Presented by Ms Wehling in partial fulfillment of the requirements for an MD degree, Ludwig-Maximilians-University of Munich Medical School, Munich, Germany.
Interleukin-1β and tumor necrosis factor α inhibit chondrogenesis by human mesenchymal stem cells through NF-κB–dependent pathways†
Article first published online: 26 FEB 2009
Copyright © 2009 by the American College of Rheumatology
Arthritis & Rheumatism
Volume 60, Issue 3, pages 801–812, March 2009
How to Cite
Wehling, N., Palmer, G. D., Pilapil, C., Liu, F., Wells, J. W., Müller, P. E., Evans, C. H. and Porter, R. M. (2009), Interleukin-1β and tumor necrosis factor α inhibit chondrogenesis by human mesenchymal stem cells through NF-κB–dependent pathways. Arthritis & Rheumatism, 60: 801–812. doi: 10.1002/art.24352
- Issue published online: 26 FEB 2009
- Article first published online: 26 FEB 2009
- Manuscript Accepted: 25 NOV 2008
- Manuscript Received: 28 MAR 2008
- AO Foundation, Davos, Switzerland. Grant Number: Research Fund project 04-B86
- Postdoctoral Fellowship from the NIH/National Institute of Biomedical Imaging and Bioengineering. Grant Number: F32-EB-005566
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 mediators of inflammation produced in response to injury or disease. The purpose of this study was to examine the effects of 2 important inflammatory cytokines, interleukin-1β (IL-1β) and tumor necrosis factor α (TNFα), on the chondrogenic behavior of human MSCs.
Aggregate cultures of MSCs recovered from the femoral intermedullary canal were used. Chondrogenesis was assessed by the expression of relevant transcripts by quantitative reverse transcription–polymerase chain reaction analysis and examination of aggregates by histologic and immunohistochemical analyses. 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 (suppressor-repressor form of IκB [srIκB]) with adenovirus vectors.
Both IL-1β and TNFα 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 manner. Alkaline phosphatase activity, in contrast, was inhibited by IL-1β regardless of srIκB delivery.
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-1β and TNFα, or the targeting of important intracellular mediators, such as NF-κB.