In vitro model of injury/cytokine-induced cartilage catabolism modulated by dynamic compression, growth factors, and glucocorticoids

• Main Author: Li, Yang, Ph. D. Massachusetts Institute of Technology
• Other Authors: Alan J. Grodzinsky.
• Format: Others
• Language: English
• Published: Massachusetts Institute of Technology 2013
• Subjects: Biological Engineering.
• Online Access: http://hdl.handle.net/1721.1/81669

Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Biological Engineering, 2013. === Cataloged from PDF version of thesis. === Includes bibliographical references. === The degradation of articular cartilage is the hallmark in the pathogenesis of osteoarthritis (OA). It still remains largely unknown which precise mechanisms initiate cartilage degradation. However, risks factors include traumatic joint injury that results in immediate upregulation of inflammatory cytokines within the joint, as well as direct mechanical damage to the cartilage, factors known to contribute to the onset of OA and its progression. The first aim of this thesis focused on elucidating the importance of post-injury mechanical loading of cartilage. An in vitro model was used to simulate aspects of joint injury: mechanically damaged cartilage was co-cultured in the presence of inflammatory cytokines (TNF-Q and IL-6). Intermittent dynamic compression was then applied to simulate different strain levels known to exist in vivo after joint injury. Strain-dependent modulation of aggrecan biosynthesis and degradation, aggrecanase cleavage of aggrecan, chondrocyte gene expression profiles and changes in cell viability (apoptosis) were observed. Results imply that appropriate biomechanical stimuli can be beneficial during rehabilitation for post traumatic OA (PTOA) treatment. In the second aim, a combination therapy of insulin-like growth factor-1 (IGF-1) and the glucocorticoid dexamethasone (Dex) was tested as a potential therapeutic for PTOA. The effects of this combination were examined at the transcriptional and protein levels in the presence of IL-i a. Our results showed that the combination of IGF- 1 and Dex significantly improved aggrecan biosynthesis, blocked aggrecan and collagen proteolysis and loss, and rescued cell viability. These dramatic results could not be achieved by using either IGF-1 or Dex alone, thus providing strong support for the concept and use of a combination therapy for PTOA treatment. Dex is used to relieve inflammation and pain for short term OA treatment; however, it has not been studied as a potential disease-modifying drug for OA. In the last aim, the pro-survival role of Dex was investigated at the signaling, gene expression, and protein levels. Results suggest that Dex inhibits caspase-dependent apoptosis pathways, possibly through suppression of the phosphorylation of JNK and NF-kB/ixB signaling pathways. Taken together, these studies support the use of glucocorticoid treatment for inflammation-related cartilage cell death such as that found in PTOA. === by Yang Li. === Ph.D.