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Simvastatin (Sim) is a clinically used lipid lowing agent, which has been indicated to increase bone morphogenetic protein-2 (BMP-2) expression. BMP-2 has been demonstrated to play a critical role in cartilage development, and is applied to promote chondrogenic differentiation of mesenchymal stem cells (MSCs). However, BMP-2 was also used for osteogenic differentiation of MSCs. Hyaluronan (HA) is one of the main extra cellular matrices during the early stage of chondrogenesis, and we previously found that HA microenvironment initiates and promotes chondrogenesis of adipose derived stem cells (ADSCs). In this study, we hypothesize that HA enhances the chondrogenic effect and prevents osteogenic effect of Sim on ADSCs, and this can be applied for cartilage regeneration. The ADSCs were cultured in vitro in HA-coating, well treated with Sim, and the BMP2 expression, chondrogenesis as well as osteogenesis of ADSCs were analyzed. The result showed that HA microenvironment enhances Sim-induced BMP-2 expression and chondrogenesis of ADSCs. The real-time PCR results showed that the BMP2 and chondrogenic genes (SOX-9, Collagen type II and Aggrecan) expressions induced by Sim in ADSCs were enhanced when cultured in HA-coated well (Figure. 1). The result from sGAG synthesis of ADSCs also shows HA microenvironment enhances more pronounced sulfated glycosaminoglycan (sGAG) synthesis of ADSCs that is induced by Sim (Figure. 2). HA microenvironment also reduces osteogenic genes expressions (osteocalcin and alkaline phosphatase) and calcium deposition of ADSCs that is induced by Sim (Figure. 3). The synergic effect of HA with Sim can promote chondrogenesis and prevent osteogenesis of ADSCs, and may be applied for articular cartilage defect regeneration. This result shows the local cue on affecting chondrogenesis and osteogenesis of BMP-2 in ADSCs induced by Sim.
Recent publications 1. Wu S C, Chen C H, Wang J Y, Lin Y S, Chang J K, et al. (2018) Hyaluronan size alters chondrogenesis of adipose-derived stem cells via the CD44/ERK/SOX-9 pathway. Acta Biomater. 15(66):224-237. 2. Chuang S C, Chen C H, Fu Y C, Tai I C, Li C J, et al. (2015) Estrogen receptor mediates simvastatin-stimulated osteogenic effects in bone marrow mesenchymal stem cells. Biochemical Pharmacology 98(3):453-64. 3. Tai I C, Wang Y H, Chen C H, Chuang S C, Chang J K and Ho M L (2015) Simvastatin enhances Rho/actin/cell rigidity pathway that contributing to mesenchymal stem cells osteogenic differentiation. International Journal of Nanomedicine 10:5881–5894. 4. Hsieh K C, Kao C L, Feng C W, Wen Z H, Chang H F, et al. (2014) A Novel Anabolic Agent: A simvastatin analogue without HMG-CoA reductase inhibitory activity. Organic Letters 16(17):4376-9. 5. Chen C H, Lin Y S, Fu Y C, Wang C K, Wu S C, et al. (2013) Electromagnetic fields enhance chondrogenesis of human adipose-derived stem cells in a chondro-genic microenvironment in vitro. Journal of Applied Physiology 114:647-655.
Je-Ken Chang is an Orthopedic Surgeon at the Kaohsiung Medical University. His research work focuses on Regenerative Medicine, especially Tissue Engineering of articular cartilage and bone, as well as degenerative diseases like osteoarthritis and osteoporosis. He has published his study results in journals including Biomaterials, Acta Biomaterialia, Journal of Tissue Engineering and Regenerative Medicine and Journal of Applied Physiology.
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