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Ye Li, et al.
A B

Figure 8. Schematic diagram of cytidine triphosphate (CTP) scaffolds promoting bone regeneration via activating Wnt/β-catenin pathway.
(A) Schematic diagram of the preparation process of the CTP scaffold and its effect on angiogenesis and osteogenesis in the bone defect. (B)
Chemical structure of carfilzomib and mechanism of carfilzomib on the canonical Wnt/β-catenin signaling.

angiogenic and have mechanical properties similar to forming osteoblasts and of bone-resorbing osteoclasts .
[29]
those of bone at the implant site . Since the CTP scaffolds showed good biomechanical
[25]
CFZ, an clinically approved proteasome inhibitor, properties and biocompatibility, we consider that the CTP
is used to replace bortezomib to treat multiple myeloma, scaffolds could be suitable for bone regeneration. In in
due to fewer side effects it causes . The previous studies vivo study, the CTP scaffolds-treated animals showed
[26]
had reported the effect of CFZ in inhibiting osteoclasts increased osteogenesis, decreased osteoclastogenesis,
formation and bone resorption, while enhancing and notably improved bone formation. It was interesting
osteogenic differentiation and matrix mineralization to note that the vascularization was also enhanced in
in vitro . In our study, with sustained release of CFZ CTP-treated group. Osteogenesis and angiogenesis are
[15]
from CTP scaffolds, we confirmed the promotion two closely related processes in bone regeneration; the
of osteogenesis in cultured mouse mesenchymal newly formed vessels transport nutrient to the cells and
cells and inhibition of osteoclastogenesis in mouse metabolic wastes away from the cells, thereby improving
[30]
leukemic monocyte cell line. The canonical Wnt/β- bone formation . In summary, CTP scaffolds promoted
catenin pathway has been found to be tightly linked to osteogenesis, inhibited osteoclastogenesis through
bone formation. Herein, after being treated with CTP activation of WNT/β-catenin signaling, and also enhanced
scaffolds, the mesenchymal cells exhibited an increased angiogenesis, thus improving bone regeneration in large
expression of active β-catenin, and we noticed that bone defect (Figure 8A and B).
β-catenin was translocated into the nucleus. Activation 4. Conclusions
of canonical WNT/β-catenin signaling not only promotes
differentiation of osteoblasts and bone production but In this study, a porous CTP scaffold was generated by
also suppresses RANKL expression to inhibit osteoclasts cryogenic 3D printing. The sustained release of CFZ
formation . Thus, we speculated that the effect of CFZ from CTP scaffolds led to the induction of osteoblastic
[27]
on osteogenesis and osteoclastogenesis may be mediated differentiation and inhibition of osteoclast formation
through activation of the WNT/β-catenin signaling. in vitro, which may be mediated by an underlying
During the progression of bone defect repair, mechanism where the CFZ activates the Wnt/β-catenin
osteoclast precursors are attracted from the invading signaling. In the treatment of rabbit radius bone defects,
blood vessels that are adjacent to the newly formed CTP scaffolds improved new bone formation and promoted
bone trabeculae . The new bone tissue is continuously the growth of new blood vessels in the regenerated
[28]
remodeled through the balancing activities of bone- tissues. Overall, this study provides a theoretical basis for
International Journal of Bioprinting (2021)–Volume 7, Issue 4 109