Osteoclast progenitors reside in the peroxisome proliferator-activated receptor -expressing bone marrow cell population.
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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 (PPAR)-tTA TRE-GFP (green fluorescent protein) reporter mice, we show that osteoclast progenitors reside specifically in the PPAR-expressing hematopoietic bone marrow population and identify the quiescent PPAR(+) cells as osteoclast progenitors. Importantly, two PPAR-tTA TRE-Cre-controlled genetic models provide compelling functional evidence. First, Notch activation in PPAR(+) cells causes high bone mass due to impaired osteoclast precursor proliferation. Second, selective ablation of PPAR(+) cells by diphtheria toxin also causes high bone mass due to decreased osteoclast numbers. Furthermore, PPAR(+) cells respond to both pathological and pharmacological resorption-enhancing stimuli. Mechanistically, PPAR 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.
author list (cited authors)
Wei, W., Zeve, D., Wang, X., Du, Y., Tang, W., Dechow, P. C., Graff, J. M., & Wan, Y.