The Effects of Dexamethasone on Human Patellar Tendon Stem Cells: Implications for Dexamethasone Treatment of Tendon Injury
Zhang J, Keenan C, Wang J H-C. J Orthopaed Res. 2012; [Epub ahead of print].
Tendinopathy is a clinical diagnosis characterized by focal tenderness, activity-related pain, weakness, and increased tendon size. Unlike the commonly used term “tendinitis” suggests, inflammation is not normally seen in the late stages of tendinopathy but may be present in early stages. Clinically, despite lack of evidence of inflammation in chronic tendinopathy, prescription of glucocorticoids, such as Dexamethasone, is often used as a quick-fix to reduce pain and “inflammation”; however, some studies suggest that administration of such drugs may worsen tendon degeneration. Tendon stem cell differentiation into non-tenocytes may contribute to the progression of tendon degeneration. The authors of this article were interested in the effects of Dexamethasone specifically on tendon stem cells to suggest a cause for Dexamethasone-induced tendon damage. Human tendon stem cells were isolated from patellar tendons (7 donors), cultured in growth medium, and confirmed to be stem cells. Cells were divided into 5 groups: control and 5, 10, 100, and 1000 nM Dexamethasone administration for 1 week. Tendon stem cell proliferation and differentiation were assessed. Target genes included collagen type I (tenocytes), PPARγ (adipocytes), Sox-9 (chondrocytes), and Runx-2 (osteocytes). In vivo experiments involved subcutaneous implantation of cells cultured for 1 week in 0, 10, 100, or 1000 nM Dexamethasone with Matrigel (mixture that mimics extracellular matrix of many tissues) into female nude rats. Three weeks following implantation, tissue was harvested for histological analysis and stained with Oil Red O (adipose-like), Safranin O (cartilage-like), and Alizarin Red S (bone-like). In vitro results showed that cell proliferation was dose-dependent: low concentrations of Dexamethasone increased cell proliferation, but high concentrations decreased proliferation. Collagen I expression was drastically diminished in all four groups of cells treated with Dexamethasone compared to control. PPARγ (adipogenesis) and Sox-9 (chondrogenesis) expression increased with increasing concentration of Dexamethasone; Runx-2 (osteogenesis) expression remained unchanged. In vivo analysis demonstrated increased fatty, cartilage-like, and bone-like tissue formed from cells treated with Dexamethasone compared to control.
The findings of this study suggest that Dexamethasone treatment may impair tendon healing. Specifically, Dexamethasone appears to increase tendon stem cell differentiation into non-tenocytes and reduce collagen I production, which could exasperate the injury. This study opens the door for future studies to investigate the mechanisms responsible for these observations. This study investigated only tendon stem cells, and the effects on tenocytes, the predominant tendon cell, still need to be identified. Furthermore, cells were taken from uninjured tendons, which may not properly mimic the cells inhabiting tendinopathic tissue or surgically repaired healing tissue. The authors chose to implant cells subcutaneously, which also may not accurately mimic the environment—mechanical and biological—of tendon. Finally, cells were cultured in Dexamethasone for 1 week prior to implantation, meaning that at implantation, the groups started from a different point, so end point comparisons may not be completely fair. Regardless of these limitations, the results of this study give clear indication that Dexamethasone as a treatment for tendon disorders may need to be reconsidered. Does this work impact your clinical recommendations? Do you prescribe Dexamethasone for tendon degeneration, and if so, will you continue? Do you think that Dexamethasone may have a different effect in tendons with early tendinopathy than chronic?
Written by: Sarah Ilkhani-Pour
Reviewed by: Stephen Thomas