Osteoporosis is generally accompanied by the fatty degeneration of the bone marrow. The enhanced deposition of adipocytes may result from adipogenic differentiation of bone-marrow mesenchymal stem cells (MSC) and from the adipogenic conversion of osteoblastic cells respectively. Thus, whether this clinical observation is a cause of the disease or rather a reaction of the afflicted bone marrow remains to be elucidated.
Previous microarray and bioinformatic analyses showed differential gene expression patterns for members of the fibroblast growth factor (FGF) signaling pathway during the onset of adipogenic conversion of osteoblastic cells and osteogenic conversion of adipocytes. FGF1 was scored as one lead candidate gene to modulate conversion processes. This factor was shown to strongly inhibit adipogenic MSC differentiation as well as the adipogenic conversion in vitro. Further investigation revealed that FGF1 not only affects adipogenic commitment and differentiation but also mineralization during osteogenic MSC differentiation and the osteogenic conversion of adipocytes. Effects were reproducible in several donors and clearly concentration-dependent. Quantitative analysis showed a decrease of approx. About 60% in calcium deposition. Gene expression analyses via quantitative RT-PCR revealed a strong down-regulation of the adipogenic differentiation factors peroxisome proliferator-activated receptor gamma 2 (PPARγ2), lipoprotein lipase (LPL) and fatty acid binding protein 4 (FABP4) during adipogenic differentiation and conversion. Additionally, integrin-binding sialoprotein (IBSP) expression was down-regulated whereas progressive ankylosis protein homolog (ANKH), an inorganic pyrophosphate transport regulator, and osteopontin (OP) were up-regulated during osteogenic differentiation and conversion, obviously linking gene expression to the decreased mineralization outcome.
We conclude that FGF1 triggers downstream signaling molecules affecting adipogenic as well as osteogenic differentiation and conversion. Future studies will focus on intracellular pathways involved in the observed effects, which might serve as possible targets for the development of novel therapeutic approaches against osteoporosis and related bone diseases.
17 - 20 May 2014
European Calcified Tissue Society