From the Department of Trauma and Orthopaedic Surgery, Keele University School of Medicine, Staffs, England.
Reprints: Prof. Nicola Maffulli, MD, PhD, MS, FRCS(Orth), Keele University School of Medicine, Thornburrow Drive, Hartshill, Stoke on Trent ST4 7QB Staffs, England (email: email@example.com).
Chronic tendinopathy is frequent in both elite and recreational athletes. Sedentary subjects may also develop tendinopathy in the absence of any history of increased physical activity.
Most research on tendon injuries has focused on a description of the condition and its management, rather than on the underlying cellular and molecular mechanisms of causation.1 Although several such mechanisms have been implicated, the causes of tendon problems in athletes are poorly understood.1 “Differential strain,” “stress shielding,” joint position, and even underuse have all been advanced as alternative biomechanical explanations to the classical overuse model for the pathogenesis of tendinopathy.2
In addition to intrinsic and extrinsic factors,1 genetics may play a role in the pathogenesis of tendinopathy. An underlying genetic factor as a contributing cause to tendon injury was originally proposed because of an association between the ABO blood group and the incidence of Achilles tendon ruptures or chronic Achilles tendinopathy evident in Hungarian and Finnish populations with blood group O.3,4 These studies implied that ABO or closely linked genes on the tip of the long arm of chromosome 9 could be associated with tendinopathy or tendon injuries. Studies in other populations, however, did not confirm this association.5,6
A genetic component has been implicated in tendinopathies involving the Achilles tendon7,8 and the rotator cuff tendons.9 Polymorphisms within the COL5A1 and tenascin-C (TNC) genes have been associated with Achilles tendon injuries in a physically active population.7,8
The ABO gene on chromosome 9q34 encodes for tranferases, which, apart from determining the structure of glycoprotein antigens on red blood cells, may also determine the structure of some proteins of the extracellular matrix of tendons.3,10 The COL5A1 gene, which is in close proximity to the ABO gene on chromosome 9q34,10 encodes for a structural component of type V collagen, which forms heterotypic fibers with type I collagen in tendons and possibly plays an important role in regulating fibrillogenesis and, therefore, tendon strength.11-13 Other gene(s) closely linked to the COL5A1 and ABO genes on the tip of the long arm of chromosome 9 may encode for protein(s) directly involved in the pathogenesis of Achilles tendinopathy. Individuals with the A2 allele of the COL5A1 gene are less likely to develop Achilles tendinopathy.8 COL1A1 and COL3A1 genes also show variable levels of expression in normal tendons and significantly increased levels of expression in painful tendinopathy.14
TNC, an extracellular matrix glycoprotein found in tendons,15 is closely linked to the ABO gene on chromosome 9q32-q34.16 The TNC gene is expressed in the myotendinous and osteotendinous junctions17 and is regulated by mechanical loading in a dose-dependent manner.17 Allele distribution of the guanine-thymine (GT) dinucleotide repeat polymorphism in the TNC gene is significantly different between patients with Achilles tendon injuries and asymptomatic controls.7 Alleles containing 12 and 14 GT repeats were significantly higher in patients with Achilles tendon injuries, whereas alleles containing 13 and 17 GT repeats were higher in the asymptomatic controls.7 Abnormal mechanical loading could also lead to altered synthesis of TNC,18 which, in turn, could disrupt the regulation of cell-matrix interactions in the tendon, lead to apoptotic changes in the tenocytes,19 and eventually result in tendinopathy.
We do not know why some people are more susceptible to developing tendinopathy when compared with others who have similar levels of physical activity. It is possible that an interaction between genetic makeup of a given individual and the various intrinsic and extrinsic factors affecting tendon health increases the likelihood of that individual developing tendinopathy. This genetic link could also explain why there is an increased risk of contralateral rupture of the Achilles tendon in subjects with a previous rupture.20
COL5A1 and TNC genes may be good markers of tendinopathy,8 but their exact roles in the pathogenesis of the condition require further investigation. Other, as yet unidentified, genes may contribute to the pathogenesis of tendinopathy. It would seem appropriate to begin the search for such genes by studying those encoding for the constituents of tendon such as collagens type I, III, V, XI, XII, and XIV; elastin; fibronectin; decorin; lumican; and fibromodulin.
In the equine model, cartilage oligomeric matrix protein (COMP) is expressed as a response to mechanical load, and its main function appears to be in the formation of a structurally competent tendon matrix.21 the future, it may be possible to upregulate COMP, providing an alternative management strategy in humans with tendinopathy.
Matrix metalloproteases (MMPs) and their regulatory genes may also play a role in the pathogenesis of tendinopathy, but their exact role is still unclear.22 Gene expression studies using complementary DNA arrays and real-time polymerase chain reaction analysis have shown downregulation of MMP-3 and upregulation of MMP-2 in tendinopathic Achilles tendons.23,24 More study is required to better understand gene expression of other MMPs and the complexities of the interplay between MMPs and their inhibitors in the pathogenesis of tendinopathy. Such enhanced understanding might permit the development of specific management strategies for patients with tendinopathy.
Family studies could prove to be a useful addition to gene expression and polymorphism studies. Athletic behavior and sport participation “runs in families,”25,26 and it is conceivable that at least some families may have more than 1 member affected by the development of tendinopathy. In these instances, collection of DNA samples from patients and their relatives may expedite the process of identification of the genes involved in the tendinopathy process. It may also be possible to identify genes actually protecting the carrier from this condition.
POTENTIAL FOR GENE THERAPY
Once causative or protective genes have been isolated, they could, in the future, form the basis of gene therapy of this condition: sustained gene expression lasts for about 6 weeks, possibly long enough for clinical applications.27 Further understanding of the genetics of tendinopathy may facilitate the transfer of specific genes for therapeutic purposes.
Healing tendon has proportionately higher levels of type V collagen, and persistently elevated levels are present up to 52 weeks after injury in the rabbit medial collateral ligament.28 Elevated levels of collagen type V may favor the formation of smaller type I collagen fibrils, which in turn results in reduced mechanical strength.28
Transfection of human patellar tenocytes with specific antisense oligonucleotides demonstrated a reduced amount of collagen type V.29 These initial findings may form the basis of future targeted gene therapy for the management of patellar tendinopathy.
Investigations into the genetic factors involved in the etiology of tendinopathy are still in their infancy. An enhanced understanding of these factors holds the promise of new approaches to the prevention and management of these common conditions.
We wish to thank Prof. Martin Schwellnus, Professor of Excercise Science and Sport Medicine, University of Cape Town, South Africa, for having fostered our understanding in this field.
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