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PPAR-γ regulates osteoclastogenesis in mice


Osteoclasts are bone-resorbing cells derived from hematopoietic precursors of the monocyte-macrophage lineage. Regulation of osteoclast function is central to the understanding of bone diseases such as osteoporosis, rheumatoid arthritis and osteopetrosis1. Although peroxisome proliferator–activated receptor-γ (PPAR-γ) has been shown to inhibit osteoblast differentiation2,3, its role, if any, in osteoclasts is unknown. This is a clinically crucial question because PPAR-γ agonists, “such as thiazolidinediones—” a class of insulin-sensitizing drugs, have been reported to cause a higher rate of fractures in human patients4,5. Here we have uncovered a pro-osteoclastogenic effect of PPAR-γ by using a Tie2Cre/flox mouse model in which PPAR-γ is deleted in osteoclasts but not in osteoblasts. These mice develop osteopetrosis characterized by increased bone mass, reduced medullary cavity space and extramedullary hematopoiesis in the spleen. These defects are the result of impaired osteoclast differentiation and compromised receptor activator of nuclear factor-κB ligand signaling and can be rescued by bone marrow transplantation. Moreover, ligand activation of PPAR-γ by rosiglitazone exacerbates osteoclast differentiation in a receptor-dependent manner. Our examination of the underlying mechanisms suggested that PPAR-γ functions as a direct regulator of c-fos expression, an essential mediator of osteoclastogenesis6. Therefore, PPAR-γ and its ligands have a previously unrecognized role in promoting osteoclast differentiation and bone resorption.

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Figure 1: Tie2Cre-mediated PPAR-γ deletion leads to extramedullary hematopoiesis in the spleen.
Figure 2: Tie2Cre-mediated PPAR-γ deletion leads to osteopetrosis represented by increased bone volume, decreased medullary cavity space and reduced bone resorption.
Figure 3: PPAR-γ and ligand promote osteoclast differentiation by regulating c-fos expression.
Figure 4: In vitro and in vivo rescues of osteoclast differentiation and extramedullary hematopoiesis.


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We would like to thank the Department of Radiology and Moores Cancer Center at the University of California at San Diego for the bone analyses, M. Yanagisawa (University of Texas Southwestern Medical Center) for providing the Tie2Cre transgenic mice, I. Verma (Salk Institute) for providing the Ub-GFP transgenic mice, S. Hong, J. Jonker, R. Yu and Y. Wan for discussion and critical reading of the manuscript, and L. Ong and S. Ganley for administrative assistance. R.E. is an investigator of the Howard Hughes Medical Institute at the Salk Institute and the March of Dimes Chair in Molecular and Developmental Biology. Y.W. is supported by a postdoctoral fellowship from the American Cancer Society (PF-03-081-01-TBE). This work was supported by the Howard Hughes Medical Institute and the National Institutes of Health (SCOR/HL569898, HL07770 and DK57978).

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Y.W. conceived the project, designed and performed most of the experiments and wrote the manuscript and L.-W.C. performed the experiments by assisting with tissue collection, DNA, RNA and protein isolation, and analyses. R.M.E. supervised the study and edited the manuscript.

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Correspondence to Ronald M Evans.

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Wan, Y., Chong, LW. & Evans, R. PPAR-γ regulates osteoclastogenesis in mice. Nat Med 13, 1496–1503 (2007).

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