Calcification increased in meniscus root tear specimens

CHAPTER II: Degeneration of meniscus roots are accompanied by fibrocartilage

3.2. Methods

3.3.7. Calcification increased in meniscus root tear specimens

AR staining results revealed higher number as well as increased size of stained calcification nodes in the order of NT, PT, and CT (NT vs. CT, p<0.0001). Calcification related gene, ENPP1, also showed increased expression in the same order (NT vs. CT, p=0.024) (Figure 3.9). Heterotrophic ossification within the root, visible in plain radiography and CT scans, was found in 4 samples (4 patients). These samples all showed complete tears, with intense SAFO staining around the ossified area (Figure 3.10).

Figure 3. 9 Calcification analysis of meniscal root tear specimens. (A) Representative calcification stainings of NT, PT, and CT groups. Increased calcification node number and size were observed in the order of NT, PT, and CT groups. Magnification X 100, Alizarin Red S staining. (B) Quantification of histological data showing significant increase in calcification area of CT group compared to NT group. (C) Mineralization marker, ENPP1 real time PCR results showing increased expression in CT group compared to NT group.

Figure 3. 10 Imaging and histological slides of a case of heterotrophic ossification in the medial meniscus root. Plain radiograph (A) and coronal (B), sagittal (C), axial CT images showing the ossified portion of root (arrow). Safranin-O (E, F) and Von-Kossa (G) staining showing the heterotrophic ossification. Matrix adjacent to heterotrophic ossification shows fibrocartilage formation (E, F). Magnification x 10 for (E, G), x 200 for (F)

3.4. Discussion

The purpose of this study was to characterize degeneration of MMPRs in osteoarthritic knees in association with the degree of tear. To the best of our knowledge, this is the first study to demonstrate that fibrocartilage metaplasia and calcification are associated with degree of tear in DMMPRTs. Histological degenerative features were more noticeable in the tear groups and correlated with the degree of tear, as shown by the Bonar tendinopathy scores. The extracellular matrix of MMPRs showed increase in fibrocartilage metaplasia and calcification correlating to the tear extent. Both changes are known to decrease the ability of the root to withstand tensile forces, possibly rendering the roots susceptible to further tear [55, 56, 58]. Furthermore, root tears were found predominantly in areas of fibrocartilage metaplasia. Tensile loads applied to fibrocartilaginous specimens induced tears within fibrocartilaginous areas. These results suggest that fibrocartilage formation and calcification may play a key role in DMMPRT progression.

The resulting fibrocartilage in DMMPRTs has several important implications. First of all, it reflects the unique biomechanical environment in which the MMPR is exposed in OA knees. Previous studies have found that fibrocartilage formation in ligamentous structures is an adaptation to compression [55, 76]. This phenomenon is normally observed in various tendons and ligaments such as the tibialis posterior or the peroneal tendons, which change their direction by ‘wrapping around’ bony pulleys [76, 77].

While MMPRs normally function in multiple vectors such as tension, torsion, and compression, OA related changes in the knee joint likely increase the compression load

[50, 65, 66]. Factors related with increased compression loads such as higher body mass index and joint space narrowing have been found to be risk factors for MMPRTs [50].

Morphologically, we have observed that normal MMPRs ‘wrap around’ the posterior surface of the tibia to some extent, which may provide a bony surface for the root to be compressed. Our gross specimens from OA knees showed flattened roots lying directly on top of the tibial surface, suggesting repetitive compression stimulus. Moreover, roots from NT and PT were elongated, a pathologic feature also present in degeneration of other tendons. Lengthening of the MMPR anatomically places the root in the location of the posterior horn of the medial meniscus, directly between the tibia and the medial femoral condyle, thereby increasing its compression load. Elongation of the MMPR also likely causes extrusion of the medial meniscus, which would exacerbate joint space narrowing and increase compressive forces to the root [49, 78].

Secondly, fibrocartilage formation renders the root matrix susceptible to tensile loads, possibly leading to tear. Pathologists often consider the presence of fibrocartilage a prelude to rupture in degenerated tendons [58, 76]. The relationship between pathologic fibrocartilage metaplasia and tendon rupture has been demonstrated in a number of tendons including the Achilles, supraspinatus, patellar, and elbow’s common extensor tendon [55, 60, 76, 79]. Although fibrocartilage increases the ability of the ligamentous structures to withstand compressive forces, it has been shown to lower the ultimate tensile strength [55, 56, 58, 80]. Our biomechanical test results also confirm this finding.

