Despite the diverse roles of tripartite motif(Trim)-containing proteins in the regulation of autophagy,the innate immune response,and cell differentiation,their roles in skeletal diseases are largely unknown.We recent...Despite the diverse roles of tripartite motif(Trim)-containing proteins in the regulation of autophagy,the innate immune response,and cell differentiation,their roles in skeletal diseases are largely unknown.We recently demonstrated that Trim21 plays a crucial role in regulating osteoblast(OB)differentiation in osteosarcoma.However,how Trim21 contributes to skeletal degenerative disorders,including osteoporosis,remains unknown.First,human and mouse bone specimens were evaluated,and the results showed that Trim21 expression was significantly elevated in bone tissues obtained from osteoporosis patients.Next,we found that global knockout of the Trim21 gene(KO,Trim2^(1-/-))resulted in higher bone mass compared to that of the control littermates.We further demonstrated that loss of Trim21 promoted bone formation by enhancing the osteogenic differentiation of bone marrow mesenchymal stem cells(BMSCs)and elevating the activity of OBs;moreover,Trim21 depletion suppressed osteoclast(OC)formation of RAW264.7 cells.In addition,the differentiation of OCs from bone marrow-derived macrophages(BMMs)isolated from Trim21^(-/-)and Ctsk-cre;Trim21^(f/f)mice was largely compromised compared to that of the littermate control mice.Mechanistically,YAP1/β-catenin signaling was identified and demonstrated to be required for the Trim21-mediated osteogenic differentiation of BMSCs.More importantly,the loss of Trim21 prevented ovariectomy(OVX)-and lipopolysaccharide(LPS)-induced bone loss in vivo by orchestrating the coupling of OBs and OCs through YAP1 signaling.Our current study demonstrated that Trim21 is crucial for regulating OB-mediated bone formation and OC-mediated bone resorption,thereby providing a basis for exploring Trim21 as a novel dual-targeting approach for treating osteoporosis and pathological bone loss.展开更多
Objective To explore the correlations of high-density lipoprotein cholesterol(HDL-C)/low-density lipoprotein cholesterol(LDL-C)with myocardial infarction(MI),all-cause mortality,haemorrhagic stroke and ischaemic strok...Objective To explore the correlations of high-density lipoprotein cholesterol(HDL-C)/low-density lipoprotein cholesterol(LDL-C)with myocardial infarction(MI),all-cause mortality,haemorrhagic stroke and ischaemic stroke,as well as the joint association of genetic susceptibility and HDL-C/LDL-C with the MI risk.Methods and results This study selected 384093 participants from the UK Biobank(UKB)database.First,restricted cubic splines indicated non-linear associations of HDL-C/LDL-C with MI,ischaemic stroke and all-cause mortality.Second,a Cox proportional-hazards model indicated that compared with HDL-C/LDL-C=0.4-0.6,HDL-C/LDL-C<0.4 and>0.6 were correlated with all-cause mortality(HR=0.97 for HDL-C/LDL-C<0.4,95%CI=0.939 to 0.999,p<0.05;HR=1.21 for HDL-C/LDL-C>0.6,95%CI=1.16 to 1.26,p<0.001)after full multivariable adjustment.HDL-C/LDL-C<0.4 was correlated with a higher MI risk(HR=1.36,95%CI=1.28 to 1.44,p<0.05)and ischaemic stroke(HR=1.12,95%CI=1.02 to 1.22,p<0.05)after full multivariable adjustment.HDL-C/LDL-C>0.6 was associated with higher risk haemorrhagic stroke risk after full multivariable adjustment(HR=1.25,95%CI=1.03 to 1.52,p<0.05).Third,after calculating the coronary heart disease Genetic Risk Score(CHD-GRS)of each participant,the Cox proportional-hazards model indicated that compared with low CHD-GRS and HDL-C/LDL-C=0.4-0.6,participants with a combination of high CHD-GRS and HDL-C/LDL-C<0.4 were associated with the highest MI risk(HR=2.45,95%CI=2.15 to 2.8,p<0.001).Participants with HDL-C/LDL-C<0.4 were correlated with a higher MI risk regardless of whether they had a high,intermediate or low CHD-GRS.Conclusion In UKB participants,HDL-C/LDL-C ratio of 0.4-0.6 was correlated with lower MI risk,all-cause mortality,haemorrhagic stroke and ischaemic stroke.Participants with HDL-C/LDL-C<0.4 were correlated with a higher MI risk regardless of whether they had a high,intermediate or low CHD-GRS.The clinical significance and impact of HDL-C/LDL-C need to be further verified in future studies.展开更多
