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1,25-Dihydroxy Vitamin D₃ Inhibits Adipocyte Differentiation and Gene Expression in Murine Bone Marrow Stromal Cell Clones and Primary Cultures¹

Departments of Pathology (K.A.K., J.M.G.), Orthodontics (K.A.K.), and Surgery (J.M.G.), University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma 73190; Immunobiology & Cancer (K.A.K., J.M.G.), Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma 73104

Address all correspondence and requests for reprints to: Dr. Jeffrey M. Gimble, Department of Surgery, University of Oklahoma Health Sciences Center, Williams Pavilion 2140, WP2140, 920 Stanton L. Young Boulevard, Oklahoma City, Oklahoma 73190. E-mail: Jeffrey-Gimble{at}ouhsc.edu

Bone marrow stromal stem cells differentiate into adipocytes and osteoblasts. These two lineages are thought to be reciprocally related, in part due to the observation that the osteoblast-inducing factor, 1,25 dihydroxy vitamin D₃ [1,25(OH)₂D₃], inhibited adipogenesis of rat femoral-derived stromal cell cultures. However, the literature is divided concerning the adipogenic effects of this steroid hormone. This work examined the effect of 1,25(OH)₂D₃ (10^-12–10^-8 M) on murine femoral-derived bone marrow stromal cell differentiation in response to adipogenic agonists employing two different classes of nuclear hormone receptors: the glucocorticoid receptor (hydrocortisone) or peroxisome proliferator-activated receptors (thiazolidinediones). Experiments used the multipotent murine bone marrow stromal cell line, BMS2, and its subclones, as well as primary-derived murine bone marrow stromal cell cultures. In all systems examined, 1,25(OH)₂D₃ blocked adipogenesis induced by hydrocortisone, methylisobutylxanthine, and indomethacin based on flow cytometric analysis of lipid accumulation. This correlated with reduced messenger RNA levels of the late adipocyte gene markers, aP2 and adipsin. In the BMS2 subclone no. 24, the 1,25(OH)₂D₃ actions were concentration dependent. Whereas 1,25(OH)₂D₃ partially inhibited thiazolidinedione-induced adipogenesis in the parental BMS2 cell line, it had minimal effect on the thiazolidinedione-induced differentiation of the BMS2 subclone and primary cultures. These findings indicate that 1,25(OH)₂D₃, at nanomolar concentrations, completely inhibits murine bone marrow stromal cell differentiation in response to glucocorticoid-based adipogenic agonists but is a less effective adipogenic antagonist following induction with thiazolidinediones. This work supports the conclusion that 1,25(OH)₂D₃ inhibits murine femoral-derived bone marrow stromal cell adipogenesis.

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