The hypothesis in this study was that there would be a difference in the pattern of plasma concentrations of MMP and TIMP between patients and controls. Although TIMP-1 was clearly different, this is only 1 of 9 proteins, and the difference could be a random effect. Thus, our hypothesis could not be reliably confirmed and the results should be regarded as descriptive and hypothesis generating. Even so, the TIMP-1 findings were striking, and the difference between partial-thickness and full-thickness tears for 3 of the proteins might reflect biological differences between these conditions.
This is the first study to investigate the systemic levels of MMPs and TIMPs in rotator cuff tear patients. Our results can therefore only be discussed in relation to studies concerning these enzymes and other tendon affections that have been investigated more extensively. A higher level of TIMP-1 gene expression in human ruptured Achilles tendons than in normal tendons has been shown, suggesting the involvement of TIMP-1 in tendon rupture (Jones et al. 2006
, Garofalo et al. 2011
). Patients with an active Dupuytren’s contracture have higher TIMP-1 concentrations in their serum than have controls, and compared to Dupuytren patients in the residual phase (Ulrich et al. 2003
). This suggests that even lesions of a limited size, like Dupuytren’s contracture, could have an influence on TIMP-1 concentrations in the blood. Ulrich et al. also showed that patients in the residual phase and controls had similar serum concentrations of TIMP-1. In addition, the same study showed that there were no significant differences in the serum levels of TIMP-2, MMP-1, MMP-2, and MMP-9 in patients with Dupuytren’s contracture and in controls (Ulrich et al. 2003
). These observations are in agreement with our findings—that TIMP-1 concentration (in particular) in the blood can reflect a local pathological condition and disease progression.
In fracture healing, serum levels of MMPs and TIMPs reflect posttraumatic processes, and they may aid in predicting outcome. Non-union of fractures has been suggested to be associated with—or even caused by—an altered balance of the MMP/TIMP system in favor of proteolytic activity (Henle et al. 2005
). Other pathological processes such as atherosclerosis, rheumatoid arthritis, and several forms of cancer also show specific time courses regarding concentrations of MMP and TIMP in serum (Chirco et al. 2006
, Pasternak and Aspenberg 2009
). Such pathological processes and also a rotator cuff tear are probably associated with a complex local biochemical environment. Factors such as age, gender, hormones, metabolic status, vascularization, and inflammatory response can influence expression of MMPs and TIMPs (Henle et al. 2005
, Shindle et al. 2011
). Our strict inclusion criteria were chosen in an attempt to minimize this cause of variation as much as possible.
There may be several reasons for alterations in MMP and TIMP levels in rotator cuff tear patients, such as local inflammation, tendon degeneration, altered mechanical loading, or genetic predisposition. Del Buono et al. (2012)
proposed that tendinopathy and tendon rupture may be separate entities with differences in symptoms, in expression of structural proteins and proteolytic enzymes, and in genetics. Our findings of significant differences in the plasma levels of TIMP-1, TIMP-3, and MMP-9 between partial-thickness and full-thickness rotator cuff tears might support this and reflect that partial-thickness tears and full-thickness tears might have different etiologies. In the present study, the partial tears were not subdivided between bursal and articular side tears but the literature suggests that articular-sided tears are associated with intrinsic degeneration and bursal-sided tears are often found in patients with impingment of the subacromial structures (Lakemeier et al. 2010
). Lakemeier et al. (2010)
found higher MMP-1 and MMP-9 levels in tissue samples from articular-sided tears than bursal-sided tears, supporting the association between size and location of a tear and the expression of MMPs. It is believed that a partial tear may progress to a full-thickness tear, and it has been shown that cuff tears are more common with increasing age (Lakemeier et al. 2010
). The differences in TIMP-1, TIMP-3, and MMP-9 levels between partial-thickness and full-thickness tears in our study might reflect increased tissue damage and tear size, but since patients with full-thickness tears were older, this may also have been due to increasing degenerative changes with age.
