Abstract
Fat infiltration within marrow cavity is one of multitudinous features of estrogen deficiency, which leads to a decline in bone formation functionality. The origin of this fat is unclear, but one possibility is that it is derived from osteoblasts, which transdifferentiate into adipocytes that produce bone marrow fat. We examined the dose-dependent effect of 17β-estradiol on the ability of MC3T3-E1 cells and murine bone marrow-derived mesenchymal stem cell (BMMSC)-derived osteoblasts to undergo osteo-adipogenic transdifferentiation. We found that 17β-estradiol significantly increased alkaline phosphatase activity (P<0.05); calcium deposition; and Alp, Col1a1, Runx2, and Ocn expression levels dose-dependently. By contrast, 17β-estradiol significantly decreased the number and size of lipid droplets, and Fabp4 and PPARγ expression levels during osteo-adipogenic transdifferentiation (P<0.05). Moreover, the expression levels of brown adipocyte markers (Myf5, Elovl3, and Cidea) and undifferentiated adipocyte markers (Dlk1, Gata2, and Wnt10b) were also affected by 17β-estradiol during osteo-adipogenic transdifferentiation. Western blotting and immunostaining further showed that canonical Wnt signaling can be activated by estrogen to exert its inhibitory effect of osteo-adipogenesis. This is the first study to demonstrate the dose-dependent effect of 17β-estradiol on the osteo-adipogenic transdifferentiation of MC3T3-E1 cells and BMMSCs likely via canonical Wnt signaling. In summary, our results indicate that osteo-adipogenic transdifferentiation modulated by canonical Wnt signaling pathway in bone metabolism may be a new explanation for the gradually increased bone marrow fat in estrogen-inefficient condition.
Highlights
The presence of bone marrow fat is indicative of aging and a consequence of osteoporosis, especially in menopausal women [1]
One possible cause of bone marrow fat deposition is the aberrant commitment of bone marrow-derived stem cells (BMMSCs) into adipocytes because of their inability to differentiate into other cell lineages, such as osteoblasts
Tuan et al [4] have shown that hBMMSC-derived osteoblasts, adipocytes, and chondrocytes had the potential to transdifferentiate to each lineage, and these findings provided new insights on the pathogenesis of skeletal diseases such as osteoporosis
Summary
The presence of bone marrow fat is indicative of aging and a consequence of osteoporosis, especially in menopausal women [1]. One possible cause of bone marrow fat deposition is the aberrant commitment of bone marrow-derived stem cells (BMMSCs) into adipocytes because of their inability to differentiate into other cell lineages, such as osteoblasts. The origin of bone marrow fat, the physiological role of adipocytes in bone marrow, and the reasons for the increase in adipogenesis during osteoporosis and the abnormal adipogenic differentiation of BMMSCs are unclear. A correlation has been established between the osteo-adipogenic transdifferentiation of bone marrow cells and numerous bone metabolism diseases. Tuan et al [4] have shown that hBMMSC-derived osteoblasts, adipocytes, and chondrocytes had the potential to transdifferentiate to each lineage, and these findings provided new insights on the pathogenesis of skeletal diseases such as osteoporosis. If and to what extent established key factors or signaling pathways of normal osteogenesis and adipogenesis play a role in the transdifferentiation process remains unknown
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