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Page 6 of 21 Mu et al. Microstructures 2023;3:2023030 https://dx.doi.org/10.20517/microstructures.2023.05

Cementum is a thin layer that covers the entire root surface and anchors the roots of teeth to the jaw.
Similar to the bone, it is composed of water, an organic matrix (mainly collagen, glycoproteins, and
proteoglycans), and minerals and is formed through the formation of HAp in deposited type I collagen by
cementoblasts [84-86] . Compared to dentin (70%) and enamel (> 95%), cementum (40%-50%) is less
mineralized . In addition to HAp, small amounts of ACPs were also found in cementum . The presence
[86]
[85]
of the amorphous phase results in a greater capacity of cementum for the adsorption of F and other
elements over time and readily decalcification in acidic environments . For example, cementum contains F
[85]
up to 0.9% ash weight and increases with age . Regulation of teeth mineralization is, in part, regulated by
[87]
the ratio of Pi and PPi, as well as other factors, such as genetic modifications, age, diet, oral hygiene, and
certain diseases, such as periodontal diseases, caries, root resorption, tumoral lesions, or trauma [88,89] .

Otoconia
Otoconia, which is composed of CaCO , is found in the inner ear of humans and other vertebrates. They are
3
[90]
positioned to sense stimuli in directions and send signals to the brain to maintain bodily balance . Similar
to the bone, the organic matrix in otoconia determines the orientation, sizes, and shapes of crystals by
[91]
providing a framework . Additionally, otoconia contain high levels of Ca, Na, Mg, K, P, sulfur (S), and
chloride (Cl) . However, the underlying molecular etiology remains unknown, neither the functions of
[90]
otoconial proteins nor the crystal formation.

PATHOLOGICAL (ECTOPIC) MINERALIZATION IN MAJOR ORGANS
Physiological mineralization is restricted within the skeletal system, including bone, teeth, and calcified
cartilage . In contrast, pathological (ectopic) mineralization can occur not only in the skeletal system but
[92]
also in soft tissues, such as the breast, blood vessels, kidney, pancreas, and prostate, mostly composed of
CaPs, CaCO , and CaO [Figure 4] [22,31] . There are three structural types of deposits observed in ectopic
x
3
calcification, single crystals, polycrystalline deposits, and calcified matrix. The specific type and
characteristics of the deposits can vary, depending on the tissue and the underlying mechanisms. For
example, single crystals are typically small and uniform in size and often are found in tendons and
ligaments [93,94] . The formation of single crystals can be initiated by the presence of specific proteins or
molecules that act as nucleation sites. Polycrystalline deposits, on the other hand, consist of multiple small
crystals randomly arranged in tissues, such as blood vessels and heart valves . In contrast, the calcified
[95]
matrix consists of alternating layers of mineralized and non-mineralized tissues and can be found in a
[96]
variety of tissues, including cartilage and blood vessels . Pathological/ectopic calcification occurs in both
genetic and acquired clinical conditions and affects the prognosis of diseases [32,97] . Pathological/ectopic
calcification can occur through different mechanisms, depending on the involvement of cells, including cell-
induced, cell-controlled, or spontaneously precipitated. For example, vascular calcification can be triggered
by damage to the endothelial cells lining the blood vessels, leading to the recruitment and differentiation of
smooth muscle cells into osteoblastic cells that actively deposit Ca and Pi . Cell-controlled calcification
[35]
occurs with specific mineralization-related factors released by cells in response to injury, inflammation, or
bacterial infection [98,99] . Spontaneous deposition may happen as a result of changes in the environment
without the involvement of cells, such as oxidative stress, local pH, and the supersaturation of ions [100,101] .
Understanding the formation, structure, and composition of crystals deposited in the physiological and
pathological conditions will aid the development of therapeutic strategies to prevent and/or regulate
pathological/ectopic calcification [31,102] [Table 1].

Bone
Bone tissue undergoes continuous remodeling to maintain its density and strength in a stable state. The
bone mineralization process is tightly regulated by osteoblasts (bone-forming cells) and osteoclasts (bone
resorption cells). Osteocytes, which are embedded in the bone matrix, also play important roles in