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Page 12 of 21 Mu et al. Microstructures 2023;3:2023030 https://dx.doi.org/10.20517/microstructures.2023.05

Pancreas
Pancreatic stones (Pancreatic calculi) occur in the main ducts, side brunches, or parenchyma . It contains
[188]
an inner nidus core and outer shell, primarily constituting CaCO , in the form of calcite (major) and
3
aragonite, besides Pi and other protein content [188,189] . The inner protein nidus contained Fe, chromium (Cr),
[190]
and nickel (Ni), whereas the outer calcite shell contained Ca and 17 other elements .
Prostate
Prostatic calculi are usually found as apatite or whitlockite, less frequently CaO x [191,192] . They are classified as
[193]
primary/endogenous or secondary/extrinsic stones . Endogenous stones are commonly caused by
obstruction of the prostatic ducts or chronic inflammation; extrinsic stones are mainly caused by urine
reflux . Klimas et al. suggested two mechanisms regarding the calcification of prostatic calculi: the
[193]
calcification of the corpora amylacea (type I calculi, composed of Na, S, P, Ca, and Zn) and the precipitation
of prostatic secretions (type II calculi, composed of Ca and P) .
[191]
Placental
The placenta, a highly vascularized organ, mediates the communications between two circulatory systems.
Placental calcification occurs when small calcium deposits build up on the placenta and is recognized as
CaPs (the ratio of Ca/P = 2.00 ± 0.05) observed in placenta tissue [194,195] . It is often found in both preterm and
term birth and serves as a predictor of adverse pregnancy outcomes . However, the mechanisms of
[196]
[194]
placental calcification are poorly understood .
Lymph nodes
[197]
Calcification in the lymph nodes occurs following diseases such as granulomatous infections . Two
patterns of calcification were found in the submandibular and neck regions: small blocks with different
[198]
textures and islets surrounded by soft tissues, respectively . In the submandibular specimen, apatite,
together with a minor amount of whitlockite, was found ; In the neck specimen, whitlockite was found
[198]
most frequently .
[198]
POSSIBLE PREVENTION AND TREATMENTS OF PATHOLOGICAL MINERALIZATION
Current treatments for the removal of calcified plaque include mechanical removal using rotary blade
ablation or chemically dissolving in situ with acid via a catheter device [199-201] . In addition to mechanical and
chemical debridement, reduced mineral ion intake from the diet or ions from bone stores have also been
[201]
considered potential treatments for pathological/ectopic calcification in clinical practices . Other
approaches have been explored in targeting regulatory molecules in the body. For example, the monoclonal
antibody Denosumab was developed to interfere with osteoclast functions and serum Ca levels, and PPi
inhibited uremic vascular calcification without interfering with the mineralization of bone [202,203] . However,
there are still no well-established and acknowledged treatments to prevent or counteract pathological/
ectopic mineralization.

Current strategies targeting cellular mechanisms of calcification provided promising avenues for better
administration of pathological mineralization in soft tissues, either reducing the nucleation of pathological
crystals and crystal growth or reducing the circulating mineral ions in the serum . Several endogenous
[204]
calcification inhibitors have been identified, such as fetuin-A, vitamin-K dependent matrix-Gla protein
(MGP), PPi, and OPN [23,33] . The serum protein fetuin-A is an important inhibitor of extra-skeletal
calcification in the plasma and tissue fluids . It is derived from the liver and acts as a chaperone,
[205]
stabilizing excess mineral ions by forming a colloid with mineral ions or completely insoluble calciprotein
particles [206-208] . MGP was the first inhibitor of artery calcification to be characterized in vivo . It serves as an
[24]
inhibitor of bone morphogenic protein-2 (BMP2), driving changes in cells toward an osteogenic-like