Abstract
Mangiferin is a natural immunomodulator found in plants including mango trees. The effects of mangiferin on chondrogenesis and cartilage repair have not yet been reported. This study was designed to determine the effect of mangiferin on chondrogenic differentiation in IL-1β-stimulated mesenchymal stem cells (MSCs) from subchondral bone and to explore the mechanisms underlying these effects. MSCs were isolated from the subchondral bone of rabbit and treated with mangiferin alone and/or interleukin-1β (IL-1β). Mangiferin induced chondrogenic differentiation in MSCs by upregulating transforming growth factor (TGF)-β, bone morphogenetic protein (BMP)-2, and BMP-4 and several key markers of chondrogenesis, including sex-determining region Y–box (SRY-box) containing gene 9 (SOX9), type 2α1 collagen (Col2α1), cartilage link protein, and aggrecan. In IL-1β-stimulated MSCs, mangiferin significantly reversed the production of TGF-β, BMP-2, BMP-4, SOX9, Col2α1, cartilage link protein, and aggrecan, as well as matrix metalloproteinase (MMP)-1, MMP-13, and a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS5). Mangiferin upregulated the phosphorylation of Smad 2, Smad 3, Smad 1/5/8, and SOX9 in IL-1β-stimulated MSCs. In the presence of mangiferin, SOX9 siRNA suppressed the activation of Smad 2, Smad 3, Smad 1/5/8, aggrecan, and Col2α1 expression. In conclusion, mangiferin exhibits both chondrogenic and chondroprotective effects on damaged MSCs and mediates these effects by targeting multiple aspects of the Smad and SOX9 signaling pathways.
Highlights
Osteoarthritis (OA) is the most common musculoskeletal disease, and it imposes heavy social, medical, and financial burdens
Mangiferin markedly increased the levels of transforming growth factor (TGF)-β (2.5- to 2.3-fold), bone morphogenetic protein (BMP)-2 (2.7- to 2.9-fold), and BMP-4 (1.8- to 1.8-fold) at days 3 and 7, respectively, compared with control; levels were reduced slightly at day 14 (Figure 2D). These results indicate that mangiferin induces chondrogenic differentiation by increasing SOX9 expression over several days and influences chondrogenic regulation induced by TGF-β, BMP-2, and BMP-4
The present study showed that mangiferin notably induced SOX9, Col2α1, cartilage link protein, aggrecan, and growth factors such as TGF-β, BMP-2, and BMP-4
Summary
Osteoarthritis (OA) is the most common musculoskeletal disease, and it imposes heavy social, medical, and financial burdens. Several novel therapeutic methods for the treating OA are being researched, and it is anticipated that these new therapies will soon enable us to halt the progression of this degenerative disease and restore cartilage homeostasis [2]. Subchondral bone is a target of current OA treatments, because subchondral bone changes in OA induce cartilage loss, and cartilage damage may, in turn, have a negative influence on subchondral bone [3,4]. A previous study showed that bone sclerosis caused by subchondral bone damage may precede cartilage degradation [5]. Microfracture can damage the tissue down to the subchondral bone and induce bleeding, allowing mesenchymal stem cells (MSCs) derived from the subchondral bone to enter the defect. Subchondral bone tissue may be a promising therapeutic target in OA
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