2015 ISAKOS Biennial Congress Paper #0

Analysis of Cellular Senescence in Human Arthroscopic Rotator Cuff Repairs

Benjamin C Hawthorne, BS, Newington, Connecticut UNITED STATES
Ian James Wellington, MD, Farmington, Connecticut UNITED STATES
Joshua Sabitsky, BS, LAT, ATC, West Hartford, CT UNITED STATES
Kyle V. Murphy, BS, Farmington, CT UNITED STATES
Owen P. Karsmarski, BS, Farmington, CT UNITED STATES
Rohin O. Thomas, BS, Farmington, CT UNITED STATES
Matthew R. Levasseur, MD, Farmington, CT UNITED STATES
Michael R. Mancini, BS, Rocky Hill, CT UNITED STATES
Maxwell T Trudeau, BS, Farmington, CT UNITED STATES
Mary Beth McCarthy, BA, Farmington, United States of Ame UNITED STATES
Mark P. Cote, PT, DPT, MSCTR, Farmington, CT UNITED STATES
Augustus D. Mazzocca, MS, MD, Waltham, MA UNITED STATES
University of Connecticut, Farmington, CT, UNITED STATES

FDA Status Not Applicable

Summary: Senescent cells accumulate in aging rotator tears and may contribute to and may impair the healing potential of the rotator cuff with advancing age.

Abstract:

Purpose

To quantify cellular senescence in supraspinatus tendon and subacromial bursa of humans with rotator cuff tears. To investigate the in vitro efficacy of Dasatinib+Quercetin (D+Q) to eliminate senescent cells and alter markers of tenogenic differentiation.

Methods

Tendon and bursa were harvested from patients undergoing arthroscopic rotator cuff tears. In part 1, cellular senescence was quantified utilizing immunohistochemistry and gene expression for senescent cell markers (p16 & p21) and the senescence-associated secretory phenotype (SASP) (IL-6, IL-8, MMP-3, MCP-1). Multiple markers were used due to a lack of specific markers for senescent cells. The amount of senescence was compared between patients <60 and =60 years old. In part 2, an in vitro culture model of rotator cuff tears was treated with D+Q or control. The ability of D+Q to kill senescent cells and alter markers of tenogenic differentiation was assessed by gene expression.

Results

Part 1 demonstrated an age-dependent significant increase in the relative expression of p21, IL-6, and IL-8 in tendon, and p21, p16, IL-6, IL-8, and MMP-3 in bursa (p<.05). A significant increase was seen in immunohistochemical staining of bursa p21 (p=0.028). Part 2 demonstrated that D+Q significantly decreased senescent markers in tendon (p21, IL-6, and IL-8) and bursa (p21 and IL-8) (p<.05). ELISA analysis demonstrated decreased release of the SASP (IL-6, MMP-3, MCP-1; p=.002, p=.024, p<.001, respectively). Both tendon (p=.022) and bursa (p=.027) treated with D+Q significantly increased the expression of type I collagen.

Conclusions

While there was an age-dependent increase in markers of cellular senescence, this relationship was not consistently seen across all markers and tissues. D+Q demonstrated moderate efficacy in decreasing senescence in these tissues and increasing type I collagen expression.
Clinical Relevance: Cellular senescence contributes to diseases of aging and may impair the healing potential of the rotator cuff with advancing age.