Inhibition of TAK1 and/or JAK can rescue impaired chondrogenic differentiation of human mesenchymal stem cells in osteoarthritis-like conditions

Tissue Engineering Part A doi:10/1089/ten.TEA.2013.0553

As it is nonvascularized and noninnervated, articular cartilage has a limited capacity to repair which presents a major clinical problem. In order to circumvent this inability to repair, stem cells can be placed into the joint or stimulated within the bone marrow. However, as the cartilage requiring repair is often in diseased joints, the factors involved in the disease state are potentially non-beneficial to the chondrogenesis of mesenchymal stem cells. In this study van Beuningen et al. investigated the effects of inhibiting protein kinases to block catabolic intracellular pathways. The pathways inhibited were TAK1 and JAK, as these are common routes of specific but differing cytokine signalling pathways. Tofacitinib was used as the JAK inhibitor and oxozeanol for the TAK1 inhibitor, between them affecting multiple cytokines such as IL-1, TNF-a, IL-6 etc. Both tofacitinib and oxozeanol improved chondrogenesis of human mesenchymal stem cells with these affects shown to be additive by measurement of glycosaminoglycan content. Both inhibitors countered the down-regulation effects of the osteoarthritis synovium-conditioned medium on the sox9 gene, the master gene of chrondrogenesis. These findings have implications on current treatment avenues being explored as they depend on the chondrogenesis of precursor cells which has been shown to fail in diseased joints and the addition of protein kinase inhibitors can rescue chondrogenic differentiation and promote cartilage regeneration.