Tendinosis develops from age- and oxygen tension-dependent modulation of Rac1 activity.

Authors

Rowena McBeath, Thomas Jefferson University; Philadelphia Hand to Shoulder CenterFollow
Richard W. Edwards, Thomas Jefferson UniversityFollow
Brian J. O'Hara, Thomas Jefferson UniversityFollow
Mitchell G. Maltenfort, The Children's Hospital of Philadelphia
Susan M. Parks, Thomas Jefferson UniversityFollow
Andrzej Steplewski, Thomas Jefferson UniversityFollow
A. Lee Osterman, Thomas Jefferson University; Philadelphia Hand to Shoulder CenterFollow
Irving M. Shapiro, Thomas Jefferson UniversityFollow

Document Type

Article

Publication Date

6-1-2019

Comments

This article has been peer reviewed. It is the author’s final published version in Aging Cell, Volume 18, Issue 3, June 2019, Article number e12934.

The published version is available at https://doi.org/10.1111/acel.12934. Copyright © McBeath et al.

Publication made possible in part by support from the Thomas Jefferson University + Philadelphia University Open Access Fund

Abstract

Age-related tendon degeneration (tendinosis) is characterized by a phenotypic change in which tenocytes display characteristics of fibrochondrocytes and mineralized fibrochondrocytes. As tendon degeneration has been noted in vivo in areas of decreased tendon vascularity, we hypothesized that hypoxia is responsible for the development of the tendinosis phenotype, and that these effects are more pronounced in aged tenocytes. Hypoxic (1% O₂ ) culture of aged, tendinotic, and young human tenocytes resulted in a mineralized fibrochondrocyte phenotype in aged tenocytes, and a fibrochondrocyte phenotype in young and tendinotic tenocytes. Investigation of the molecular mechanism responsible for this phenotype change revealed that the fibrochondrocyte phenotype in aged tenocytes occurs with decreased Rac1 activity in response to hypoxia. In young hypoxic tenocytes, however, the fibrochondrocyte phenotype occurs with concomitant decreased Rac1 activity coupled with increased RhoA activity. Using pharmacologic and adenoviral manipulation, we confirmed that these hypoxic effects on the tenocyte phenotype are linked directly to the activity of RhoA/Rac1 GTPase in in vitro human cell culture and tendon explants. These results demonstrate that hypoxia drives tenocyte phenotypic changes, and provide a molecular insight into the development of human tendinosis that occurs with aging.

Recommended Citation

McBeath, Rowena; Edwards, Richard W.; O'Hara, Brian J.; Maltenfort, Mitchell G.; Parks, Susan M.; Steplewski, Andrzej; Osterman, A. Lee; and Shapiro, Irving M., "Tendinosis develops from age- and oxygen tension-dependent modulation of Rac1 activity." (2019). Department of Orthopaedic Surgery Faculty Papers. Paper 124.
https://jdc.jefferson.edu/orthofp/124

Creative Commons License

This work is licensed under a Creative Commons Attribution 4.0 License.

PubMed ID

30938056

Language

English