Interleukin‐1β and tumor necrosis factor α inhibit chondrogenesis by human mesenchymal stem cells through NF‐κB–dependent pathways

Abstract

Objective-The differentiation of mesenchymal stem cells (MSCs) into chondrocytes provides an attractive basis for the repair and regeneration of articular cartilage. Under clinical conditions, chondrogenesis will often need to occur in the presence of inflammatory mediators produced in response to injury or disease. Here we examine the effect of two important inflammatory cytokines, interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α), on the chondrogenic behavior of human MSCs.Methods-Aggregate cultures of MSCs recovered from the femoral intermedullary canal were used. Chondrogenesis was assessed by the expression of relevant transcripts by quantitative RT-PCR and examination of aggregates by histology and immunohistochemistry. The possible involvement of NF-κB in mediating the effects of IL-1β was examined by delivering a luciferase reporter construct and a dominant negative inhibitor of NF-κB (srIκB), with adenovirus vectors.Results-Both IL-1β and TNF-α inhibited chondrogenesis in a dose-dependent manner. This was associated with a marked activation of NF-κB. Delivery of srIκB abrogated the activation of NF-κB and rescued the chondrogenic response. Although expression of type X collagen followed this pattern, other markers of hypertrophic differentiation responded differently. Matrix metalloproteinase-13 was induced by IL-1β in a NF-κB dependent fashion. Alkaline phosphatase activity, in contrast, was inhibited by IL-1β regardless of srIκB delivery.Conclusions-Cell-based repair of lesions in articular cartilage will be compromised in inflamed joints. Strategies for enabling repair under these conditions include the use of specific antagonists of individual pyrogens, such as IL-1 and TNF, or the targeting of important intracellular mediators, such as NF-κB. There are two general strategies to harnessing MSCs for this purpose. In a tissue engineering approach, MSCs are recovered from the patient and used to generate a graft that is subsequently implanted into the site of cartilage damage (4). Although the graft can be developed in a bioreactor into mature cartilage, there is increasing interest in grafting immature tissue, allowing chondrogenesis to occur in situ. The second strategy, which is already in wide clinical use, supplies MSCs to the defect by penetrating the subchondral bone, thereby allowing marrow to enter the lesion. Various related surgical techniques, including microfracture and subchondral drilling, are used for this purpose. These procedures have the convenience of being performed arthroscopically in large joints (1).Repair strategies that rely on the in situ differentiation of MSCs are attractive, but in many instances require chondrogenesis to take place within an inflamed environment. Intraarticular inflammation may result from disease, such as arthritis, or trauma, including the iatrogenic trauma of the cartilage repair surgery itself. Because interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α) are major mediators of local inflammatory processes in joints, the present ...

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