Catabolic Factors and Osteoarthritis-Conditioned Medium Inhibit Chondrogenesis of Human Mesenchymal Stem Cells

Abstract

Articular cartilage has a very limited intrinsic repair capacity leading to progressive joint damage. Therapies involving tissue engineering depend on chondrogenic differentiation of progenitor cells. This chondrogenic differentiation will have to survive in a diseased joint. We postulate that catabolic factors in this environment inhibit chondrogenesis of progenitor cells. We investigated the effect of a catabolic environment on chondrogenesis in pellet cultures of human mesenchymal stem cells (hMSCs). We exposed chondrogenically differentiated hMSC pellets, to interleukin (IL)-1α, tumor necrosis factor (TNF)-α or conditioned medium derived from osteoarthritic synovium (CM-OAS). IL-1α and TNF-α in CM-OAS were blocked with IL-1Ra or Enbrel, respectively. Chondrogenesis was determined by chondrogenic markers collagen type II, aggrecan, and the hypertrophy marker collagen type X on mRNA. Proteoglycan deposition was analyzed by safranin o staining on histology. IL-1α and TNF-α dose-dependently inhibited chondrogenesis when added at onset or during progression of differentiation, IL-1α being more potent than TNF-α. CM-OAS inhibited chondrogenesis on mRNA and protein level but varied in extent between patients. Inhibition of IL-1α partially overcame the inhibitory effect of the CM-OAS on chondrogenesis whereas the TNF-α contribution was negligible. We show that hMSC chondrogenesis is blocked by either IL-1α or TNF-α alone, but that there are additional factors present in CM-OAS that contribute to inhibition of chondrogenesis, demonstrating that catabolic factors present in OA joints inhibit chondrogenesis, thereby impairing successful tissue engineering.

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

“…4 In the present study, we investigated the rescue of chondrogenetic differentiation in OA-like conditions by the inhibition of protein kinases. Our studies indicate for the first time that both the JAK inhibitor tofacitinib and the TAK1 inhibitor oxozeaenol can improve chondrogenesis of both fetal and adult hMSCs in the presence of OAS-CM.…”

“…Krüger et al 3 showed that chondrogenic differentiation of human subchondral progenitor cells is affected by synovial fluid from donors with osteoarthritis (OA) or rheumatoid arthritis (RA). Previously, we have shown that factors secreted by the synovial membrane of OA joints inhibit chondrogenic differentiation of human mesenchymal stem cells (hMSCs), 4 thereby impairing successful tissue engineering. We could not discern a clear relationship between the levels of our primary suspects interleukin-1 (IL-1) and tumor necrosis factor-a (TNF-a) in the osteoarthritic synovium-conditioned medium (OAS-CM) and the strength of inhibition of chondrogenesis.…”

“…We could not discern a clear relationship between the levels of our primary suspects interleukin-1 (IL-1) and tumor necrosis factor-a (TNF-a) in the osteoarthritic synovium-conditioned medium (OAS-CM) and the strength of inhibition of chondrogenesis. 4 So, the exact catabolic factors and pathways responsible for the inhibition of chondrogenesis remain to be identified. Since specific knowledge on the nature of these factors is lacking, we aimed at modulating this effect by targeting common signaling pathways.…”

Anatomically shaped tissue-engineered cartilage with tunable and inducible anticytokine delivery for biological joint resurfacing

“…There is growing evidence indicating that proinflammatory cytokines, and particularly IL-1, play an important role in the pathogenesis of OA (17)(18)(19), as well as the inhibition of mesenchymal stem cell (MSC)-based repair of cartilage (20)(21)(22)(23)(24)(25). However, natural inflammatory modulators such as IL-1 receptor antagonist (IL-1Ra) can inhibit IL-1 signaling (26), and studies have shown that biomaterial-mediated delivery of IL-1Ra can mitigate the degradative effects of IL-1 (27).…”

Immune Modulation to Improve Tissue Engineering Outcomes for Cartilage Repair in the Osteoarthritic Joint

“…102 In addition to these findings, OA synoviumconditioned medium and synovial fluid have been shown to inhibit MSC chondrogenesis. 103,104 It is evident that modulation of the inflammatory environment in an OA joint is vital to maintain the integrity of engineered cartilage, or achieve efficient cell-based repair.…”