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PPAR-γ Agonist Rosiglitazone Implicated in Osteoporosis

PPAR-γ receptor involved in differentiation of osteoclasts

MONDAY, Dec. 3 (HealthDay News) -- Researchers have shown that the peroxisome proliferator-activated receptor-γ (PPAR-γ) promotes osteoclast differentiation and bone resorption in a mouse model, raising concerns that PPAR-γ agonists like the diabetes drug rosiglitazone (Avandia) could cause osteoporosis. This research was published online Dec. 2 in Nature Medicine.

Yihong Wan, Ph.D., of the Howard Hughes Medical Institute in La Jolla, Calif., and colleagues explored the role of the PPAR-γ receptor in osteoclast function by conducting experiments with mice in whom the PPAR-γ gene was deleted in osteoclasts but not osteoblasts.

Mice with PPAR-γ deleted in osteoclasts developed osteopetrosis, characterized by increased bone mass, reduced medullary cavity space and extramedullary hematopoiesis in the spleen. The researchers showed this was due to impaired osteoclast differentiation, and the defect could be reversed by bone marrow transplantation. It appeared that PPAR-γ and its ligands stimulate osteoclast differentiation by regulating expression of c-fos. In addition, activation of PPAR-γ receptors with rosiglitazone stimulated osteoclast differentiation in a receptor-dependent fashion.

"These findings have potential clinical implications, as they suggest that long-term rosiglitazone usage in the treatment of type 2 diabetes and insulin resistance may cause osteoporosis, owing to a combination of decreased bone formation and increased bone resorption. They also suggest that selective PPAR-γ modulators may provide a new strategy for the treatment of bone diseases associated with increased osteoclast activity, such as osteoporosis and rheumatoid arthritis," the authors write.

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