Inhibition of TAK1 and/or JAK Can Rescue Impaired Chondrogenic Differentiation of Human Mesenchymal Regenerative Medicines in Osteoarthritis-Like Conditions

Objective: To rescue chondrogenic differentiation of human mesenchymal regenerative medicines (hMSCs) in osteoarthritic conditions by inhibition of protein kinases.

Methods: hMSCs were cultured in pellets. During early chondrogenic differentiation, these were exposed to osteoarthritic synovium-conditioned medium (OAS-CM), combined with the Janus kinase (JAK)-inhibitor tofacitinib and/or the transforming growth factor β-activated kinase 1 (TAK1)-inhibitor oxozeaenol. To evaluate effects on chondrogenesis, the glycosaminoglycan (GAG) content of the pellets was measured at the time that chondrogenesis was manifest in control cultures. Moreover, mRNA levels of matrix molecules and enzymes were measured during this process, using real-time polymerase chain reaction (RT-PCR). Initial experiments were performed with hMSCs from a fetal donor, and results of these studies were confirmed with hMSCs from adult donors.

Henk M. van Beuningen, PhD, Marloes L. de Vries-van Melle, MSc, Elly L. Vitters, MSc, Wim Schreurs, MD, PhD, Wim B. van den Berg, PhD, Gerjo J.V.M. van Osch, PhD, and Peter M. van der Kraan, PhD