Sodium Tungstate for Promoting Mesenchymal Stem Cell Chondrogenesis

Abstract

Articular cartilage has a limited ability to heal. Mesenchymal stem cells (MSCs) derived from the bone marrow have shown promise as a cell type for cartilage regeneration strategies. In this study, sodium tungstate (Na 2 WO 4 ), which is an insulin mimetic, was evaluated for the first time as an inductive factor to enhance human MSC chondrogenesis. MSCs were seeded onto three-dimensional electrospun scaffolds in growth medium (GM), complete chondrogenic induction medium (CCM) containing insulin, and CCM without insulin. Na 2 WO 4 was added to the media leading to final concentrations of 0, 0.01, 0.1, and 1 mM. Chondrogenic differentiation was assessed by biochemical analyses, immunostaining, and gene expression. Cytotoxicity using human peripheral blood mononuclear cells (PBMCS) was also investigated. The chondrogenic differentiation of MSCs was enhanced in the presence of low concentrations of Na 2 WO 4 compared to control, without Na 2 WO 4 . In the induction medium containing insulin, cells in 0.01 mM Na 2 WO 4 produced significantly higher sulfated glycosaminoglycans, collagen type II, and chondrogenic gene expression than all other groups at day 28. Cells in 0.1 mM Na 2 WO 4 had significantly higher collagen II production and significantly higher sox-9 and aggrecan gene expression compared to control at day 28. Cells in GM and induction medium without insulin containing low concentrations of Na 2 WO 4 also expressed chondrogenic markers. Na 2 WO 4 did not stimulate PBMC proliferation or apoptosis. The results demonstrate that Na 2 WO 4 enhances chondrogenic differentiation of MSCs, does not have a toxic effect, and may be useful for MSC-based approaches for cartilage repair.

Biodegradable zinc oxide composite scaffolds promote osteochondral differentiation of mesenchymal stem cells

“…IGF-1 has been shown to enhance MSC chondrogenesis by promoting proliferation and expression of chondrocyte markers independently from TGF-β signaling (Longobardi et al, 2006). Although the chondrogenic medium has insulin, sodium tungstate and vanadium, which are also insulin mimetics, were found to enhance chondrogenesis and osteogenesis, respectively, synergistically with insulin (Khader et al, 2016;Schussler et al, 2017). transition between G1 to S and G2 to M phases (Santala et al, 2014), was high for cells on 2.5%, 5%, and 10% ZnO composite scaffolds.…”

“…Relative gene expression of Runx2, SP7 (osterix), BGLAP (osteocalcin), and vascular endothelial growth factor (VEGF) were determined for osteogenesis. Samples ( n = 5 per group) were harvested and digested using TRIzol™ reagent (Fisher Scientific) according to manufacturer's protocol followed by isolating the RNA using RNeasy Micro Kit (Qiagen) that includes DNA digestion step (RNase Free DNase Set; Qiagen).Quantitative RT‐PCR analysis was evaluated according to previously published protocol (Khader et al, ). The value of each gene was normalized to the reference gene ribosomal protein, large, P0 (RPLP0) for the same sample (Δ C T ).…”

“…Furthermore, local insulin therapy has been found to improve bone healing and cartilage formation in animal models (Dedania et al, ; Gandhi, Beam, O'Connor, Parsons, & Lin, ; Park et al, ). Other insulin mimetics, such as vanadyl acetylacetonate, magnesium chloride, and sodium tungstate, have been shown to improve the osteogenesis of mesenchymal stem cells (MSCs; Schussler et al, ), bone healing (Hreha et al, ) and chondrogenic differentiation (Khader, Sherman, Rameshwar, & Arinzeh, ) respectively. Zinc supplementation in the cell culture medium has been shown to enhance mineralization and osteocalcin gene expression of MC3T3‐E1 osteoblasts (Nagata & Lonnerdal, ).…”

Nucleic acids and analogs for bone regeneration

“…27 Recent studies have shown that adipose-derived stem cells (ADSCs) and mesenchymal stem cells (MSCs) have promise for use in tissue repair due to their multi-directional differentiation abilities. 28–30 MSCs are derived from the mesoderm during early embryonic development and are pluripotent stem cells that can differentiate into bone, cartilage, fat, and other cell types under specific induction conditions. 31–36 As a subtype of MSCs, ADSCs are ideal stem cells for the regeneration of bone tissue.…”

Sodium tungstate: Is it a safe option for a chronic disease setting, such as diabetes?

“…Some of the many beneficial antidiabetic and antiobesity effects of Na 2 WO 4 (Table 1) have been recently and extensively reviewed (Bertinat, Nualart, Li, Yanez, & Gomis, 2015): Normalization of blood glucose and triglyceride levels (Munoz et al, 2001;Nocito et al, 2012); restoration of hepatic glucose metabolism through inhibition of gluconeogenesis and stimulation of glycogen synthesis (Barberà et al, 2001(Barberà et al, , 1994Munoz et al, 2001;Nocito et al, 2012); and induction of weight loss through complex antiobesity mechanisms (Amigo-Correig et al, 2011), among others, with the very unique characteristic that it does not produce hypoglycemic episodes. Other positive effects of Na 2 WO 4 have been reported in the last few years, such as protection of epithelial integrity in renal cells (Bertinat, Silva, et al, 2015), induction of chondrogenic differentiation of bone marrow-derived mesenchymal stem cells for cartilage regeneration strategies (Khader, Sherman, Rameshwar, & Arinzeh, 2016), protection of visual pathways (Bulut et al, 2016), improvement of reduced bone mechanical quality (Donmez et al, 2014), and antiplatelet activity (Fernandez-Ruiz et al, 2015). Given the entire spectrum of positive effects, Na 2 WO 4 has received considerable attention in the search for new antidiabetic drugs during the last two decades, having yielded very promising results.…”