The skeletal anatomy's potential importance on the genesis of rotator cuff tear has been studied for decades and remains a controversial subject. Recently, tendon degeneration (age-related or degeneration induced by genetics and medical conditions) seems to be the most credited theory for cuff rupture [14–15]. The origin of RCT is represented by an area of the tendon within a few mm of its insertion characterized by relative hypovascularization . The inadequate blood supply is only partially improved by vascular anastomoses of the critical zone, near the tendon insertion. Micro vascularization may become worse in many patients with smoking and alcoholic habit [17–18], hypertension , and lung and other cardiovascular diseases . Obesity is also considered a risk factor for rotator cuff tear  because it contributes to peripheral vascular deficiencies through its associations with an increased production of adipokines (leptin; adiponectin; plasminogen activator inhibitor; tumor necrosis factor-a; angiotensinogen; interleukins 6, 8, 10, and 18). All these molecules induce oxidative stress, inflammation, thrombosis, and endothelial dysfunction . The consequent release of many reactive oxygen species (ROS) may lead to degeneration of the tendon causing oxidative stress and cell apoptosis .
When cuff tear occurs, multiple stimuli, both mechanical and inflammatory, lead to the altered expression of proteins; some of them are probably synthesized as an attempt to tendon healing. In this regard, increasing in periostin on rotator cuff margins was attributed to the attempt of the tendon to change its viscoelastic properties to prevent increased damage . Our study revealed a moderate intensity of type V intermediate filament proteins lamin A in the healthy cuff tendons (control group), a higher expression of this protein in the small tears, and a significant decrease of lamin A presence with increasing tear size. Since it was demonstrated that cells lacking lamin A have elevated ROS level [22–23], it is plausible that the initial increasing in lamin A observed in our specimens belonged to patients with small rotator cuff tear is ascribable to an attempt to face up ROS levels. However, this attempt is destined to wane given the progressive cell depletion observed in large and massive tears.
In an immunohistochemical analysis on rotator cuff tear margins, nuclear transcription factors, as NF-kB have been observed . Furthermore, activated NF-kB on the tear edge increases with increasing tear size. The role of lamin A and of NF-kB as anti-apoptotic is well documented [2, 25–27], such as it is well known that the same factors that regulate NF-kB activation act as neoangiogenesis inductors . Interactions between lamin and nuclear transcription factors have been demonstrated in vivo and in vitro [27–28]. We hypothesize that the increased expression of lamin A in the nuclei of small tear tendon tenocytes is initially related to the NF-kB activation. Therefore, lamin A's action as anti-apoptotic would occur not only through the protective effect that lamin carries out on the cell nucleus [7–8, 10] but also through the regulation of the NF-kB.
A proteomic analysis conducted by Swift and Discher  revealed that, in vitro, nuclei of mesenchymal cells on a soft substrate are wrinkled and relaxed. In contrast, on the stiff substrate, they are flattened by stress fibers and appear taut and smooth. Furthermore, the native fold of lamin A is maintained on a stiff substrate, but the total quantity of lamin A protein is upregulated. Lammerding et al.  observed that the viability of fibroblasts lacking lamin A was significantly reduced under mechanical strain, while under unstrained conditions were similar to wild-type fibroblasts. Our study revealed a moderate intensity and a high H scores of lamin A in the normal cuff, Instead, the Chi square analysis documented a statistically significant correlation between the nuclear expression of lamin A and rotator cuff tear size; in particular, the greatest expression of lamin A was found in the small tears with a significant decrease in lamin A presence with increasing tear size. Increased lamin A levels, in response to extracellular tension, prevent distortion of the nucleus by physical stress, thereby identifying lamin A as a mechanostat factor in cells . Andarawis-Puri et al. , in a biomechanical study, demonstrated that the maximum principal strains were directly medial to the tear, corresponding to the direction of tear propagation and to the site where we performed the biopsies. Locke et al.  observed that in rat rotator cuff tendons strain concentrations develop near attachment defects. In a biomechanical study conducted on cadaveric cuff tendons, Miller et al  registered that the largest strain is particularly concentrated medial and posterior to the tear. With increasing tear size, we observed a decrease in lamin A staining and the H score. In massive tears, no 3–4 points H score were found. This may be due to the reduction of the mechanical stress acting on an extended margin of the tear (and not in a concentrated area, as in small tears occur) and the progressive fatty infiltration to which the muscle of the involved tendon undergoes. This analysis seems to be supported by Swift e Discher theory , according to which mechanical loading can cause inhomogeneous straining, making it beneficial to have mechanisms of lamin regulation that act at the local level of individual cells.
The “cellular protection” mechanism progressively fails, and programmed cell death develops. However, in massive tears, some functional cells remain, probably due to the permanent high levels of NFkB.
The relatively low number of studied patients represents a limit of our study. However, the evaluation of lamin A immunohistochemical staining is a novel and expensive methodology.