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Mechanical Loading Down-Regulates Peroxisome Proliferator-Activated Receptor in Bone Marrow Stromal Cells and Favors Osteoblastogenesis at the Expense of Adipogenesis

Institut National de la Santé et de la Recherche Médicale Unité 890 and Université Jean Monnet (V.D., A.M., M.-H.L.-P., L.M., S.P., L.V., A.G.), F-42023 St-Etienne, France; and Experimental Orthopedics and Biomechanics (D.B.J.), Philipps University, Baldingerst, D-35033 Marburg, Germany

Address all correspondence and requests for reprints to: Alain Guignandon, Institut National de la Santé et de la Recherche Médicale Unité 890, Faculté de Médecine 15 rue Ambroise Paré, F-42023 Saint-Etienne Cedex 2, France. E-mail: Alain.Guignandon{at}univ-st-etienne.fr.

Because a lack of mechanical information favors the development of adipocytes at the expense of osteoblasts, we hypothesized that the peroxisome proliferator-activated receptor (PPAR)-dependent balance between osteoblasts and adipocytes is affected by mechanical stimuli. We tested the robustness of this hypothesis in in vivo rodent osteogenic exercise, in vitro cyclic loading of cancellous haversian bone samples, and cyclic stretching of primary stromal and C3H10T1/2 cells. We found that running rats exhibit a decreased marrow fat volume associated with an increased bone formation, presumably through recruitment of osteoprogenitors. In the tissue culture model and primary stromal cells, cyclic loading induced higher Runx2 and lower PPAR2 protein levels. Given the proadipocytic and antiosteoblastic activities of PPAR, we studied the effects of cyclic stretching in C3H10T1/2 cells, treated either with the PPAR activator, Rosiglitazone, or with GW9662, a potent antagonist of PPAR. We found, through both cytochemistry and analysis of lineage marker expression, that under Roziglitazone cyclic stretch partially overcomes the induction of adipogenesis and is still able to favor osteoblast differentiation. Conversely, cyclic stretch has additive effects with GW9662 in inducing osteoblastogenesis. In conclusion, we provide evidence that mechanical stimuli are potential PPAR modulators counteracting adipocyte differentiation and inhibition of osteoblastogenesis.

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