Replicative Senescence and Aging of Human Chondrocytes
            Sponsor:  The National Institute on Aging             


James A Martin, Ph.D.
Associate Research Scientist

Department of Orthopaedic Surgery

The University of Iowa
Iowa City, IA  52242

                        e-mail:  James-Martin@uiowa.edu

 

Name

Organization

Role on Project

Joseph A. Buckwalter, M.D.

University of Iowa

Co-Investigator

 

This proposal addresses Research Objective #17.  Basic Underlying Mechanisms of Musculoskeletal Aging (cartilage).  Senescence refers to the irreversible decline and cell cycle arrest displayed by cells that have exhausted their replicative potential.  Recent evidence shows that senescent cells accumulate with age in human tissues where cell turnover is common.  These studies also show that the slow growth and metabolism of senescent cells can lead to tissue failure and degenerative disease.  The striking age–dependent incidence of articular cartilage degeneration in osteoarthritis suggests that articular chondrocytes become less vigorous with advancing age, a decline that leaves cartilage increasingly susceptible to degeneration.  Recent studies in our laboratory showed for the first time that telomere length, which determines the replicative lifespan of somatic cells, declines in chondrocytes with increasing donor age.  In addition we found that expression of a senescence marker increased with donor age, confirming that telomere erosion and senescence are linked.  The significance of this finding derives from the fact that telomeres erode with each round of cell division and excessive erosion induces the onset of senescence, thus, the data support the idea that chondrocyte turnover over several decades of life leads to significant progress toward senescence.  Despite the probable relevance of these findings to osteoarthritis, little is know about the effects of progressive telomere erosion on chondrocyte performance.  The purpose of the present proposal is to better understand these effects and to begin to identify molecules involved in the regulation of chondrocyte senescence by telomere erosion.  The specific aims are: 

  1. Determine the rate of telomere loss in proliferating chondrocyte cell lines. 
  2. Correlate telomere length with changes in the chondrocyte phenotype. 
  3. Identify genes regulated by telomere erosion. 

We expect these studies will elucidate the effects of replication and telomere erosion on the chondrocyte phenotype and will yield important new tools for evaluating chondrocyte senescence in vivo and its role in osteoarthritis.

 

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