High Glucose Modulates Transforming Growth Factor-β Signalling to Enhance Adipogenic Differentiation of Bone Marrow-Derived Progenitor Cells

Abstract

Enhanced bone marrow adiposity is commonly seen in both human diabetes and in experimental models of the disease. We have shown that high levels of glucose favour adipogenic differentiation of bone marrow-derived progenitor cells while suppressing osteoblastogenesis. In our screening for putative signalling mediators of this imbalanced differentiation of marrow cells, we identified the transforming growth factor-β1 (TGF-β1) pathway as being suppressed by high levels of glucose. Therefore, we tested the hypothesis that altered TGF-β1 signalling in diabetes causes mesenchymal cell differentiation in the bone marrow to favour adipogenesis. We show that marrow cells induced to differentiate into adipocytes activate canonical SMAD1/5. Interestingly, supplementation with TGF-β1 normalizes SMAD1/5 activation and suppresses adipogenic differentiation in marrow cells. We modulated various TGF-β signalling arms and found that the inhibition of the non-canonical TAK1-JNK axis reverses the effect of TGF-β1 and normalizes adipogenic differentiation. TAK1 has been previously reported to negatively regulate SMAD1/5 and inhibit precocious differentiation. Our studies show that restoring TGF-β1 signalling activates the TAK1-JNK axis, disrupts SMAD1/5 activation and hinders adipogenic differentiation in marrow cells. Our findings suggest that diabetes may fine-tune the balance between canonical and non-canonical TGF-β pathways in marrow cells to favor adipogenic differentiation. Elucidation of the intracellular signalling balance to inhibit enhanced adipogenesis in the diabetic marrow is the focus of our current studies.