Introduction
Frozen shoulder (FS) is a common shoulder disorder, characterized by pain and gradual loss of active and passive glenohumeral joint motion. FS has been considered as a sequential pathologic process from synovial inflammation to capsular fibrosis. But pathogenesis of FS is not yet determined.
The function of matrix metalloproteinases (MMPs) is related to extracellular matrix remodeling but some MMPs are over-expressed during abnormal remodeling processes. In 1998, Hutchinson et al. reported that MMPs and MMP inhibitors (TIMPs) might be related to the development of FS. However, previous human studies had many limitations in unveiling the pathologic processes of FS.
We hypothesized that MMP-2 and MMP-9 which are best studied among many MMPs would be over-expressed patients with FS. And for additional information, animal model of primary FS is introduced.
The purposes of this study were to investigate the pattern of sequential expression of MMPs in a rat model of shoulder contracture and to compare the expression of MMPs in the joint capsule between patients with FS and control group.
Methods: Rats are immobilized using molding plaster (a shoulder contracture model) as an alternative of primary FS. (Figure 1)
We obtained joint capsules at baseline, 3 days, 1 week, and 3 weeks (4 rats per time point; 16 rats in total 16 rats). The expression of the inflammatory cytokine interleukin-6 (IL-6), MMP-2, and MMP-9 was examined by immunohistochemistry. We also obtained joint capsules from 21 patients with FS and 13 control subjects with instability to quantify the expression levels of MMP-2 and MMP-9 by immunohistochemistry.
Results: In the rat model, IL-6 and MMP-9 tended to be over-expressed in the joint capsule at 3 days and 1 week and MMP-2 at 3 days, 1 week, and 3 weeks. (Figure 2)
MMP-2 and MMP-9 were significantly over-expressed in the joint capsules of the patients with FS compared with those of control subjects. (Figure 3)
Conclusion: The results from both human and animal studies suggest the involvement of MMP-2 and MMP-9 in the development of FS. Animal study showed that the sequential expression of IL-6 and MMPs may be associated with fibrosis of the joint capsule.
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Rat contracture model. Immobilization is achieved by applying molding plaster around the whole left arm and thorax.
Serial hematoxylin and eosin (H&E) and immunohistochemical (IHC) staining for metalloproteinases (MMP) 2 and 9, and interleukin-6 (IL-6) of the axillary recess of the glenohumeral joint in a rat contracture model. In the control group, H&E staining shows no inflammation or fibrosis and IHC staining shows no expression of MMP-2, 9, or IL-6. At 3 days after contracture, inflammation and mild fibrosis develop and IHC staining reveals increased expression of MMP-2, 9, and IL-6 compared to the control group. At 1 week after contracture, capsular fibrosis is dominant and MMP-9 and IL-6 expression peaks. At 3 weeks after contracture, inflammatory cells disappear and MMP-9 and IL-6 expression is lower than that at 1 week, whereasMMP-2 expression tends to be remain to that at 3 days and 1 week.
Hematoxylin and eosin (H&E) and immunohistochemical (IHC) staining for MMP-2 and 9 in patients with frozen shoulder and control subjects. H&E staining reveals increased cellularity, and IHC staining shows greater expression of both MMPs in the frozen shoulder group than in the control group.
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