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This version published online on January 28, 2004
Endocrinology, doi:10.1210/en.2003-1156
A more recent version of this article appeared on May 1, 2004
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Submitted on September 3, 2003
Accepted on January 16, 2004

Modeled Microgravity Inhibits Osteogenic Differentiation of Human Mesenchymal Stem Cells and Increases Adipogenesis

Majd Zayzafoon, William E. Gathings, and Jay M. McDonald*

Department of Pathology, University of Alabama at Birmingham, Birmingham, AL 35233; Consortium for Materials Development in Space, The University of Alabama at Huntsville, Huntsville, AL 35899; Veterans Administration Medical Center, Birmingham, AL 35233

* To whom correspondence should be addressed. E-mail: mcdonald{at}path.uab.edu.

Space flight-induced bone loss has been attributed to a decrease in osteoblast function, without a significant change in bone resorption. To determine the effect of microgravity on bone, we used the Rotary Cell Culture System (developed by NASA) to model microgravity (MG). Cultured mouse calvariae demonstrated a 3-fold decrease in alkaline phosphatase (ALP) activity and failed to mineralize after 7 days of MG. ALP and osteocalcin gene expression were also decreased. To determine the effects of MG on osteoblastogenesis, we cultured human mesenchymal stem cells (hMSC) on plastic microcarriers and osteogenic differentiation was induced immediately before the initiation of modeled microgravity. A marked suppression of hMSC differentiation into osteoblasts was observed as the cells failed to express ALP, collagen I and osteonectin. The expression of runt-related transcription factor 2 (Runx2) was also inhibited. Interestingly, we found that Peroxisome Proliferator-Activated Receptor {gamma} (PPAR{gamma}2), which is known to be important for adipocyte differentiation, adipsin, leptin and glucose transporter-4 (Glut 4) are highly expressed in response to MG. These changes were not corrected after 35 days of readaptation to normal gravity. In addition, MG decreased ERK- and increased p38-phosphorylation. These pathways are known to regulate the activity of Runx2 and PPAR{gamma}2, respectively. Taken together, our findings indicate that modeled microgravity inhibits the osteoblastic differentiation of hMSC and induces the development of an adipocytic lineage phenotype. This work will increase understanding and aid in the prevention of bone loss, not only in microgravity, but also potentially in age-and disuse-related osteoporosis.
Key words: Osteoblastogenesis • microgravity • aging • Runx2 • Osteoblast




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