MMPRs would lose the ability to withstand physiologic tensile stresses in the course of fibrocartilage formation, likely contributing to radial tears.

Another interesting finding is the morphology of DMMPRTs, which clearly differ from the classic, traumatic tear morphology of ligamentous structures. Tears with smooth margins resembling ‘cracks’ were both found and induced within fibrocartilaginous areas in our study. This distinctive tear morphology, similar to the tears found in the adjoining ‘fibrocartilaginous’ meniscus, may be the reason behind the confusion in diagnosing and erroneously classifying these tears as posterior horn meniscus tears [49].

Calcification within the root was another key finding in our study. Calcification in other tendons and ligaments have been extensively studied, with reported incidence of 2.7 to 22% in the rotator cuffs [60, 81]. Consequences of tendon calcification include pain, tendon weakness, and tear [60, 82]. Our results also show an increase of calcification in the CT group compared to the NT group. The proposed mechanism of calcification in overused tendons is via endochondral ossification [82]. Endochondral ossification within the tendon can result in calcification or ossification, both evident in our root samples. Riley et al. has shown a strong association between calcification and fibrocartilage in supraspinatus tendons, suggesting that calcification originates from fibrocartilage [83]. We believe that calcification, together with fibrocartilage metaplasia, subsequently alters the biomechanical properties of the root, possibly increasing the root’s susceptibility to tear [81, 82].

Readers should note that due to the cross-sectional nature of our study design, we cannot devise a cause-and-effect relationship between fibrocartilage metaplasia or calcification and root tear progression from our data. The presence of fibrocartilage and calcification simply demonstrates degeneration within the root matrix and implies

subsequent pathological changes such as tear progression. Moreover, the present study design does not represent the complete disease continuum of DMMPRTs. Nevertheless, we believe that the categorization of root samples used in this study represent key phases during tear progression of DMMPRTs. The natural disease course of rotator cuff tears, similarly affected by fibrocartilage metaplasia and calcification, show that nearly 80% of partial thickness tears progress in size within two years [84]. Another limitation is that the samples used in our study were harvested during joint replacement surgery, originating from knees with advanced chondral pathology. Further histological analysis of root tears in repair-surgery candidates without advanced cartilage damage is required.

Clinical implications of our study are as follows. In terms of diagnosis, root tears have been difficult to detect, with reported detection rates of 72.9% to 89%, even after using stringent MRI diagnostic criteria [47, 49, 51, 53]. Detection of fibrocartilage and calcification signals within the root with imaging modalities such as MRI and CT may improve the diagnostic accuracy of root tears. Secondly, these signals may provide signs of impending tear in cases where tears are absent. The majority of specimens in the NT group showed flattening and elongation under gross observation as well as micro-tears within fibrocartilage under light microscopy. The presence of these tear-related degenerative features in the NT group strongly suggests that these roots may be in danger of tear. Thirdly, detection of fibrocartilage and calcification with preoperative imaging may aid in assessing the tissue quality of such tears when in doubt, thereby affecting the decision of treatment modality. There are currently no specific signs that allow the differentiation between acute, traumatic tears and chronic, degenerative root tears [43]. Finally, meniscus root repairs are increasingly gaining popularity compared

to partial meniscectomy, especially for treating acute, traumatic root tears, in efforts to restore joint biomechanics and retard the progression of OA [52]. Controversy still exists, however, regarding the repair of chronic, DMMPRTs. With our results in mind, further studies are needed to explore appropriate surgical approaches in repairing degenerated, fibrocartilaginous roots.

Conclusions

This study aimed to devise a disease model for meniscus degeneration. First, we have analyzed inflammatory changes and related degeneration of the meniscus, along with cartilage and synovium, against polyethylene wear particles in a unicompartmental knee arthroplasty model. The key finding of this study was the active role of meniscus fibrochondrocytes in a clinical inflammation model. Secondly, we have characterized the degeneration process of meniscus root tears in osteoarthritic knees, with emphasis on fibrocartilage and calcification, thereby establishing a clinical degenerative tear model. The key finding of this study was characterization of the tissue adaptation and pathological degeneration process during tear progression in humans.

Further studies are required to devise clinically relevant meniscus degeneration models for multiple purposes, especially detection and management of early stage degeneration. Clinically relevant meniscus degeneration models would allow degeneration stage specific treatment modality development and testing, hopefully solving meniscus degeneration related problems, one of the key components in osteoarthritis of the knee.

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