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Mu et al. Microstructures 2023;3:2023030 https://dx.doi.org/10.20517/microstructures.2023.05 Page 9 of 21

OCP [116,117,119,120] . Articular cartilage calcification that occurs in end-stage OA shows the accumulation of
predominant HAp crystals [116,121] . The deposition of HAp initiates from articular cartilage vesicles (ACVs)
and induces stress in articular chondrocytes, which ultimately results in the phenotypic change of
chondrocytes and the formation of more HAp crystals [121,122] . Besides, whitlockite, another kind of CaP-based
mineral, has also been found in the mineral phase of osteoarthritic articular cartilage and intervertebral
disc [123,124] . Under certain circumstances, such as elevated Mg concentrations, acidic microenvironments, and
the presence of specific proteins or organic molecules, Mg partly substitutes Ca, inhibits apatite originating
from ACP, and aids the precipitation of whitlockite.

Tendon
Tendon mineralization (calcific tendinitis) is the cell-mediated calcification of living tissues that causes joint
pain . It typically affects the shoulder and hip, as well as other sites, such as the hand and wrist, foot and
[94]
[125]
ankle, and neck . Four well-defined phases of calcific tendinitis are formative (pre-calcific), calcific,
resorptive, and reparative [94,126] . In the formative phase, a portion of the tendon undergoes a
fibrocartilaginous transformation. During the calcific phase, calcium crystals are deposited in small vascular
structures located between collagen fibrils [126,127] . Followed by calcification, the appearance of thin-walled
vascular channels at the periphery of the calcium deposits marks the initiation of the resorptive phase,
[128]
which involves Ca removal by macrophages and multinucleated giant cells . Computed tomography
studies showed the porous structure of calcific deposits throughout the tendon . Structural and
[129]
compositional analysis revealed that the chemical composition of mineralized deposits in calcific tendinitis
is poorly crystallized carbonate HAp, having a Ca/P molar ratio ranging between 0.9 and 1.5 [128,130-132] .

Teeth
Pathological mineralization on teeth results from a variety of factors, such as changes in the oral
environment, genetic predisposition, or underlying medical conditions [88,89] . In dentin, pathological
mineralization happens in the form of dentinogenesis imperfecta, causing weakened teeth that are prone to
cavities and fractures . Dental calculus builds up on teeth (both supragingival and subgingival), is
[133]
composed of inorganic components (brushite, dicalcium phosphate dihydrate, OCP, HAp, and whitlockite)
and salivary proteins adsorbed on the tooth surface [134,135] . The level of dental calculus is affected by oral
hygiene habits, diet, age, systemic diseases, and medications . In enamel, pathological mineralization
[135]
appears as spots on the surface of the tooth. It can be caused by malnutrition, high fever during childhood,
[77]
or exposure to excessive F .
Salivary gland
A salivary gland stone (salivary calculi or sialolithiasis) found in the salivary gland consists of a central
organic core and a layered cortex of inorganic components . The crystals found in the salivary gland were
[136]
randomly oriented carbonate HAp, whitlockite, and less frequently brushite and OCPs [137-139] .

Heart and blood vessels
Cardiovascular calcification, the deposition of apatite and whitlockite, is closely associated with increased
risks of several mortal diseases, such as blood vessel stenosis, ischemia, stroke, and heart disease [20,35,140-142] .
Based on its histological appearance, the calcification can be distinguished as amorphous (lacking tissue
architecture) and chondro-osseous (having the tissue architecture of cartilage or bone) .
[143]
Calcification that occurs in the intimal layer of the arteries links to arterial obstruction and atherosclerotic
plaque rupture, leading to stroke or myocardial infarction [35,144] . Calcification that occurs in the medial layer,
also known as Monckeberg’s medial sclerosis, is associated with vessel stiffness, systolic hypertension, and
progressively increased risks of diastolic dysfunction and heart failure [35,145,146] . Even though the mechanism