Enhanced bone formation in lipodystrophic PPARγ^hyp/hyp mice relocates haematopoiesis to the spleen

Abstract

The peroxisome proliferator-activated receptor gamma (PPARc) controls adipogenesis and metabolism. We demonstrate here that the absence of PPARc in fat has potent osteogenic activities, which affect haematopoiesis. The congenital absence of PPARc in fat of lipodystrophic PPARc hyp/hyp mice, strongly enhanced bone mass and consequentially reduced the bone-marrow cavity. Consistent with this, PPARc hyp/hyp mice had a significant decrease in bone marrow cellularity and resorted to extramedullary haematopoiesis in the spleen to maintain haematopoiesis. Our data indicate that antagonizing PPARc activity in fat could be an effective way to combat osteoporosis and suggest that haematopoietic function should be scrutinized in lipodystrophic subjects.

PPARγ in human and mouse physiology

“…On the other hands, heterozygous PPARγ-deficient mice have enhanced osteoblastogenesis resulting in increased bone mass [132]. Similarly, the specific absence of PPARγ in fat robustly increases bone mass as it favors osteogenic rather than adipogenic differentiation of mesenchymal precursor cells [26]. The absence of PPARγ in adipocytes also limits their capacity to secrete antiosteogenic-signaling factors, including leptin, further enhancing the bone phenotype [26].…”

“…Similarly, the specific absence of PPARγ in fat robustly increases bone mass as it favors osteogenic rather than adipogenic differentiation of mesenchymal precursor cells [26]. The absence of PPARγ in adipocytes also limits their capacity to secrete antiosteogenic-signaling factors, including leptin, further enhancing the bone phenotype [26]. In addition, the strongly enhanced bone mass consequentially reduces the bone marrow cavity volume and suppressed hematopoiesis which is, however, compensated for by extramedullary hematopoiesis in the spleen [26].…”

“…However, the clinical use of these full PPARγ agonists is limited by weight gain due to increased adiposity, fluid retention, and heart failure in up to 15% of patients [22][23][24]. In addition, despite their fairly wide use, the long-term adverse effects of TZDs are not very well known, and they may increase the risk for osteoporosis [25,26] and colon cancer [27,28].…”

Skeletal aging and the adipocyte program

“…PPARγ is a member of the PPAR family of transcriptional factors and nuclear receptors which possess a critical role in adipogenesis and osteogenesis as evidenced by the fact that haploinsufficiency or hypomorphic mutation of PPARγ result in the high-bone mass phenotype and reduced marrow adiposity. 34,35 In addition, as shown in a number of in vitro models of MSC differentiation, as well as in primary bone marrow cells, the activation of PPARγ2 with either natural (fatty acids and ecosanoids) or artificial (TZD) ligands directs MSC differentiation toward the adipocyte lineage at the expense of osteoblast formation. 3,6,32,36 Moreover, activation of PPARγ2 in cells of the osteoblast lineage converts them to terminally differentiated adipocytes and irreversibly adipocytes are all but absent in the bone marrow and hematopoietic cells primarily occupy the marrow cavity at this stage.…”

Safety of Antidiabetic Therapies on Bone

“…An essential role of PPARγ in maintenance of bone homeostasis was demonstrated in several animal models of either bone accrual or bone loss depending on the status of PPARγ activity (51)(52)(53)(54)(55)(56). In models of bone accrual, a decrease in PPARγ activity in either heterozygous PPARγ-deficient mice or mice carrying a hypomorphic mutation in the PPARγ gene locus led to increased bone mass due to increased quantity of osteoblasts (54; 56).…”