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International Journal of Bioprinting 3D bone: Current & future

cells (i.e., in bone and cartilage tissues) then develop into 2.3.3. Growth factors and cytokines in the
8,24
osteoblasts and chondrocytes, where the osteoblasts then development of bone tissues
divide and produce bone matrix, while the chondrocytes Bone generation is regulated by several integrated
mature into hypertrophic chondrocytes. The final step of signaling pathways, such as the bone morphogenic protein
(BMP), transforming growth factor (TGF), Wingless/int1
differentiation is maturation, where bone cells develop into (WNT), fibroblast growth factor (FGF), hedgehog (HH),
osteocytes and the chondrocytes mineralize the cartilage Notch, and parathyroid hormone-related protein (PTHrP)
tissues around them. MSCs are usually extracted for signaling pathways. These signaling pathways regulate the
research and therapeutic purposes. 8,22,24 expressions of different genes and transcription factors,

Table 3. Signaling pathways, growth factors, cytokines, and expressed genes in bone generation

Ossification Cells Signaling molecules Effect of signals Gene markers
(i.e., growth factors
and cytokines)
Intramembranous Cranial neural crest cells SHH, SOX10, FGF8, Differentiation Selective markers: SOX10, B3GAT1, BARX1, FRZB
FGF9, BMP4 (Sfrp3), GEMIN2, HAND2, LHX6, LHX8 (Lhx7),
MSX1 (Hox7), MSX2 (Hox8), PITX1 (Ptx1),
SATB2, SOX9, TFAP2A (AP2alpha)
Selectively unexpressed marker: HOXA2
Expressed markers: AP3D1, COL1A2, DLX1,
DLX2, DLX3, DLX4, DLX5, DLX6, EZH2, FBLN5
(Fibulin 5), FOXC1 (Mf1), FOXC2, FOXD1 (BF-2),
BMP4, ET1, FGF8, Uncategorized FOXD2, FOXF1 (HFH-8), FOXF2 (forkhead box
miR452 F2), HAPLN1 (Crtl1), LIX1, LMAN1, MARVELD1,
MIR129, MIR149, MIR18, MIR184, MIR185,
MIR214, MIR290A, MIR292, MIR296, MIR299A,
MIR30A, MIR320, MIR341, MIR342, MIR346,
MIR351, MIR370, MIR376B, MIR376C, MIR423,
MIR429, MIR452, MIR468, MIR483, MIRLET7A-1,
MIRLET7B, MIRLET7E, MRC2, NOG, NRP2
(Npn2), PAX3 (splotch), PF4, SLC39A7, SPRY1,
STEAP1, TNFAIP6, TNFRSF19 (Troy), TSPAN14,
WNT1, WNT5A
Osteochondroprogenitor FGF18 Proliferation Selective markers: EZH2, RUNX2 (Cbfa-1), SOX9,
cells TAZ
BMPs, EZH2 Differentiation Selectively unexpressed markers: HOXA2, HOXA3,
HOXB4, PPARG (PPAR-gamma)
Twist1, WNTs Inhibition of Expressed markers: COL2A1, DLX5, DLX6, FGFR2
differentiation (Fgfr-2), PAX1, PAX9, PKD1, TGFBR2 (TbetaRII),
TWIST1 (Twist)
Immature/pre-osteoblasts BMPs Proliferation Selective markers: COL1A1, COL1A2, SP7 (Osx),
ALPL (Akp-2), MSX1 (HOX7), MSX2 (Hox8),
BMP2, FGF18, Differentiation POSTN (Osf2), PTH1R (Pthr1), RUNX2 (Cbfa-1),
RUNX2/Cbfa-1, SATB2, SPARC, SPP1 (BSPI), TNC (tenascin-C)
WNTs Selectively unexpressed markers: HOXA2, SOX9
Expressed markers: BGLAP (OC), DLX5, FGF18,
BMP4 Uncategorized FGFR1 (Flt-2), FN1 (Fn-1), GATA3, TAZ, TWIST1
(Twist)
Mature osteoblasts ATF4, BMP2, BMPs, Differentiation Selective markers: SP7 (Osx), ALPL (Akp-2), ATF4,
FGF18, RUNX2/ BGLAP (OC), MSX1 (Hox7), MSX2 (Hox8),
Cbfa-1, SATB2 PTH1R (Pthr1), RUNX2 (Cbfa-1), SATB2, SPARC,
TAZ, TNC (tenascin-C)
Selectively unexpressed markers: HOXA2, SOX9
Expressed markers: FN1 (Fn-1), SMO, SPP1 (BSPI)
Osteocytes FGF18 Uncategorized Selective markers: SP7 (Osx), ATF4, BGLAP (OC),
MSX2 (Hox8), SPARC, SPP1 (BSPI)
Expressed markers: FGFR2 (Fgfr-2), FN1 (Fn-1),
RUNX2 (Cbfa-1)
(Continued)
Volume 10 Issue 3 (2024) 150 doi: 10.36922/ijb.2056