Abstract

The causation of tendinopathy is multifactorial and there is increasing evidence that genetic factors play an important role in its aetiology. Some of the genes implicated encode: (i) structural components of connective tissue (collagens and glycoproteins); (ii) extracellular matrix (ECM) proteinases (MMPs); and (iii) cytokines and growth factors.1 ,2 Although several genes have been implicated to date, variants within the 3′-untranslated region (UTR) of COL5A1 were shown to associate with chronic Achilles tendinopathy3 ,4 and lower limb range of motion measurements,5 ,6 an additional intrinsic risk factor for chronic Achilles tendinopathy. COL5A1 encodes the α1 chain of type V collagen, a quantitatively minor fibrillar collagen that regulates type I fibrillogenesis.

We have recently described two major functional forms of the COL5A1 3′-UTR, namely the C- and T-forms, which contained a set of seven strongly linked sequence variants that showed significant differences in mRNA stability.7 Four of these COL5A1 variants are associated with Achilles tendinopathy and appear to alter the predicted mRNA secondary structure of the 3′-UTR. We propose that this change in secondary structure causes the altered COL5A1 mRNA stability and, by implication, type V collagen production.

In addition the COL5A1 3′-UTR contains several putative cis-acting elements including a functional microRNA binding site for Hsa-miR-608.7 Two forms of the mature Hsa-miR-608, which are produced by the polymorphic MIR608 gene, can potentially bind this miRNA binding site (http://www.ncbi.nlm.nih.gov). This variant within the MIR608 gene is also independently associated with chronic Achilles tendinopathy. These genetic association studies of the COL5A1 and MIR608 genes, together with the functional studies of the COL5A1 3′-UTR, suggest that type V collagen synthesis is involved in the molecular mechanisms of, at least, chronic Achilles tendinopathy.

We hypothesise that the T-functional form of the COL5A1 3′-UTR, which is associated with chronic Achilles tendinopathy, results in increased type V collagen production, decreased mean fibril diameter, and increased fibril density. These structural changes in the fibril result in changes to the mechanical properties of tendons. More specifically, we hypothesise that the changes in mechanical properties associated with the T-functional form result in (i) a reduced tensile strength and (ii) increased creep inhibition and/or stiffness. However, future work is required to test this hypothesis.8