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Letter
Nature Medicine 13, 1496 - 1503 (2007)
Published online: 2 December 2007 | doi:10.1038/nm1672
PPAR-
regulates osteoclastogenesis in mice
Yihong Wan1, Ling-Wa Chong1 & Ronald M Evans1
Abstract
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-
(PPAR-) has been shown to inhibit osteoblast differentiation2, 3, its role, if any, in osteoclasts is unknown. This is a clinically crucial question because PPAR- 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- by using a Tie2Cre/flox mouse model in which PPAR- 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-
B ligand signaling and can be rescued by bone marrow transplantation. Moreover, ligand activation of PPAR- by rosiglitazone exacerbates osteoclast differentiation in a receptor-dependent manner. Our examination of the underlying mechanisms suggested that PPAR- functions as a direct regulator of c-fos expression, an essential mediator of osteoclastogenesis6. Therefore, PPAR- and its ligands have a previously unrecognized role in promoting osteoclast differentiation and bone resorption.
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