Neurogenic, mast cell, and gender variables in tendon biology: Potential role in chronic tendinopathy

Abstract

Tendinopathies are frequent complications of athletic activities and of certain occupations, and occur as secondary sequelae of some diseases. The incidence, and awareness, of repetitive motion syndromes and overuse syndromes affecting tendons has increased in recent years. These increases may be in part be related to increased participation in recreational sports, increased numbers of individuals involved in some occupations, and/or increased reporting of such complaints. While some problems, particularly occupation-related cases, can likely be traced to ergonomic considerations, a number of other factors such as genetics, gender, and fitness levels could also play a role in either the initiation of such tendinopathies or their progression to loss of function. In athletes, a number of other factors may also contribute to tendinopathy development [1]. However, most of these cases respond to conservative treatment [2,3]. A review of this field was published in 1995 [4], and the reader is referred to that information source, or other chapters in this monograph, for many aspects of the problem which will not be rediscussed in this chapter. Since 1995, the problem of the prevention, diagnosis and effective treatment of tendinopathies have evolved somewhat, but much is still unknown regarding the inciting events and the mechanisms responsible for the progression of the problems. Because not all individuals involved in a particular athletic activity or occupation develop tendinopathies, it is difficult to identify factors that could contribute to either initiation or progression of these tendon problems. Similarly, not all patients respond to existing treatments equally. Some respond to rest and anti-inflammatory interventions, while others are either nonresponsive or relapse as soon as activity levels are reinstituted. Thus, there is a need for more basic information on the regulation of tendons at the level of cell and molecular biology, as well as physiology. Tendons are not all the same, a fact that complicates understanding of disease development and progression. While they all have intrinsic cells (tenocytes), have a vascular supply, and are innervated, they appear to be differentiated to perform functions unique to specific environments. Some tendons have a surface layer of cells that may be unique (epitenon), while others are surrounded by a paratenon, and still others function in a sheath lubricated by synovial fluid. In addition, some tendons are differentiated along their length and may contain fibrocartilage-like areas where they traverse bony prominences [6]. Thus, tendons are complex structures that connect muscles to bones, and an understanding of the workings of one tendon likely cannot be extrapolated to tendons in other environments. The study of tendinopathies, particularly those of the upper extremities, has been hampered by a number of limitations. One of the major limitations is at the level of understanding the etiology of tendinopathy. Most patients present with established disease, which is treated conservatively. If the condition persists, more invasive options can be entertained, but this means that clinical samples are potentially available for assessment only from individuals with advanced tendinopathy. Thus, the critical window of early disease is usually not available for study. The second major limitation to our understanding of the regulation of tendons at the cell and molecular biology, biochemical, and physiological levels is the paucity of animal models which "mimic" human tendinopathies, particularly those involving the upper extremities. While it could be argued that the study of tendons in quadrupeds cannot mimic conditions in bipeds, the availability of animal models could assist in our understanding of potential regulatory mechanisms in these tissues. While there is not a "wealth " of animal models available, a number of recent reports indicate that new models are being developed and characterized and may share some characteristics with human disease [7-10]. One model that has received some investigative attention is that of Backman et al. [11,12], who studied overuse injury development in the Achilles tendon complex of the rabbit. Subjecting rabbits to several weekly bouts of loading led to development of histological changes in the paratenon and tendon, which were consistent with what may occur in humans. The changes were dependent on the length of time the animals were chronically loaded, and the number of cycles of loading per minute the legs were subjected to during each loading experience. However, based on the weights of the rabbits used in these experiments, it is likely that the animals were skeletally immature. If this is true, then repetitive motion induced changes in a growing tendon could be different from those induced in tendons when the animals are skeletally mature. Similarly, based on the loading cycles per minute (150 cycles/min) required to observe changes in the tendons, it is likely that the loading regimen used in these studies was supraphysiologic. Studies undertaken using a modified Backman protocol in skeletally mature (1-year-old animals) for up to 11 weeks of chronic loading (75 cycles/min, 3x per week, 2hr per exposure) has not led to extensive changes in the paratenon or the tendon at the molecular or histologic levels, although there were some trends observed [13,14]. Therefore, there are some limitations to this model that may indicate that it has limited approximation to what is occurring in mature humans, although it cannot be ruled out that the ease in inducing disease in skeletally immature animals could be relevant to conditions arising in young elite athletes. Recent studies from this laboratory have taken a somewhat different tack and focused on better understanding of potential regulatory systems that may influence the function of normal tendons in order to gain insights into potential points of failure, and which, in turn, could lead to tendinopathy development or areas which could contribute to disease progression. We have focused our efforts on neurogenic regulation of tendon cell function and how gender-related variables may affect this regulation. The studies are related to the hypothesis raised in a previous review, which proposed that neuroregulation of inflammation in tendons could be a contributing factor in the development and progression of at least a subset of tendinopathies [5]. This hypothesis proposed that neuropeptides, either directly or indirectly through tissue mast cells, are involved in normal tendon regulatory control, and during development of tendon dysfunction this regulatory "loop " becomes dysfunctional and contributes to either inflammation in the tissues or a failure to mount a productive repair response.This hypothesis is outlined in Figure 6-1, and laboratory investigations and literature evidence in support of the proposed regulatory schemes will be discussed throughout this chapter.(figure Presented).