Transcriptional reprogramming during human osteoclast differentiation identifies regulators of osteoclast activityOAMEDLINE
Enhanced osteoclastogenesis and osteoclast activity contribute to the development of osteoporosis,which is characterized by increased bone resorption and inadequate bone formation.As novel antiosteoporotic therapeutics are needed,understanding the genetic regulation of human osteoclastogenesis could help identify potential treatment targets.This study aimed to provide an overview of transcriptional reprogramming during human osteoclast differentiation.Osteoclasts were differentiated from CD14+monocytes from eight female donors.RNA sequencing during differentiation revealed 8980 differentially expressed genes grouped into eight temporal patterns conserved across donors.These patterns revealed distinct molecular functions associated with postmenopausal osteoporosis susceptibility genes based on RNA from iliac crest biopsies and bone mineral density SNPs.Network analyses revealed mutual dependencies between temporal expression patterns and provided insight into subtype-specific transcriptional networks.The donor-specific expression patterns revealed genes at the monocyte stage,such as filamin B(FLNB)and oxidized low-density lipoprotein receptor 1(OLR1,encoding LOX-1),that are predictive of the resorptive activity of mature osteoclasts.The expression of differentially expressed G-protein coupled receptors was strong during osteoclast differentiation,and these receptors are associated with bone mineral density SNPs,suggesting that they play a pivotal role in osteoclast differentiation and activity.The regulatory effects of three differentially expressed G-protein coupled receptors were exemplified by in vitro pharmacological modulation of complement 5 A receptor 1(C5AR1),somatostatin receptor 2(SSTR2),and free fatty acid receptor 4(FFAR4/GPR120).Activating C5AR1 enhanced osteoclast formation,while activating SSTR2 decreased the resorptive activity of mature osteoclasts,and activating FFAR4 decreased both the number and resorptive activity of mature osteoclasts.In conclusion,we report the occurrence of transcriptional reprogramming during human osteoclast differentiation and identified SSTR2 and FFAR4 as antiresorptive G-protein coupled receptors and FLNB and LOX-1 as potential molecular markers of osteoclast activity.These data can help future investigations identify molecular regulators of osteoclast differentiation and activity and provide the basis for novel antiosteoporotic targets.
Morten S.Hansen;Kaja Madsen;Maria Price;Kent Søe;Yasunori Omata;Mario M.Zaiss;Caroline M.Gorvin;Morten Frost;Alexander Rauch;
Molecular Endocrinology Laboratory(KMEB),Department of Endocrinology,Odense University Hospital,DK-5000 Odense C,Denmark Department of Clinical Research,Faculty of Health Sciences,University of Southern Denmark,DK-5000 Odense C,Denmark Clinical Cell Biology,Pathology Research Unit,Department of Clinical Research,University of Southern Denmark,DK-5000 Odense C,DenmarkMolecular Endocrinology Laboratory(KMEB),Department of Endocrinology,Odense University Hospital,DK-5000 Odense C,Denmark Department of Clinical Research,Faculty of Health Sciences,University of Southern Denmark,DK-5000 Odense C,DenmarkInstitute of Metabolism and Systems Research(IMSR)and Centre for Diabetes,Endocrinology and Metabolism(CEDAM),University of Birmingham,Birmingham B152TT,UK Centre for Membrane Proteins and Receptors(COMPARE),Universities of Birmingham and Nottingham,Birmingham B152TT,UKClinical Cell Biology,Pathology Research Unit,Department of Clinical Research,University of Southern Denmark,DK-5000 Odense C,Denmark Department of Molecular Medicine,University of Southern Denmark,DK-5000 Odense C,DenmarkDepartment of Orthopedic Surgery,Faculty of Medicine,The University of Tokyo,Tokyo 113-8655,Japan Department of Internal Medicine 3,Rheumatology and Immunology,Friedrich-Alexander-University Erlangen-Nürnberg(FAU)and Universitätsklinikum Erlangen,D-91054 Erlangen,GermanyDepartment of Internal Medicine 3,Rheumatology and Immunology,Friedrich-Alexander-University Erlangen-Nürnberg(FAU)and Universitätsklinikum Erlangen,D-91054 Erlangen,Germany Deutsches Zentrum Immuntherapie(DZI),Friedrich-Alexander-University Erlangen-Nürnberg and Universitätsklinikum Erlangen,D-91054 Erlangen,GermanyMolecular Endocrinology Laboratory(KMEB),Department of Endocrinology,Odense University Hospital,DK-5000 Odense C,Denmark Department of Clinical Research,Faculty of Health Sciences,University of Southern Denmark,DK-5000 Odense C,Denmark Steno Diabetes Center Odense,Odense University Hospital,DK-5000 Odense C,Denmark
临床医学
osteoclastprogrammingidentif
《Bone Research》 2024 (001)
P.180-198 / 19
This work was funded by grants from the Novo Nordisk Foundation(NNF18OC0052699)(M.S.H.)and NNF18OC0055047(M.F.);the Region of Southern Denmark(ref:18/17553(M.S.H.));Odense University Hospital(ref:A3147)(M.F.);a faculty fellowship from the University of Southern Denmark(K.M.);the Lundbeck Foundation(ref:R335-2019-2195)(K.M.and A.R.);Academy of Medical Sciences Springboard Award supported by the British Heart Foundation,Diabetes UK;the Global Challenges Research Fund;the Government Department of Business,Energy and Industrial Strategy and the Wellcome Trust(ref:SBF0041034,C.M.G);a Sir Henry Dale Fellowship jointly funded by the Wellcome Trust and the Royal Society(Grant Number 224155/Z/21/Z to C.M.G.).
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