Page 49 - Read Online

Page 10 of 21 Mu et al. Microstructures 2023;3:2023030 https://dx.doi.org/10.20517/microstructures.2023.05

of cardiovascular calcification is not fully understood, it is no longer acknowledged as a passive
accumulation of minerals but an active inflammatory and/or osteogenesis-related signaling process [147,148] .
Several influencing factors have also been identified in the past few decades, such as the loss of inhibition,
[98]
induction of osteogenesis, accumulation of nuclei, and cell death . For example, cell-secreted small
membrane-bound microparticles, such as apoptotic bodies and matrix vesicles, showed their capacities to
concentrate Ca and Pi and initiate crystal nucleation in response to inflammatory stimuli [100,144] . Additionally,
lipids and cytokines released by macrophages were also found to accelerate osteogenic differentiation and
calcification of vascular smooth muscle cells (VSMCs) [100,101] .

Kidney
[149]
Kidney stones are one of the most common and painful urinary disorders . In most cases, they result from
the nucleation and aggregation/growth of crystals from supersaturated urine [Figure 5] [150,151] . Based on their
composition and pathogenesis, kidney stones are commonly classified into five types: (a) Ca-containing
crystals; (b) struvite or magnesium ammonium phosphate stones; (c) uric acid stones or urate; (d) cystine
[152]
stones; and (e) drug-induced stones .

Ca-containing stones are predominant renal stones, typically composed of CaO (50%), CaP (5%), or a
x
mixture of both (45%) . CaO exists in the form of CaO monohydrate (COM, or whewellite), CaO
[153]
x
x
x
dihydrate (COD, or weddellite), or a mixture of both forms [151,154] . Struvite stones in the body are shown to
be a mixture of struvite magnesium ammonium phosphate [MgNH PO ·6H O] and carbonate HAp . In
[155]
2
4
4
addition to the most common Ca-containing stone that comprises 80% of urinary calculi, struvite accounts
for 10%-15%, and uric acid stones account for 9%, leaving 1% of the rest of the stone types, including cystine
stones and drug-induced stones [152,156,157] .
The pathogenesis of kidney stones is a multi-step process, including crystal nucleation, aggregation, and
retention. The nucleation of calculus occurs in a supersaturated liquid, where Ca and oxalate combine to
form insoluble micro-clusters or start with existing nucleation centers [Figure 5] [150,152,157] . Crystal aggregation
and secondary nucleation of crystals account for crystal growth and interactions between crystals and cells
[158]
and extracellular matrix . The formation of kidney stones is affected by the supersaturation of Ca and
oxalate in the urine, urinary pH, and some molecular modulators in the environment [157,159,160] . For instance,
the growth of CaO crystals is associated with a urinary pH range of 5.0 to 6.5; uric acid stones form at low
x
[152]
urinary pH (pH < 5.05), whereas CaP and struvite favor a pH range over 7 . In addition to factors that
affect the formation of kidney stones by altering the environment, there are several modulators actively
modulating the nucleation and aggregation of pathological crystals. For example, PPi and citrate reduce the
nucleation and growth of Ca-containing crystals, as well as Mg [157,160,161] ; Biomolecules, such as OPN,
prothrombin F1 fragment, and calgranulin, have been shown to inhibit the crystallization of CaO and CaP
x
by binding to Ca and hindering crystal growth [157,162-164] .

Brain
Brain mineralization occurs in the basal ganglia and other regions, such as the cerebellum, thalamus, and
brainstem [165,166] . Patients presenting brain calcification exhibit impaired motor and cognition, such as
dystonia, parkinsonism, psychosis, and dementia [165,167,168] . It is associated with neurological or metabolic
disorders (secondary hypoparathyroidism and mitochondrial diseases) and other acquired conditions, such
as injuries (infection, ischemia, and trauma) and toxicity related to manganese (Mn), Fe, lead (Pb), carbon
monoxide, and normal aging [165,169,170] . The major composition of brain mineralization is HAp [171,172] . Other
components, such as Zn, Fe, and Mg, are also present in the deposits . However, currently, there is no
[173]
established method to determine whether it is a passive process, which can be attributed to normal aging, or
an active process mediated by cellular activities [171,172] .