Development and Utilization of a Transgenic Mouse Injury Model to Investigate the Role of Interleukin-4 and Interleukin-6 in Tendon Healing

Tendon injuries heal by forming a disorganized and mechanically inferior scar, whose properties improve over time but do not return to normal levels. Studies have shown that the exogenous application of cytokines, which are signaling molecules that play an important role in the wound healing process, to injured tendons can improve these inferior properties. Although such experiments are straightforward to perform, these studies often report conflicting results due to the many factors associated with exogenous application, such as the correct dosage, timing, and method of delivery. Therefore, in this study, a transgenic mouse injury model was developed and utilized to investigate the role of interleukin-4 (IL-4) and interleukin-6 (IL-6) in tendon healing through their absence. Overall, it was hypothesized that the lack of IL-4 or IL-6 would result in opposing effects on mechanical and organizational properties, with the lack of IL-6 resulting in superior properties. Overall, the results of the analyses for the uninjured tendons were as hypothesized. However, the results of the analyses for the injured tendons were not magnified with the addition of an injury but were instead found to be opposite. This study shows that a certain level of inflammation is necessary for tendon healing to occur, and it also demonstrates that a distinct and reproducible tendon injury can be created and tested in mice and supports the future use of this animal model to investigate the role of cytokines in tendon healing.

Year	Entry
1978	Kastelic J, Galeski A, Baer E. The multicomposite structure of tendon. Connect Tissue Res. 1978;6(1):11-23.
1980	Kastelic J, Palley I, Baer E. A structural mechanical model for tendon crimping. J Biomech. 1980;13(10):887-893.
1996	Soslowsky LJ, Carpenter JE, DeBano CM, Banerji I, Moalli MR. Development and use of an animal model for investigations on rotator cuff disease. J Shoulder Elbow Surg. September–October 1996;5(5):383-392.
1998	Dickey JP, Hewlett BR, Dumas GA, Bednar DA. Measuring collagen fiber orientation: a two-dimensional quantitative macroscopic technique. J Biomech Eng. August 1998;120(4):537-540.
1987	Woo SL-Y, Inoue M, McGurk-Burleson E, Gomez MA. Treatment of the medial collateral ligament injury, II: structure and function of canine knees in response to differing treatment regimens. Am J Sports Med. January–February 1987;15(1):22-29.
2003	Thomopoulos S, Williams GR, Gimbel JA, Favata M, Soslowsky LJ. Variation of biomechanical, structural, and compositional properties along the tendon to bone insertion site. J Orthop Res. May 2003;21(3):413-419.
2000	Woo SL-Y, Debski RE, Zeminski J, Abramowitch SD, Chan Saw SS, Fenwick JA. Injury and repair of ligaments and tendons. Annu Rev Biomed Eng. 2000;2:83-118.
1991	Weiss JA, Woo SL-Y, Ohland KJ, Horibe S, Newton PO. Evaluation of a new injury model to study medial collateral ligament healing: primary repair versus nonoperative treatment. J Orthop Res. July 1991;9(4):516-528.
1996	Martin RB, Lau ST, Mathews PV, Gibson VA, Stover SM. Collagen fiber organization is related to mechanical properties and remodeling in equine bone: a comparsion of two methods. J Biomech. December 1996;29(12):1515-1521.
1997	Schechtman H, Bader D. In vitro fatigue of human tendons. J Biomech. August 1997;30(8):829-835.
2000	Soslowsky LJ, Thomopoulos S, Tun S, Flanagan CL, Keefer CC, Mastaw J, Carpenter JE. Overuse activity injures the supraspinatus tendon in an animal model: a histologic and biomechanical study. J Shoulder Elbow Surg. March–April 2000;9(2):79-84.
2000	Yamamoto E, Hayashi K, Yamamoto N. Effects of stress shielding on the transverse mechanical properties of rabbit patellar tendons. J Biomech Eng. December 2000;122(6):608-614.
1999	Derwin KA, Soslowsky LJ. A quantitative investigation of structure-function relationships in a tendon fascicle model. J Biomech Eng. December 1999;121(6):598-604.
1993	Woo SL-Y, Johnson GA, Smith BA. Mathematical modeling of ligaments and tendons. J Biomech Eng. November 1993;115(4B):468-473.
1994	Soslowsky LJ, An CH, Johnston SP, Carpenter JE. Geometric and mechanical properties of the coracoacromial ligament and their relationship to rotator cuff diseas. Clin Orthop Relat Res. July 1994;304:10-17.
1994	Derwin KA, Soslowsky LJ, Green WDK, Elder SH. A new optical system for the determination of deformations and strains: calibration characteristics and experimental results. J Biomech. October 1994;27(10):1277-1285.
1997	Frank C, McDonald D, Shrive N. Collagen fibril diameters in the rabbit medial collateral ligament scar: a longer term assessment. Connect Tissue Res. 1997;36(3):261-269.
2003	Elliott DM, Robinson PS, Gimbel JA, Sarver JJ, Abboud JA, Iozzo RV, Soslowsky LJ. Effect of altered matrix proteins on quasilinear viscoelastic properties in transgenic mouse tail tendons. Ann Biomed Eng. May 2003;31(5):599-605.

Year

Entry

1978

Kastelic J, Galeski A, Baer E. The multicomposite structure of tendon. Connect Tissue Res. 1978;6(1):11-23.

1980

Kastelic J, Palley I, Baer E. A structural mechanical model for tendon crimping. J Biomech. 1980;13(10):887-893.

1996

Soslowsky LJ, Carpenter JE, DeBano CM, Banerji I, Moalli MR. Development and use of an animal model for investigations on rotator cuff disease. J Shoulder Elbow Surg. September–October 1996;5(5):383-392.

1998

Dickey JP, Hewlett BR, Dumas GA, Bednar DA. Measuring collagen fiber orientation: a two-dimensional quantitative macroscopic technique. J Biomech Eng. August 1998;120(4):537-540.

1987

Woo SL-Y, Inoue M, McGurk-Burleson E, Gomez MA. Treatment of the medial collateral ligament injury, II: structure and function of canine knees in response to differing treatment regimens. Am J Sports Med. January–February 1987;15(1):22-29.