Deferoxamine synergizes with transforming growth factor-β signaling in chondrogenesis

Abstract

Osteoarthritis, also known as degenerative arthritis or degenerative joint disease, is an epidemic disease that affects millions of people worldwide. Despite extensive recent work on the cellular biology of osteoarthritis, the precise mechanisms involved are still poorly understood and there is no effective treatment for this disease. The role of transforming growth factor-beta (TGF-β) in promoting chondrogenesis and inducing the expression of cartilage-specific extracellular matrix molecules to form cartilage is well-established. Historically, TGF-β has been considered to prevent osteoarthritis, but recent work suggests that TGF-β overexpression accelerates the progression of osteoarthritis in vivo. Clinically, it is therefore important to limit TGF-β expression while still providing effective treatment of osteoarthritis. One possible approach to achieve this effect would be to use a combination of TGF-β with other small molecular chemical compounds. Hypoxia promotes chondrogenesis and the usefulness of deferoxamine, a chelating agent that mimics hypoxia, in stimulating chondrogenesis has been investigated in clinical trials. In this study, we investigated the role of deferoxamine in TGF-β-induced chondrogenesis in pre-chondrogenic cells and examined whether deferoxamine synergizes with the TGF-β signaling pathway to promote chondrocyte differentiation.

Hypoxia mimicking hydrogels to regulate the fate of transplanted stem cells

“…Either hypoxia or HIF-1a overexpression has been shown to be effective and sufficient to induce chondrogenesis of MSCs [19], while HIF-1α has been shown to potentiate BMP2-induced cartilage formation and inhibit endochondral ossification during ectopic bone/cartilage formation [20]. A number of studies have also demonstrated that HIF stabilizing compounds can enhance chondrogenesis of MSCs [19,21,22], with a recent comparison of three such compounds demonstrating that DMOG stimulation induce a more chondrogenic transcriptional profile [23].…”

Differential Regulation of Human Bone Marrow Mesenchymal Stromal Cell Chondrogenesis by Hypoxia Inducible Factor-1α Hydroxylase Inhibitors

“…The importance of hypoxia and HIF in cartilage development and maintenance point towards its potential utility in cartilage tissue engineering strategies. Indeed, chemical agents that upregulate HIF have been shown to drive the chondrogenic differentiation of MSC and promote articular chondrocytes to produce a cartilage-like ECM [12, 20, 21]. However, studies which compare the efficacy of different HIF-stimulating compounds in driving the chondrogenesis of hBM-MSC compared to standard protocols which utilise transforming growth factor-β (TGF-β), are lacking.…”

DMOG Negatively Impacts Tissue Engineered Cartilage Development

“…7 With the addition of DFO and TGF-β to chondrocytes, Col2a1, Sox9, and aggrecan expression, as well as cell proliferation, were significantly increased, compared to the null control, DFO alone, and TGF-β alone. 18 A previous study using PC12 cells (rat adrenal phaeochromocytoma) grown in monolayer treated with DMOG at a concentration of 1 mM for 2 hours showed HIF stabilization by Western blot analysis. 19 The current study is the first to assess the effect of DMOG by consideration of spatial localization, and investigation of HIF-1α stabilization co-localized with nuclei.…”

“…Deferoxamine (DFO or desferrioxamine) is a chelating agent initially designed to remove excess iron in the bloodstream and has been shown to have additional biological applications by synergizing with the action of TGF-β to induce chondrogenesis. 18 The mechanism of action of DFO is related to the sequestration of iron, which is necessary for the action factor inhibiting HIF (FIH) and PHD2, thereby amplifying the concentration of HIF-1α within the cell and simulating the effects of hypoxia. 7 With the addition of DFO and TGF-β to chondrocytes, Col2a1, Sox9, and aggrecan expression, as well as cell proliferation, were significantly increased, compared to the null control, DFO alone, and TGF-β alone.…”