Moderate dynamic compression inhibits pro-catabolic response of cartilage to mechanical injury, TNF-α and IL-6, but accentuates degradation above a strain threshold

Objective—Traumatic joint injury can initiate early cartilage degeneration in the presence of elevated inflammatory cytokines (e.g., TNF-α and IL-6). The positive/negative effects of postinjury dynamic loading on cartilage degradation and repair in vivo is not well-understood. This study examined the effects of dynamic strain on immature bovine cartilage in vitro challenged with TNF-α + IL-6 and its soluble receptor (sIL-6R) with/without initial mechanical injury. Methods—Groups of mechanically injured or non-injured explants were cultured in TNF-α + IL-6/sIL-6R for 8 days. Intermittent dynamic compression was applied concurrently at 10%, 20%, or 30% strain amplitude. Outcome measures included sGAG loss (DMMB), aggrecan biosynthesis (35S-incorporation), aggrecanase activity (Western blot), chondrocyte viability (fluorescence staining) and apoptosis (nuclear blebbing via light microscopy), and gene expression (qPCR). Results—In bovine explants, cytokine-alone and injury-plus-cytokine treatments markedly increased sGAG loss and aggrecanase activity, and induced chondrocyte apoptosis. These effects were abolished by moderate 10% and 20% strains. However, 30% strain-amplitude greatly increased apoptosis and had no inhibitory effect on aggrecanase activity. TNF+IL-6/sIL-6R downregulated matrix gene expression and upregulated expression of inflammatory genes, effects that were rescued by moderate dynamic strains but not by 30% strain. Conclusions—Moderate dynamic compression inhibits the pro-catabolic response of cartilage to mechanical injury and cytokine challenge, but there is a threshold strain-amplitude above which © 2013 OsteoArthritis Society International. Published by Elsevier Ltd. All rights reserved. Address correspondence and reprint requests to: Alan J. Grodzinsky, ScD, MIT NE47-377, Cambridge, MA 02139, Phone: 617-253-4969; Fax: 617-258-5239, alg@mit.edu. CONFLICTS OF INTEREST All authors have no financial interests or personal relationships with other people or organizations that could potentially and inappropriately influence the conduct or reporting of this work. AUTHOR CONTRIBUTIONS YL contributed to the conception and design of the study, including collection, analysis, and interpretation of data, drafting and revising of the manuscript. EHF contributed to the design of the study and data interpretation. WY and HH contributed to the collection of experimental data. SC contributed to obtaining and interpretation of data on human tissue. AJG contributed to the conception and design of the study, including obtaining of funding, interpretation of data, and drafting and critical revision of the article for intellectual content. All authors approved the final version of the article. First and last authors take responsibility for the integrity of the work as a whole, from inception to finished article. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. NIH Public Access Author Manuscript Osteoarthritis Cartilage. Author manuscript; available in PMC 2014 December 01. Published in final edited form as: Osteoarthritis Cartilage. 2013 December ; 21(12): . doi:10.1016/j.joca.2013.08.021. N IH PA Athor M anscript N IH PA Athor M anscript N IH PA Athor M anscript loading becomes detrimental to cartilage. Our findings support the concept of appropriate loading for post-injury rehabilitation.