Fat mass and obesity-associated protein in mesenchymal stem cells inhibits osteoclastogenesis via lnc NORAD/miR-4284 axis in ankylosing spondylitis  

作　　者：Wen-Jie Liu Jia-Xin Wang Quan-Feng Li Yun-Hui Zhang Peng-Fei Ji Jia-Hao Jin Yi-Bin Zhang Zi-Hao Yuan Pei Feng Yan-Feng Wu Hui-Yong Shen Peng Wang 

机构地区：[1]Department of Orthopedics,The Eighth Affiliated Hospital,Sun Yat-sen University,Shenzhen 518033,Guangdong Province,China [2]Guangdong Provincial Clinical Research Center for Orthopedic Diseases,The Eighth Affiliated Hospital,Sun Yat-sen University,Shenzhen 518033,Guangdong Province,China [3]Center for Biotherapy,The Eighth Affiliated Hospital,Sun Yat-sen University,Shenzhen 518033,Guangdong Province,China

出　　处：《World Journal of Stem Cells》2025年第3期28-43,共16页世界干细胞杂志(英文)

基　　金：Supported by Guangdong Provincial Clinical Research Center for Orthopedic Diseases,No.2023B110001;the Excellent Medical Innovation Talent Program of the Eighth Affiliated Hospital of Sun Yat-sen University,No.YXYXCXRC202101;the National Natural Science Foundation of China,No.82172349,No.82372372,No.22105229,No.32170708,No.82102530,No.82102541,No.82103098,No.82103909,No.82104182,No.82104350,No.82170427,No.82171291,No.82172215,No.82172385,and No.82302661;Guangdong Natural Science Foundation,No.2023A1515010568 and No.2021A1515111057;Shenzhen Science and Technology Program,No.JCYJ20220530144201004 and No.RCBS20210609104445097;and Futian Healthcare Research Project,No.FTWS2022022,No.FTWS2021013,No.FTWS2023072,and No.FTWS2022047.

摘　　要：BACKGROUND Ankylosing spondylitis(AS)is recognized as a long-term inflammatory disorder that leads to inflammation in the spine and joints,alongside abnormal bone growth.In previous studies,we reported that mesenchymal stem cells(MSCs)derived from individuals with AS demonstrated a remarkable inhibition in the formation of osteoclasts compared to those obtained from healthy donors.The mechanism through which MSCs from AS patients achieve this inhibition remains unclear.AIM To investigate the potential underlying mechanism by which MSCs from individuals with ankylosing spondylitis(AS-MSCs)inhibit osteoclastogenesis.METHODS We analysed fat mass and obesity-associated(FTO)protein levels in AS-MSCs and MSCs from healthy donors and investigated the effects and mechanism by which FTO in MSCs inhibits osteoclastogenesis by coculturing and measuring the levels of tartrate-resistant acid phosphatase,nuclear factor of activated T cells 1 and cathepsin K.RESULTS We found that FTO,an enzyme responsible for removing methyl groups from RNA,was more abundantly expressed in MSCs from AS patients than in those from healthy donors.Reducing FTO levels was shown to diminish the capacity of MSCs to inhibit osteoclast development.Further experimental results revealed that FTO affects the stability of the long non-coding RNA activated by DNA damage(NORAD)by altering its N6-methyladenosine methylation status.Deactivating NORAD in MSCs significantly increased osteoclast formation by affecting miR-4284,which could regulate the MSC-mediated inhibition of osteoclastogenesis reported in our previous research.CONCLUSION This study revealed elevated FTO levels in AS-MSCs and found that FTO regulated the ability of AS-MSCs to inhibit osteoclast formation through the long noncoding RNA NORAD/miR-4284 axis.

关 键 词：Ankylosing spondylitis Mesenchymal stem cells OSTEOCLASTOGENESIS Fat mass and obesity-associated protein Non-coding RNA activated by DNA damage 

分 类 号：R32[医药卫生—人体解剖和组织胚胎学]