Approach to the development of regenerative therapies for Osteoarthritis based on the silencing of anti-chondrogenic microRNAs in Mesenchymal Stem Cells

Abstract

Osteoarthritis (OA) is a highly prevalent musculoskeletal disease and a major cause of disability with an annual cost for the Spanish health system equivalent to 0.5% of the gross domestic product. Current treatments for OA are mainly surgical and have a low percentage of success long-term, frequently resulting in unavoidable joint replacement surgery. The intra-articular injection of Mesenchymal Stem Cells (MSCs) is a promising therapy for OA treatment, although due to an inefficient chondrogenic differentiation and to the low survival of the MSCs after the procedure, this approach only seems to be effective when a high number of cells are injected. However, increasing cell number is also associated to unwanted side effects such as the formation of scar tissue. In order to increase the effectiveness of these MSCs-based procedures we propose to enhance the chondrogenic capacity of MSCs through the silencing of anti-chondrogenic microRNAs (miRNAs) using Lock Nucleic Acid-Antisense Oligonucleotides (LNA-ASOs). This would allow us to reduce the number of MSCs necessary to perform the procedure and avoid unwanted side effects. Alternatively, if effective, these LNA-ASOs could be directly applied to the joint through intra-articular injection to promote chondrogenic differentiation in endogenous MSCs. Here we have assayed the pro-chondrogenic effect of the silencing of four different miRNAs, which expression is significantly augmented in the osteoarthritic cartilage, in order to select the miRNA(s) inhibitor or inhibitors combination that better stimulates MSCs chondrogenic potential in 3D MSCs in vitro cultures while avoiding the formation of the biomechanically inferior fibrous cartilage.