All of our patients complained of pain, and it is possible that such pain is a result of local inflammation, which in itself may affect the expression of MMPs. Substance P, a pain-mediating neurotransmitter capable of regulating the expression of MMPs and TIMPs, has been suggested to be responsible for disturbance in the homeostasis of the MMP and TIMP system in tendinopathy (Del Buono et al. 2012
). A recent study has found that the expression of synovial inflammation, tissue degeneration, and expression of MMPs and TIMPs in the glenohumeral synovium correlate with tear size (Shindle et al. 2011
). Our findings with higher levels of TIMP-1, TIMP-3, and MMP-9 in full-thickness tear patients (compared to partial-thickness tear patients) would appear to support this correlation. On the other hand, it appears that a full-thickness tear is not necessarily more painful than a partial-thickness tear, and pain is not necessarily part of the progression from a partial-thickness to a full-thickness tear (Jones et al. 2006
, Garofalo et al. 2011
). We found no difference in the Constant-Murley score between the partial-thickness and full-thickness tear groups that would have supported an association between pain-generating mechanisms and the levels of MMPs and TIMPs. Altered tension of the tendon in full-thickness tear rather than in partial-thickness tear may also play a role in the enzyme differences identified, since MMP expression in tendon cells is known to be modulated by mechanical loading. Both increased load and loss of tension may precede activation of destructive mechanisms leading to apoptosis and tendon degeneration (Jones et al. 2006
, Millar et al. 2009
, Garofalo et al. 2011
, Shindle et al. 2011
Genetic predisposition is another possible explanation of the altered MMP and TIMP levels (Kalichman and Hunter 2008
, Shindle et al. 2011
). For example, accelerated degeneration of intervertebral discs may be partly genetically predetermined, through MMPs (Kalichman and Hunter 2008
). Painful Achilles tendinopathy has been associated with gene variants of MMP-3 (Raleigh et al. 2009
). Siblings of patients with known rotator cuff tears have an increased incidence of rotator cuff tears and tear-size progression compared to controls (Harvie et al. 2004
). These findings indicate that genetic factors are involved in the development and progression of rotator cuff tears (Gwilym et al. 2009
), and genetic factors might influence the different plasma levels of MMPs and TIMPs in different degrees of tendon degeneration.
Corticosteroids have been found to have detrimental effects on the extracellular matrix in both in vitro and in vivo studies, but the extent of this effect is unknown (Tillander et al. 1999
, Tempfer et al. 2009
). The choice of excluding patients who had had a corticosteroid injection during the previous 6 months was a pragmatic choice based on the current literature, to minimize any potential effects of the steroids (Lo et al. 2004
). It is unlikely that the plasma alterations in our study and the differences between partial-thickness and full-thickness tears can be explained by the steroid injections, since both groups received injections.
We measured the levels of MMP and TIMP in plasma because the levels in serum do not reliably reflect the circulating levels of these biomarkers (Gerlach et al. 2007
). With the centrifugal speed we used, the plasma produced cannot be defined as platelet-poor plasma as some platelets may have been left in the samples when analyzed for MMPs and TIMPs. These platelets may have released some of the MMP-9 detected. All the samples were treated in the same way; thus, it is unlikely that the centrifugation would have had an effect on the difference in MMP-9 levels detected between groups.
The strengths of the present study are the inclusion and exclusion criteria, the matched controls, and the fact that we divided the tears into partial-thickness and full-thickness tears, which adds more information compared to other studies. Despite the fact that asymptomatic conditions may have affected tendons and connective tissues, the risk of this was equal for both groups. With strict exclusion criteria, we reduced this risk as far as possible and the only difference identified between the groups was the rotator cuff tears in the patient group.
One limitation of the study is that no samples from the subacromial tissue were taken to correlate the local levels of MMP and TIMP with circulating levels. However, only 6 of the patients with cuff tears underwent surgery, and surgical exploration would not have been justifiable for ethical reasons in the patients who were treated nonoperatively.
This study shows that alterations in the MMP and TIMP system may be measured systemically in patients with rotator cuff tears, and this knowledge may help in future development of diagnostic and prognostic disease markers. Further knowledge about the relationship between these potent enzymes and rotator cuff degeneration may also be valuable for potential biological modulation of the system.