Periodontitis is caused by overactive osteoclast activity that results in the loss of periodontal supporting tissue and mesenchymal stem cells(MSCs)are essential for periodontal regeneration.However,the hypoxic period...Periodontitis is caused by overactive osteoclast activity that results in the loss of periodontal supporting tissue and mesenchymal stem cells(MSCs)are essential for periodontal regeneration.However,the hypoxic periodontal microenvironment during periodontitis induces the apoptosis of MSCs.Apoptotic bodies(ABs)are the major product of apoptotic cells and have been attracting increased attention as potential mediators for periodontitis treatment,thus we investigated the effects of ABs derived from MSCs on periodontitis.MSCs were derived from bone marrows of mice and were cultured under hypoxic conditions for 72 h,after which ABs were isolated from the culture supernatant using a multi-filtration system.The results demonstrate that ABs derived from MSCs inhibited osteoclast differentiation and alveolar bone resorption.miRNA array analysis showed that miR-223-3p is highly enriched in those ABs and is critical for their therapeutic effects.Targetscan and luciferase activity results confirmed that Itgb1 is targeted by miR-223-3p,which interferes with the function of osteoclasts.Additionally,DC-STAMP is a key regulator that mediates membrane infusion.ABs and pre-osteoclasts expressed high levels of DC-STAMP on their membranes,which mediates the engulfment of ABs by pre-osteoclasts.ABs with knock-down of DC-STAMP failed to be engulfed by pre-osteoclasts.Collectively,MSC-derived ABs are targeted to be engulfed by pre-osteoclasts via DC-STAMP,which rescued alveolar bone loss by transferring miR-223-3p to osteoclasts,which in turn led to the attenuation of their differentiation and bone resorption.These results suggest that MSC-derived ABs are promising therapeutic agents for the treatment of periodontitis.展开更多
基金grants from National Key R&D Program of China(Grant No.2022YFC2504200)the National Nature Science Foundation of China(81991504 and 81974149 to Y.L.+7 种基金82201052 to X.Y.L.)the Beijing Municipal Administration of Hospitals Clinical Medicine Development of Special Funding Support(ZYLX202121 to Y.L.)the Innovation Research Team Project of Beijing Stomatological Hospital,Capital Medical University(CXTD202202)the Beijing Municipal Administration of Hospitals’Ascent Plan(DFL20181501 to Y.L.)the Beijing Municipal Administration of Hospitals’Youth Programme(QML20181501 to L.J.G.QML20231505 to X.Y.L.)the Beijing Stomatological Hospital,Capital Medical University Young Scientist Program(No.YSP202103 to X.Y.L.)the Innovation Foundation of Beijing Stomatological Hospital,Capital Medical University(21-09-18 to L.J.G.).
文摘Periodontitis is caused by overactive osteoclast activity that results in the loss of periodontal supporting tissue and mesenchymal stem cells(MSCs)are essential for periodontal regeneration.However,the hypoxic periodontal microenvironment during periodontitis induces the apoptosis of MSCs.Apoptotic bodies(ABs)are the major product of apoptotic cells and have been attracting increased attention as potential mediators for periodontitis treatment,thus we investigated the effects of ABs derived from MSCs on periodontitis.MSCs were derived from bone marrows of mice and were cultured under hypoxic conditions for 72 h,after which ABs were isolated from the culture supernatant using a multi-filtration system.The results demonstrate that ABs derived from MSCs inhibited osteoclast differentiation and alveolar bone resorption.miRNA array analysis showed that miR-223-3p is highly enriched in those ABs and is critical for their therapeutic effects.Targetscan and luciferase activity results confirmed that Itgb1 is targeted by miR-223-3p,which interferes with the function of osteoclasts.Additionally,DC-STAMP is a key regulator that mediates membrane infusion.ABs and pre-osteoclasts expressed high levels of DC-STAMP on their membranes,which mediates the engulfment of ABs by pre-osteoclasts.ABs with knock-down of DC-STAMP failed to be engulfed by pre-osteoclasts.Collectively,MSC-derived ABs are targeted to be engulfed by pre-osteoclasts via DC-STAMP,which rescued alveolar bone loss by transferring miR-223-3p to osteoclasts,which in turn led to the attenuation of their differentiation and bone resorption.These results suggest that MSC-derived ABs are promising therapeutic agents for the treatment of periodontitis.
