Divergent Effects of Selective Peroxisome Proliferator-Activated Receptor- 2 Ligands on Adipocyte Versus Osteoblast Differentiation

Abstract

PPAR gamma is activated by diverse ligands and regulates the differentiation of many cell types. Based on evidence that activation of PPAR gamma 2 by rosiglitazone stimulates adipogenesis and inhibits osteoblastogenesis in U-33/gamma 2 cells, a model mesenchymal progenitor of adipocytes and osteoblasts, we postulated that the increase in marrow fat and the decrease in osteoblast number that occur during aging are due to increased PPAR gamma 2 activation. Here, we show that the naturally occurring PPAR gamma ligands 9,10-dihydroxyoctadecenoic acid, and 15-deoxy-Delta(12,14)-PGJ(2), also stimulate adipocytes and inhibit osteoblast differentiation of U-33/gamma 2 cells. Strikingly, 9,10-epoxyoctadecenoic acid and the thiazolidine acetamide ligand GW0072 [(+/-)-(2S,5S)-4-(4-(4-carboxyphenyl)butyl)-2-heptyl-4-oxo-5-thaizolidineN,N-dibenzyl-acetamide] prevent osteoblast differentiation, but do not stimulate adipogenesis, whereas 9-hydroxyoctadecadienoic acid stimulates adipogenesis but does not affect osteoblast differentiation. The divergent effects of PPAR gamma 2 ligands on osteoblast and adipocyte differentiation were confirmed in primary murine bone marrow cultures using rosiglitazone and GW0072. These findings indicate that the proadipogenic and antiosteoblastogenic effects of PPAR gamma 2 are mediated by distinct regulatory pathways that can be differentially modulated depending on the nature of the ligand, and they support the idea that increased fatty acid oxidation during aging may inhibit osteoblast differentiation. Moreover, there may be selective PPAR gamma 2 modulators that block the adverse effects of fatty acid oxidation products while retaining beneficial activities such as insulin sensitization.

Long-chain polyunsaturated fatty acids: Selected mechanisms of action on bone

“…However, only a few studies on the effect of PPARs acting specifically via fatty acids in osteoblast maturation are available at this point in time. In an excellent study, Lecka-Czernik et al [144] …”

“…In addition, the LA peroxidation products 9, 10-epoxyoctadecenoic acid (9,10 EOA), 9,10 dihydroxyoctadecenoic acid (9,10DHOA) and 9-hydroxyoctadecadienoic acid (9-HODE) have also been reported to be ligands for PPARγ2 [144]. Still et al [147] have reported action of LA on bone via binding to PPARα/δ.…”

Gene expression analysis of major lineage‐defining factors in human bone marrow cells: Effect of aging, gender, and age‐related disorders

“…That can be reasonably explained as follows. Lecka-Czernik et al 40 and Ali et al 41 reported the effect of ppar-gamma expression on adipocyte versus osteoblast differentiation. They showed evidence that the activation of ppar-gamma2 stimulates adipogenesis and inhibits osteoblastogenesis in mesenchymal progenitor cells.…”

Effects of arachidonic acid and docosahexaenoic acid on differentiation and mineralization of MC3T3‐E1 osteoblast‐like cells

“…24,25,27 Figure 3. Photomicrograph of mineralized nodules after 14 days of exposure to polyunsaturated fatty acids.…”

“…23 These receptors are activated by free fatty acids and their oxidation products as well as by some prostaglandins derived from fatty acids that induce the differentiation of preadipocytes into adipocytic cells. [24][25][26][27] AA, which is a precursor for prostaglandins of the -2-family, has specifically been implicated in adipocyte differentiation. 23 With ageing there is a decrease in osteoprogenitor cells with an accompanying increase in adipocytes in bone marrow.…”