title: Osteoclast progenitors reside in the peroxisome proliferator-activated receptor γ-expressing bone marrow cell population.
abstract: Osteoclasts are bone-resorbing cells essential for skeletal development, homeostasis, and regeneration. They derive from hematopoietic progenitors in the monocyte/macrophage lineage and differentiate in response to RANKL. However, the precise nature of osteoclast progenitors is a longstanding and important question. Using inducible peroxisome proliferator-activated receptor γ (PPARγ)-tTA TRE-GFP (green fluorescent protein) reporter mice, we show that osteoclast progenitors reside specifically in the PPARγ-expressing hematopoietic bone marrow population and identify the quiescent PPARγ(+) cells as osteoclast progenitors. Importantly, two PPARγ-tTA TRE-Cre-controlled genetic models provide compelling functional evidence. First, Notch activation in PPARγ(+) cells causes high bone mass due to impaired osteoclast precursor proliferation. Second, selective ablation of PPARγ(+) cells by diphtheria toxin also causes high bone mass due to decreased osteoclast numbers. Furthermore, PPARγ(+) cells respond to both pathological and pharmacological resorption-enhancing stimuli. Mechanistically, PPARγ promotes osteoclast progenitors by activating GATA2 transcription. These findings not only identify the long-sought-after osteoclast progenitors but also establish unprecedented tools for their visualization, isolation, characterization, and genetic manipulation.
authors.affiliation: Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX 75390-9041, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Wei
authors.forename: Daniel
authors.initials: D
authors.lastname: Zeve
authors.forename: Xueqian
authors.initials: X
authors.lastname: Wang
authors.forename: Yang
authors.initials: Y
authors.lastname: Du
authors.forename: Wei
authors.initials: W
authors.lastname: Tang
authors.forename: Paul C
authors.initials: PC
authors.lastname: Dechow
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Graff
authors.forename: Yihong
authors.initials: Y
authors.lastname: Wan
mesh_terms: D000135:Acid Phosphatase / Q000235:genetics / Q000378:metabolism; D000818:Animals; D000943:Antigens, Differentiation / Q000378:metabolism; D001854:Bone Marrow Cells / Q000166:cytology* / Q000378:metabolism; D002454:Cell Differentiation; D019070:Cell Lineage; D002478:Cells, Cultured; D024042:Collagen Type I / Q000652:urine; D005260:Female; D050989:GATA2 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D015870:Gene Expression; D020869:Gene Expression Profiling; D017930:Genes, Reporter; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009929:Organ Size; D015675:Osteocalcin / Q000097:blood; D010010:Osteoclasts / Q000166:cytology* / Q000378:metabolism; D047495:PPAR gamma / Q000235:genetics / Q000378:metabolism*; D010446:Peptide Fragments / Q000652:urine; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics / Q000378:metabolism; D011859:Radiography; D051881:Receptor, Notch1 / Q000235:genetics / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D013234:Stem Cells / Q000166:cytology* / Q000378:metabolism; D000071681:Tartrate-Resistant Acid Phosphatase; D013977:Tibia / Q000033:anatomy & histology / Q000166:cytology / Q000000981:diagnostic imaging; D014158:Transcription, Genetic
chemical_list: D000943:Antigens, Differentiation; D024042:Collagen Type I; D050989:GATA2 Transcription Factor; C494712:Gata2 protein, mouse; D007527:Isoenzymes; C497762:Notch1 protein, mouse; D047495:PPAR gamma; D010446:Peptide Fragments; D016760:Proto-Oncogene Proteins c-fos; D051881:Receptor, Notch1; D011993:Recombinant Fusion Proteins; D015675:Osteocalcin; D049452:Green Fluorescent Proteins; D000135:Acid Phosphatase; D000071681:Tartrate-Resistant Acid Phosphatase