The aetiopathogenesis of CT is still controversial, especially because it remains difficult to clarify the first steps causing this condition and those involved in the development of calcifications.
Rather than being formed by precipitation of inorganic ions, CT results from an active cell-mediated process in which resident progenitor cells with multidifferentiation potential may play a determinant role [73
Many different factors such as acute injury, repetitive microtrauma, and chemical-induced injury may cause damage to the tendon and start the natural healing process. Tendon healing includes many sequential processes such as matrix synthesis and remodeling, synthesis of pro-inflammatory cytokines, neovascularization, neural modulations, recruitment of healing cells, multipotent cells, TDSCs, proliferation, apoptosis [74
]. Disturbances at different stages of healing may lead to different combinations of histopathological changes. The normal healing processes are then diverted onto an abnormal pathway (Figure ). Clinical features such as chronic pain, swelling, functional limitations and tendon ruptures are the consequences.
The abnormal pathway that may lead to calcific tendinopathy (CT).
Since ossified tendons will have increased stiffness, ossification can be seen as a localized attempt to compensate for the original decreased stiffness of the weak tendon. It is possible that the erroneous differentiation of tendon progenitor cells into chondrocytes or osteoblasts instead of tenocytes may contribute to the pathogenesis of CT. The mechanism leading to the erroneous differentiation of TDSCs is not completely understood. Probably, the expression of BMPs, biglycan, fibromodulin and an unfavorable micro-environment induced by overuse modify the natural healing process of the tendon. Conservative management modalities such as non-steroidal anti-inflammatory drugs (NSAIDs) or corticosteroids are often prescribed, and may further influence the pathways of the failed healing [75
]. NSAIDs could modulate tendon cell proliferation [76
], the expression of extracellular matrix components [78
] and degradative enzymes in cells culture studies [46
]. Corticosteroids can induce a fibrocartilaginous phenotype in tendon cells [78
], and induce osteogenic differentiation in human spinal ligament derived cells [79
Many questions remain unanswered about the pathogenesis of CT. Calcium carbonate apatite appears the only component of calcific deposits, but inorganic component of Achilles and patellar CT has been less investigated than CT of the RCTs. Histological and imaging studies show that the three-dimensional structure of calcific deposits is quite different. Calcific depositions in the RCTs appear as a toothpaste-like fluid, while calcific deposits in the Achilles and patellar tendons have a porous structure [35
] and a vascular core [34
]. Therefore, we can speculate that their mineralogical structure could also be different.
'Calcific tendinopathy' and 'insertional calcific tendinopathy' are caused by two distinct pathogenetic mechanisms. In RCTs, degenerative changes in the extracellular matrix seem to play an important role for the formation of calcific deposits. The pathogenesis of CT involves matrix vesicles, macrophages and multinucleated giant cells with a typical osteoclast phenotype, producing a toothpaste-like material [25
]. No vascular invasion has been documented. This process has not been observed in other tendons. Recently, Gohr et al. elucidated the role of matrix vesicles also in the patellar tendon [25
], but, as the enthesis was removed, this model is more similar to a CT of the main body of the tendon than to an insertional CT. We also think that degenerative changes cannot be solely responsible, because we are not able to explain the deposition of calcium salt in twin brothers and children only with a reactive degenerative theory [65
The mechanism of insertional CT has been clarified by Benjamin and coworkers, and essentially accepted worldwide [34
] (Table ). Increased vascularity in insertional Achilles tendinopathy was observed also by other authors [37
Pathogenetic models proposed for calcific tendinopathy (CT) of rotator cuff tendons (RCTs) and insertional CT of the Achilles tendon.
CT of the rotator cuff has been investigated with histological studies of specimens obtained from human biopsies, while the study of CT of Achilles and patellar tendons is based on animal models of collagenase-induced tendinopathy. Therefore, we do not know whether the pathogenesis of CT of the rotator cuff can be compared to CT of the Achilles and patellar tendons. Moreover, no pathogenetic studies on the rotator cuff have been published since the late 1970s, and no animal CT studies are present in literature [80
]. We do not know why the calcific deposits of the rotator cuff involve the main body of the tendon, while the most common presentation of CT in the Achilles tendon is insertional. Animal models of CT of RC seem necessary to understand its pathogenesis. No histological and epidemiological studies on CT of the main body of Achilles tendon are published.
Furthermore, no clinical or imaging classification has been published in the literature, except for the CT of RCTs [1
]. Also, it is not clear whether the gross morphological anatomy of tendons (for example, the RC is a flat tendon, while the Achilles tendon is cylindrical) plays a role.
The involvement of mesenchymal stem cells (MSCs) in the pathogenesis of the CT process [46
] and the role of autologous growth factors have been postulated, but not clarified [54
While emerging data seem to indicate an association between tendinopathies and endocrine disorders such as diabetes, hypercholesterolemia, hypertriglyceridemia, thyroid disorders, and estrogen levels alterations [81
], the association with CT is unclear, and no physiopathological investigations have been performed.