly decreased chondrocyte viability. Aberrant FSS induces remarkable inflammatory mediators production, leading to cartilage degeneration and degradation. In depth mechanistic study showed that FSS results in more than 10-fold upregulation of H3K4me3, and the modulatory effect of H3K4me3 on cartilage was obtained by directly targeting ZBTB20. Furthermore, Wnt signaling was strongly activated in high FSS-induced OA pathogenesis, and the negative impact of ZBTB20 on chondrocytes was also achieved through activating Wnt signaling pathway. Moreover, pharmacological inhibition of H3K4me3 activation by MM-102 or treatment with Wnt pathway inhibitor LF3 could effectively alleviate the destructive effect of FSS on chondrocytes. In vivo UAC mice model validated the dysregulation of H3K4me3 and ZBTB20 in aberrant force-induced cartilage pathogenesis.Conclusion: Through the combination of in vitro FSS model and in vivo UAC model, KMT2B-H3K4me3-ZBTB20 axis was first identified in aberrant FSS-induced cartilage pathogenesis, which may provide evidences for epigenetic-based therapy in the future.Keywords: osteoarthritis, fluid shear stress, H3K4me3, epigenetic, cartilage degeneration |
| format |
article |
| author |
Jin Y Li Z Wu Y Li H Liu Z Liu L Ouyang N Zhou T Fang B Xia L |
| author_facet |
Jin Y Li Z Wu Y Li H Liu Z Liu L Ouyang N Zhou T Fang B Xia L |
| author_sort |
Jin Y |
| title |
Aberrant Fluid Shear Stress Contributes to Articular Cartilage Pathogenesis via Epigenetic Regulation of ZBTB20 by H3K4me3 |
| title_short |
Aberrant Fluid Shear Stress Contributes to Articular Cartilage Pathogenesis via Epigenetic Regulation of ZBTB20 by H3K4me3 |
| title_full |
Aberrant Fluid Shear Stress Contributes to Articular Cartilage Pathogenesis via Epigenetic Regulation of ZBTB20 by H3K4me3 |
| title_fullStr |
Aberrant Fluid Shear Stress Contributes to Articular Cartilage Pathogenesis via Epigenetic Regulation of ZBTB20 by H3K4me3 |
| title_full_unstemmed |
Aberrant Fluid Shear Stress Contributes to Articular Cartilage Pathogenesis via Epigenetic Regulation of ZBTB20 by H3K4me3 |
| title_sort |
aberrant fluid shear stress contributes to articular cartilage pathogenesis via epigenetic regulation of zbtb20 by h3k4me3 |
| publisher |
Dove Medical Press |
| publishDate |
2021 |
| url |
https://doaj.org/article/55785ee77a3a4b0e9eedf9ea28556add |
| work_keys_str_mv |
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