Arthritis & Rheumatism, Volume 60,
October 2009 Abstract Supplement
The 2009 ACR/ARHP Annual Scientific Meeting
Philadelphia October 16-21, 2009.
Glucocorticoid-Induced Fat Accrual Is Mediated by the Osteoblast
Henneicke1, Holger, Herrmann1, Markus, Street1, Janine, Modzelewski1, James, Buttgereit2, Frank, Zhou1, Hong, Seibel1, Markus
Osteoblasts may be involved in the regulation of energy metabolism. To define whether the metabolic effects of glucocorticoids (GC) are mediated via the osteoblast, we used a transgenic mouse model in which a GC inactivating enzyme, 11b-hydroxysteroid-dehydrogenase type 2 (11bHSD2), has been targeted exclusively to mature osteoblasts via the 2.3kb collagen type Ia1 promoter. This transgene is expressed in osteoblasts/osteocytes but not in fat, pancreas, liver, muscle or the CNS.
Transgenic (tg, n=16) and wild type (WT, n=16) mice received either corticosterone (CS) or placebo (PLC) via s.c. pellet implantation for 28 days. In a second experiment, WT mice (n=29) received either CS, CS + warfarin (1.25mg/L drinking water), PLC, or PLC + warfarin for 4 weeks. At day 28, body composition was measured by DXA. Gonadal (GF), retroperitonal (RF) and inter-scapular (IF) fat pads were dissected and weighed. Serum total and uncarboxylated (uc) osteocalcin (OCN), PINP (a marker of bone formation) and cholesterol were measured on day 0, 14 & 28.
At day 28, CS treatment resulted in significant bone loss in WT but not in tg mice. Body weight gain over 28 days was greater in CS-treated WT mice (3.7g) than in CS-treated tg animals (1.9g). Fat masses (total body: 12.1 vs. 8.1g, p<.01; GF: 1.41 vs. 0.81g, p<.01; RF: 0.29 vs. 0.18, p<.05; IF: 0.60 vs. 0.36, p<.01) as well as serum cholesterol levels (p<.05) were all lower in CS-treated tg than in WT mice. None of these parameters differed significantly between PLC-treated tg and WT mice.
Serum OCN decreased in both CS-treated WT (-75%) and tg (-58%) animals, with total OCN levels remaining higher in tg than in WT mice during CS-treatment (p<.01). At day 28, serum ucOCN levels were reduced in CS-treated WT mice (p<.01) with no difference between CS-treated tg mice and controls (Fig.1). In contrast, serum PINP levels changed similarly in tg and WT animals during CS exposure.
In pilot studies, warfarin increased the ucOCN fraction from 29% to 54%. Total body fat (11.5 vs. 10.4; NS), GF (1.34 vs. 1.16, NS), RF (0.27 vs. 0.21, p<.05) and IF (0.43 vs. 0.36, p=.08) masses were lower in CS+warfarin-treated WT mice as compared to CS only-treated mice.
Osteoblast-targeted disruption of GC signalling attenuates GC-induced fat accrual and hyperlipidaemia in mice. Some of the effects of GC on energy metabolism appear to be, at least in part, mediated by osteocalcin.
To cite this abstract, please use the following information:
Henneicke, Holger, Herrmann, Markus, Street, Janine, Modzelewski, James, Buttgereit, Frank, Zhou, Hong, et al; Glucocorticoid-Induced Fat Accrual Is Mediated by the Osteoblast [abstract]. Arthritis Rheum 2009;60 Suppl 10 :609