Osteoclast progenitors reside in the peroxisome proliferator-activated receptor γ-expressing bone marrow cell population

W. Wei, Daniel Zeve, Xueqian Wang, Yang Du, Wei Tang, Paul C. Dechow, Jonathan M. Graff, Yihong Wan

Research output: Contribution to journalArticlepeer-review

32 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)4692-4705
Number of pages14
JournalMolecular and cellular biology
Volume31
Issue number23
DOIs
StatePublished - Dec 2011

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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