OR31-1 Transgenic Mice with Induced Gsá Signaling in Osteoblasts Have Alterations to Bone Marrow Adipocyte and Metabolic Homeostasis

Program: Abstracts - Orals, Poster Preview Presentations, and Posters
Session: OR31-Novel Signaling Mechanisms and Bone Cell Biology
Basic
Monday, June 23, 2014: 11:30 AM-1:00 PM
Presentation Start Time: 11:30 AM
W475 (McCormick Place West Building)

Outstanding Abstract Award
Corey Cain, PhD1, Joel Valencia2 and Edward C. Hsiao, MD, PhD1
1University of California, San Francisco, San Francisco, CA, 2University of California, San Francisco
Purpose:  Osteoporosis and obesity are significant medical conditions that contribute to morbidity and mortality. Although obesity is traditionally associated with increased bone mass, large studies show that obese patients are not protected from fractures. One feature common to diseases with bone fragility such as diabetes, obesity, and aging is increased bone marrow adiposity. Although marrow adiposity is thought to contribute to bone fragility, our understanding of skeletal changes in metabolic disease is limited by an incompletely described pathway of osteoblast-adipocyte communication and a paucity of complementary models with high bone mass and low marrow fat mass. In this study, we hypothesize that osteoblastic Gs-G protein coupled receptor signals can influence marrow adiposity by changing bone metabolism and directing bone marrow cell fate.

Methods: We used the ColI(2.3)+/Rs1+ transgenic mouse model where an engineered G-protein coupled receptor Rs1 activates Gs signaling in osteoblastic cells. We previously showed that these mice have 5-15 fold increases in trabecular bone formation resembling fibrous dysplasia of the bone. O2 consumption, CO2 production, movement, food, and water consumption were measured. Additionally, total body and bone marrow fat content were measured by EchoMRI, and blood was analyzed for glucose, insulin, and triacylglyceride levels after fasting. qPCR on whole bone was used to determine mRNA levels of genes involved in adipogenesis and osteoblast development. Seahorse metabolic stress tests were used to characterize the respiration capacity of bone marrow cells from control and ColI(2.3)+/Rs1+  mice. 

Results: We found an unexpected 15% loss of total body fat and a 90% loss in tibial fat, as well as a 73% loss of blood triglyceride levels. Furthermore, ColI(2.3)+/Rs1+ mice showed decreased movement, food, and water consumption without alterations to energy expenditure. Seahorse mitochondrial stress test analysis on ColI(2.3)+/Rs1+ hematopoietic cells revealed a 50% decrease in basal respiration. qPCR indicated a decrease in genes expressed by mature adipocytes including Adiponectin and PRDM16. We also found increased levels of Wnt expression in ColI(2.3)+/Rs1+ bones. 

Conclusions: ColI(2.3)+/Rs1+ mice show increased bone formation but decreased marrow adiposity, in contrast to other conditions of decreased bone formation and increased marrow adiposity. In addition, the ColI(2.3)+/Rs1+ bones showed decreased expression of mature adipocyte markers, possibly caused by a non-cell autonomous mechanism from the Rs1-expressing osteoblasts. Our findings suggest that osteoblasts may influence the metabolic homeostasis of bone through both changes in bioenergetics and cellular differentiation.

Nothing to Disclose: CC, JV, ECH

*Please take note of The Endocrine Society's News Embargo Policy at https://www.endocrine.org/news-room/endo-annual-meeting

Sources of Research Support: NIH K08 AR056299-03 to ECH; UCSF RAPtr Summer Fellowship to JV, and NIH 5T32GM7085-35 to CC.
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