Molecular Response of the Patellar Tendon to Fatigue Loading Explained in the Context of the Initial Induced Damage and Number of Fatigue Loading Cycles

Andarawis-Puri N, Sereysky JB, Sun HB, Jepsen KJ, Flatow EL. J Orthop Res. 2012 Jan 6. doi: 10.1002/jor.22059. [Epub ahead of print]

Tendinopathy is a common painful and debilitating clinical condition. Unfortunately, the mechanism by which tendinopathy occurs is poorly understood. Clinical data has observed degenerative changes in ruptured tendons and extracellular matrix (ECM) disorganization in “normal” tendons, implicating sub-rupture damage accumulation as a causative factor for the progression of tendinopathy. However, data from these studies are primarily from biopsied tendons (representative of late-stage diseases); therefore, in vivo models of overuse/cyclic loading profiles are important to understand the mechanism by which mechanical loading leads to ECM degeneration and degradation. Andarawis-Puri et al. used a previously developed in vivo model of fatigue damage accumulation in the rat patellar tendon to determine if the number of applied loading cycles and initial mechanical parameters (indicative of induced damage) were predictive of the molecular response 7 days after fatigue loading. Previous studies have shown that loading can be beneficial (i.e. healthy exercise) but that higher level fatigue loading (greater number of cycles) can be detrimental (i.e. overuse injury), leading to structural damage. Rats were assigned to fatigue loading protocols to induce a range of damage severities (low, moderate, and high level fatigue damage) and were sacrificed 7 days after loading. The tendons were isolated to examine 15 genes thought to contribute to tendon degeneration, including remodeling factors such as matrix metalloproteinases (MMPs), tissue inhibitors of metalloproteinases (TIMPs), and collagens. The molecular response was evaluated to determine if the tendon is attempting to adapt, repair, or degenerate itself. Results showed correlations between molecular response and mechanical damage parameters. Additionally, loading resulted in upregulation of several ECM genes that suggest an adaptive response and an attempt to maintain homeostasis in response to fatigue loading; however, several of these genes (Col-I, Col-XII, MMP-2, and TIMP-3) shut down after a higher level of damage was induced. The authors conclude that the tendon’s ability to effectively respond to mechanical loading diminishes with greater fatigue damage.

This study provides further evidence that physiologic tendon loading generally results in an adaptive response; however, as sub-rupture damage accumulates, the tendon’s ability to repair itself (through remodeling and repair) deteriorates. It implicates a mechanical factor, fatigue loading, as a key component of the mechanism involved in the tendon’s molecular response following sub-rupture damage accumulation. The correlations observed between mechanical damage and gene expression suggest a relationship between the tissue level strain, the local mechanical environment around the cell, and the subsequent cellular response. Implications of this study are of particular concern in populations who perform repetitive overuse activities (e.g. laborers, athletes) and an important next step may be to identify a threshold by which fatigue loading leads to irreversible structural damage. This in vivo model can be used as an example of “too much too soon” seen in the “weekend warrior”, where the tendon is unable to recover due to the abrupt, extreme loading conditions placed on it. Would a gradual introduction to loading cycles over a period of time give the tendon an opportunity to adapt and heal? In addition, will periods of rest inserted in between loading cycles allow for a “healthy” tendon molecular response? Clinically, do you think there is a feasible way to monitor an athlete’s “loading profile” in an attempt to avoid potentially debilitating tendon damage? Several preventative and therapeutic interventions (i.e. stretching, modalities) may help mitigate the effects of fatigue loading. What do you think is the most effective way to currently treat tendinopathy? 

Written by: Katherine Reuther
Reviewed by:  Stephen Thomas

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Andarawis-Puri N, Sereysky JB, Sun HB, Jepsen KJ, & Flatow EL (2012). Molecular response of the patellar tendon to fatigue loading explained in the context of the initial induced damage and number of fatigue loading cycles. Journal of Orthopaedic Research PMID: 22227881