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Madindoline A Affects the Osteogenic Potential and the Wnt Signaling Pathways during Osteogenic Differentiation of Human Mesenchymal Stem Cells in vitro

Thorfve A, Svala A, Brisby H, Thomsen P, Lindahl A and Tengvall P

Background: Human mesenchymal stem cells (hMSCs) have the potential to differentiate at least into adipocytes, chondrocytes and osteoblasts. The differentiation capacity can be modulated by drugs, or chemical substances that affect diverse mechanisms essential for e.g. bone formation. The aim of this study was to investigate the osteoinductive capacity of the interleukin-6 (IL-6) inhibitor Madindoline A (MadA) and its relation to the bone-inducing Wnt signaling pathways.
Methods: After stimulation with MadA of hMSC from 4 donors (aged 13-33 years) in an in vitro culture, alkaline phosphatase (ALP) activity and extracellular matrix (ECM) mineralization of hMSCs were quantified and calcification visualized by von Kossa staining. The expression of bone- and Wnt related markers was further studied at gene and protein levels. In addition, stimulation with the non-canonical Wnt5a ligand was added as a positive control, and the effect of MadA on IL-6 gene expression and STAT3 phosphorylation was evaluated.
Results: Stimulation with MadA induced increased ECM mineralization and upregulated the expression of the bone related genes RUNX2, COL1A1 and Osteocalcin, although large donor-to-donor differences were observed. Further, MadA affected both the canonical and non-canonical Wnt signaling pathways and displayed a superior osteoinducing property compared to Wnt5a in some cases.
Conclusion: In summary, all donors displayed higher gene expression of IL-6 and reduced STAT3 phosphorylation after MadA stimulation. The present results provide for the first time indications of an in vitro osteoinduction potential of the IL-6 inhibitor MadA.