基金supported by the Natural Science Foundation with grants from the National Key R&D Program of China(2018YFC2002500)National Natural Science Foundation of China(81602360,82072470,82350003,92049201)+6 种基金Key Laboratory Construction Project of Guangzhou Science and Technology Bureau(202102100007)supported by the Clinical Frontier Technology Program of the First Affiliated Hospital of Jinan University,China(No.JNU1AF-CFTP-2022-a01221)Natural Science Foundation of Guangdong Province(2021A1515012154,2019A1515011082,2017A030313665,2018A030313544,2020B1515120038)Science and Technology Projects in Guangzhou(201707010493,202102010069)Macao Foundation for Development of Science and Technology(0029/2019/A)Youth Talent Support Project of Guangzhou Association for Science&Technology(X20200301018)pilot project of clinical collaboration from National Administration of Traditional Chinese Medicine and National Health Commission of the People’s Republic of China and Logistics Support Department of the Central Military Commission。
文摘Despite the diverse roles of tripartite motif(Trim)-containing proteins in the regulation of autophagy,the innate immune response,and cell differentiation,their roles in skeletal diseases are largely unknown.We recently demonstrated that Trim21 plays a crucial role in regulating osteoblast(OB)differentiation in osteosarcoma.However,how Trim21 contributes to skeletal degenerative disorders,including osteoporosis,remains unknown.First,human and mouse bone specimens were evaluated,and the results showed that Trim21 expression was significantly elevated in bone tissues obtained from osteoporosis patients.Next,we found that global knockout of the Trim21 gene(KO,Trim2^(1-/-))resulted in higher bone mass compared to that of the control littermates.We further demonstrated that loss of Trim21 promoted bone formation by enhancing the osteogenic differentiation of bone marrow mesenchymal stem cells(BMSCs)and elevating the activity of OBs;moreover,Trim21 depletion suppressed osteoclast(OC)formation of RAW264.7 cells.In addition,the differentiation of OCs from bone marrow-derived macrophages(BMMs)isolated from Trim21^(-/-)and Ctsk-cre;Trim21^(f/f)mice was largely compromised compared to that of the littermate control mice.Mechanistically,YAP1/β-catenin signaling was identified and demonstrated to be required for the Trim21-mediated osteogenic differentiation of BMSCs.More importantly,the loss of Trim21 prevented ovariectomy(OVX)-and lipopolysaccharide(LPS)-induced bone loss in vivo by orchestrating the coupling of OBs and OCs through YAP1 signaling.Our current study demonstrated that Trim21 is crucial for regulating OB-mediated bone formation and OC-mediated bone resorption,thereby providing a basis for exploring Trim21 as a novel dual-targeting approach for treating osteoporosis and pathological bone loss.
文摘Objective To explore the correlations of high-density lipoprotein cholesterol(HDL-C)/low-density lipoprotein cholesterol(LDL-C)with myocardial infarction(MI),all-cause mortality,haemorrhagic stroke and ischaemic stroke,as well as the joint association of genetic susceptibility and HDL-C/LDL-C with the MI risk.Methods and results This study selected 384093 participants from the UK Biobank(UKB)database.First,restricted cubic splines indicated non-linear associations of HDL-C/LDL-C with MI,ischaemic stroke and all-cause mortality.Second,a Cox proportional-hazards model indicated that compared with HDL-C/LDL-C=0.4-0.6,HDL-C/LDL-C<0.4 and>0.6 were correlated with all-cause mortality(HR=0.97 for HDL-C/LDL-C<0.4,95%CI=0.939 to 0.999,p<0.05;HR=1.21 for HDL-C/LDL-C>0.6,95%CI=1.16 to 1.26,p<0.001)after full multivariable adjustment.HDL-C/LDL-C<0.4 was correlated with a higher MI risk(HR=1.36,95%CI=1.28 to 1.44,p<0.05)and ischaemic stroke(HR=1.12,95%CI=1.02 to 1.22,p<0.05)after full multivariable adjustment.HDL-C/LDL-C>0.6 was associated with higher risk haemorrhagic stroke risk after full multivariable adjustment(HR=1.25,95%CI=1.03 to 1.52,p<0.05).Third,after calculating the coronary heart disease Genetic Risk Score(CHD-GRS)of each participant,the Cox proportional-hazards model indicated that compared with low CHD-GRS and HDL-C/LDL-C=0.4-0.6,participants with a combination of high CHD-GRS and HDL-C/LDL-C<0.4 were associated with the highest MI risk(HR=2.45,95%CI=2.15 to 2.8,p<0.001).Participants with HDL-C/LDL-C<0.4 were correlated with a higher MI risk regardless of whether they had a high,intermediate or low CHD-GRS.Conclusion In UKB participants,HDL-C/LDL-C ratio of 0.4-0.6 was correlated with lower MI risk,all-cause mortality,haemorrhagic stroke and ischaemic stroke.Participants with HDL-C/LDL-C<0.4 were correlated with a higher MI risk regardless of whether they had a high,intermediate or low CHD-GRS.The clinical significance and impact of HDL-C/LDL-C need to be further verified in future studies.
