Abstract/Details

In Vitro Model of lnjury/Cytokine-Induced Cartilage Catabolism Modulated by Dynamic Compression, Growth Factors, and Glucocorticoids

Li, Yang. 
 Massachusetts Institute of Technology ProQuest Dissertations Publishing,  2013. 0829417.

Abstract (summary)

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-α 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-1α. 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-κB/iκB signaling pathways. Taken together, these studies support the use of glucocorticoid treatment for inflammation-related cartilage cell death such as that found in PTOA. (Copies available exclusively from MIT Libraries, libraries.mit.edu/docs - [email protected])

Indexing (details)


Subject
Biomedical engineering;
Biomechanics
Classification
0541: Biomedical engineering
0648: Biomechanics
Identifier / keyword
Biological sciences; Applied sciences
Title
In Vitro Model of lnjury/Cytokine-Induced Cartilage Catabolism Modulated by Dynamic Compression, Growth Factors, and Glucocorticoids
Author
Li, Yang
Number of pages
0
Degree date
2013
School code
0753
Source
DAI-B 75/02(E), Dissertation Abstracts International
Place of publication
Ann Arbor
Country of publication
United States
Advisor
Grodzinsky, Alan J.
Committee member
White, Forest
University/institution
Massachusetts Institute of Technology
Department
Biological Engineering
University location
United States -- Massachusetts
Degree
Ph.D.
Source type
Dissertation or Thesis
Language
English
Document type
Dissertation/Thesis
Dissertation/thesis number
0829417
ProQuest document ID
1450036284
Copyright
Database copyright ProQuest LLC; ProQuest does not claim copyright in the individual underlying works.
Document URL
https://www.proquest.com/docview/1450036284