Calcific tendinitis is an interesting clinical condition in the shoulder, as it can be clinically silent and can be found incidentally in an asymptomatic patient, or it can also present with severe and acute pain. The underlying pathophysiology is not well understood. In addition, due to our lack of understanding of what initiates formation of the calcific deposit in the tendon, we also do not know what factors trigger the pain that can acutely develop in patients with a calcific deposit.
The study by Hackett et al. demonstrates that there is an accumulation of inflammatory cells, neovascularization, and nerve fiber ingrowth in and around calcific deposits in symptomatic patients. This is consistent with the clinical presentation in patients with calcific tendinitis, as they can present with acute pain. The immunohistochemistry findings are consistent with the basic pathophysiology of inflammation, as it is known that inflammation is associated with neovascularization. Furthermore, neoinnervation is associated with new capillary formation. Similar findings of new capillary formation and expression of nociceptive mediators have been reported in analyses of angiofibroblastic hyperplasia lesions seen in rotator cuff tendinosis1. The presence of nociceptive chemicals and mediators in the rotator cuff, as found by Hackett et al., is consistent with the severe pain in these patients.
A distinct limitation in this study is the inability to study biopsy specimens in asymptomatic patients with calcific deposits. This leads to consideration of one of the primary outstanding questions related to calcific tendinitis: what initiates the onset of acute pain in a patient who has a chronic calcific deposit? A patient may have a quiescent, asymptomatic lesion that then becomes acutely painful. It is not known what factors trigger this process. The current understanding is that the calcific deposit begins to undergo a cell-mediated process of active resorption. The influx of inflammatory cells and new capillaries reported in the current study is consistent with such a mechanism. It is believed that osteoclasts eventually invade the lesion and activate resorption of the calcium. Patients who present with acute pain are presumably in this active resorption phase, and it is fascinating to see that a radiograph made several weeks later can often show complete resorption of the calcific deposit. Of course, as a clinician, it is hard to do nothing when the patient presents with very severe pain, and thus subacromial injection is often performed. The patient has improvement, and we as clinicians assume that the injection was helpful. The reality is that this improvement in pain may just be the natural history of the condition, and the patient may well have improved spontaneously as the calcific deposit underwent resorption, even if no treatment was rendered. This is indeed a fascinating condition.
This study of calcific tendinitis can contribute more broadly to our understanding of tendon biology. A much more common problem than calcific tendinitis is degenerative tendinosis, and a rather common clinical scenario in sports medicine is shoulder pain in an overhead athlete (such as a thrower or swimmer) in whom magnetic resonance imaging demonstrates changes in tendon signal and morphology that are consistent with tendinosis. It is not known what causes pain in tendinosis, but this study shows that inflammatory and nociceptive mediators can be present in the tendon. The classic teaching is that tendinopathy is not associated with inflammation because of the absence of inflammatory cells in surgical biopsy specimens. However, more recent studies on the cellular and molecular mechanisms of tendon injury and repair have suggested that inflammatory mediator expression does play a role in the initiation of tendinopathy. Lavagnino et al. suggested that an important inciting factor is microscopic collagen fibril injury2. When such localized matrix damage occurs, the tendon cells in that region are stress-deprived and will produce interleukin-1 beta (IL-1β), matrix metalloproteases, and perhaps other inflammatory mediators and proteases. In turn, these matrix metalloproteases lead to further local tendon matrix damage, resulting in propagation of the tendon injury. This pathophysiologic mechanism suggests tendon underloading (at the microscopic level), rather than the commonly held belief that injury is due to tendon overloading. The reality is that the mechanical loading environment at the cellular level is complex, and further data are required to understand the relationship between mechanical loading of tendon and subsequent biologic responses.
However, these points bring us back to reconsideration of what initiates the onset of severe and acute pain in calcific tendinitis. As stated above, this is one of the outstanding and important clinical questions. Hackett et al. show that there is ingrowth of blood vessels, inflammatory cells, and nerve fibers, but what triggers this process? How does a patient go from having a quiescent, asymptomatic calcific deposit to having an acute onset of severe pain? It might be that this occurs in response to microscopic tendon injury in the area of the calcific deposit. Microscopic collagen fiber failure in this area and the resultant stress deprivation-induced changes in tendon cell biology, as postulated by Lavagnino et al.2, may trigger the process that ultimately leads to active, cell-mediated resorption of the calcific deposit. Clearly, further study is required in this area. The study by Hackett et al. is an important first step toward further understanding the pathophysiology of calcific tendinitis.
I will conclude with some thoughts on the underlying etiology of calcific tendinitis or tendinosis. The current study provides information about what happens in these lesions once they are present; however, we do not really know what initiates the deposition of crystalline calcium phosphate (hydroxyapatite) in the first place. Various theories have been proposed, including reactive or dystrophic calcification, formation by a process resembling endochondral ossification (perhaps due to regional hypoxia, which transforms tenocytes into chondrocytes), or metaplasia of mesenchymal stem cells normally present in the tendon into calcium-producing cells. Zhang and Wang showed that, like many other tissues, the tendon harbors an intrinsic niche of tendon stem cells. These tendon stem cells can become normal tendon fibrocytes and can contribute to maintenance of tendon health. However, under certain circumstances, such as inflammatory mediator presence or mechanical overloading, tendon stem cells can differentiate into non-tendon cells, such as osteoblasts, chondrocytes, or adipocytes, leading to the abnormalities in the tendon matrix that are seen in tendinosis3. It may be that calcific tendinosis is also initiated by metaplasia of intrinsic tendon stem cells into calcium-producing cells. I believe that further studies of the underlying biology of the intrinsic stem-cell niche in the tendon will shed further light on processes such as calcific tendinitis and degenerative, painful tendinosis.
↵* The author did not receive payments or services, either directly or indirectly (i.e., via his institution), from a third party in support of any aspect of this work. The author, or his institution, has had a financial relationship, in the thirty-six months prior to submission of this work, with an entity in the biomedical arena that could be perceived to influence or have the potential to influence what is written in this work. The author has not had any other relationships, nor has engaged in any other activities, that could be perceived to influence or have the potential to influence what is written in this work. The complete Disclosures of Potential Conflicts of Interest submitted by authors are always provided with the online version of the article.
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