Biomedical Engineering Reference
In-Depth Information
Differentiation is marked by increasing alkaline phosphatase activity and expression of osteoblast-
specific genes such as osteocalcin [86] . Opposing bone formation by osteoblasts is bone resorption
by osteoclasts. Osteoclast precursors circulate within the monocyte population and express on their
membranes receptor activator of nuclear factor kappa B (RANK), the receptor for the key osteo-
clastogenic cytokine RANK ligand (RANKL) [87] . In the presence of RANKL, the upregulation of
key transcription factors including nuclear factor kappa B (NF-
B), c-Fos, and nuclear factor of
activated T cells (NFAT) induce early osteoclast precursors to differentiate into mononucleated pre-
osteoclasts, characterized by expression of the enzyme tartrate-resistant acid phosphatase (TRAP).
These multinucleated preosteoclasts fuse together to form giant multinucleated mature bone-
resorbing osteoclasts.
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4.6.2 Silica and osteoblasts
Silicon has been suggested to play a physiological role in bone formation [88,89] and silica
deficiency leads to detrimental effects on the skeleton including skull and peripheral bone deformi-
ties, poorly formed joints, defects in cartilage and collagen, and disruption of mineral balance in
the femur and vertebrae [5] . Osteoblasts grown on silica-coated disks demonstrated increased
hydroxyapatite formation although alkaline phosphatase and cell number was not changed [90] .
Orthosilicate (10
μ
M) was demonstrated to increase proliferation, mineralization, and
osteoprotegerin (OPG) RNA of human osteoblast like SaOS-2 cells [91] . OPG acts as a decoy
receptor for RANKL, inhibiting RANKL-induced RANK-mediated activation of important signal
transduction pathways, including NF-
1000
B, that are necessary for osteoclast formation. Silica has also
been incorporated into hydroxyapatite/bioceramic artificial bone scaffolds, where it is reported to
enhance osteoconductivity and proliferation [92
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95] . A recent study synthesized mesoporous silica
gel process with different surface area (401, 647 and 810 m 2 /g, respectively)
and found an increase in proliferation and osteoblast synthesis of attachment proteins [96] . MSNs
were not found to affect viability, proliferation, immunophenotype, or differentiation of mesenchy-
mal stem cells (osteoblast precursors) in vitro [27] .
xerogels by the sol
4.6.3 Silica nanoparticles and bone metabolism
We recently reported that engineered silica nanoparticles (50 nm) possess intrinsic properties that
endow them with therapeutic properties for the skeleton. The nanoparticles were demonstrated to
have a direct promoting effect on osteoblasts in culture, not only increasing mineralization but
also increasing gene expression associated with osteoblast differentiation such as osterix and osteo-
calcin [97] . These data suggested that the particles are capable of altering cell behavior and not
simply altering the matrix. We also examined the effect on bone-resorbing osteoclasts and found
a strong inhibition of osteoclast formation by the silica nanoparticles as measured by the number
of TRAP-positive multinucleated cells [97] . This study also identified NF-
B signaling as target
of the particles, resulting in decreased signaling activity in both preosteoblasts and preosteoclasts.
These in vitro studies predicted a positive effect on bone mass accrual. Intraperitoneal injection of
mice with the 50 nm fluorescent PEGylated silica nanoparticles ( Figure 4.7 ) twice a week for 6
weeks increased bone mineral density relative to vehicle injection. The results suggested that silica
nanoparticles, absent of significant surface functionalization or deliverable cargo, are capable of
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