Table 1.

Transcription factors involved in chondrocyte fate and differentiation decisions

Transcription factors	Expression											Cell fate and differentia tion actions	Trans cr. role	DNA-binding motif	Human skeletal diseases
	S S C	P C	E C	C C	P H C	H C	T C	per iC	J P	A C C	O B
1. Beta-scaffold transcription factors with minor groove contacts
1.1. HMG-domain transcription factors
1.1.1. SOX transcription factors
SOX9	+	+	+	+	+	+			+	+	−	Master activator of the PC to the HC and ACC stages	TA (TR)	[T/A][T/A]CAA[T/A]G[n3-4] C[A/T]TTG[A/T][A/T]	Campomelic dysplasia
SOX5/SOX6	−	+	+	+	+					+	+	Promote EC, CC, HC, and ACC differentiation	help in TA	ATTGTT[nN]ATTGTT	LAMSHF syndrome (SOX5)
SOX8	+	+	+							+	+			(A/T)(A/T)CAA(A/T)G
SOX4/SOX11/SOX12	+	+	+	+	+	+	+	+	+		+	Promote cell survival, SSC/JP non-chondrogenic fate, and CC alignment	TA	AACAA	Coffin-Siris syndrome (SOX11)
1.1.2. TCF/LEF transcription factors
TCF7L2						+						Promotes HC differentiation	TA	CTTTG[A/T][A/T]
1.2. RUNX transcription factors
RUNX1/2/3	+	+		+	+	+	+	+	+		+	Master activators of the PHC to TC stages	TA	[A/G]ACC[A/G]CA	Cleidocranial dysplasia (RUNX2)
1.3. MADS-domain transcription factors
MEF2C/D				+	+	+					+	Activators of the PHC to TC stages	TA	CC[A/T]6GG
1.4. REL-homology-domain (RHD) transcription factors
RELA/p65	+		+	+	+	+					+	Promotes SSC and GPC survival and proliferation	TA	GGG[A/G]n[C/T][C/T][C/T]CC
NFATC1/2/3					+	+				+	+	Promote ACC maintenance	TA	GGAAA
1.5. STAT transcription factors
STAT1 and STAT5	+	+	+	+	+	+	+	+	+	+	+	Inhibit CC proliferation	TA	TTC[N2–4]GAA
2. Zinc-coordinating transcription factors
2.1. C2H2 zinc-finger transcription factors
SP1	+	+	+	+	+	+	+	+	+	+	+		TA	GGCGGGG
SP7					+	+	+				+	Promotes TC differentiation	TA	GGCGGGG
ZNF521/ZFP521					+	+					+	Slows down CC to PHCs/HC transition	TR
ZBTB20/ZNF288			+		+	+	+					Inhibits chondrocyte hypertrophy	TR		Primrose syndrome
SNAI1 and SNAI2	+		+	+	+	+	+	+	+	+	+	Promote CC proliferation and PHC/HC differentiation	TR	CAGGTG
GLI1 to 3	+	+	+	+			+	+	+		+	Mediator/Inhibitor of Hedgehog signaling	TA/TR
2.2. C4 zinc-finger of nuclear receptor- type
Glucocorticoid receptor	+	+	+	+	+	+	+	+	+	+	+	Dispensable in normal conditions	TA/TR	AGAACA[n3]TGTTCT
Thyroid hormone receptors α and β				+	+	+		+			+	Accelerates (NR1A1) and inhibits (NR1A2) GPC maturation	TA/TR	AGGTCA[n4]TGACCT
Retinoic acid receptors α, β and γ				+	+			+			+	Enhance CC proliferation and matrix production	TA/TR	AGGTCA[n5]AGACCA
Peroxisome proliferator-activated receptors α, β/δ and γ	+			+	+	+						Enhances GPC gene expression (PPARG)	TA/TR	AGGTCA
2.3. Diverse C4-type zinc-finger transcription factors
GATA6	+	+										Inhibits ectopic expression of Shh in SSCs	TA	[A/T]GATA[A/G]
TRPS1	+	+			+			+	+		+	Facilitates PHC to HC transition	TR	[A/T]GATA[A/G]	Tricho-Rhino-Phalangeal syndrome
3. Helix-turn-helix transcription factors
3.1. Homeodomain transcription factors
HOX family	+							+				Specify skeletal element identity and early patterning	TA	(C/G)TAATTG	Synpolydactyly; hand-foot-genital syndrome
SHOX and SHOX2	+								+			Delay GPC maturation non-cell-autonomously	TA		Leri-Weill dyschondrosteosis and Langer mesomelic dysplasia
PRRX1	+								+			Contributes to skeletal early patterning	TA	AATTA	Agnathia-otocephaly
DLX5/DLX6	+					+	+		+		+	Promote PHC/HC differentiation	TA	[C/T]AATT[A/T]	Split-hand/foot malformation syndrome
NKX3.2/BAPX1	+	+		+						+		Promotes EC differentiation; represses GPC and ACC maturation	TR	TTAATTG	Spondylo-megaepiphyseal-metaphyseal dysplasia
3.2. Paired-domain transcription factor
PAX1/PAX9	+								+			Support cell survival	TA/TR	GTCACGGT
3.3. Forkhead-domain transcription factors
FOXC1/FOXC2	+		+	+	+	+		+			+	Contribute to skeletal patterning; promote endochondral ossification	TA	[A/C]AA[C/T]
FOXA2/FOXA3				+	+	+						Promote HC differentiation	TA	[A/C]AA[C/T]
FOXP1/FOXP2/FOXP4	+	+						+	+			Delay GP maturation and EO	TR	T[G/A]TTTAC[T/A[T/C][T/A]
FOXO1/FOXO3/FOXO4	+	+	+	+	+	+	+	+	+	+	+	Promote TC maturation	TA	[T/G]TAAACA[A/T]
3.4. Tryptophan cluster transcription factors
ERG	+	+							+			Promotes AC homeostasis	TA	ACAGGAA[G/A]
4. Basic-domain transcription factors
4.1. Basic helix-loop-helix (bHLH) transcription factors
TWIST1	+							+				Prevents SSC differentiation into skeletal cells	TR	CANNTG, E-box	Saethre-Chotzen syndrome
HIF1α/2α	+	+	+	+	+	+	+	+	+	+	+	Promote JP and GPC survival and differentiation	TA	CANNTG, E-box
HES and HEY	+		+	+	+	+		+				Delay EC differentiation; promote HC differentiation	TR	CACGTGC
SREBP1/2	+	+	+	+	+	+	+	+	+	+	+	Essential for lipid homeostasis	TA	ACTACANNTCCC
4.2. Basic leucine-zipper (bZIP) transcription factors
4.2.1. ATF/CREB family													TA/TR	GTGACGT[A/C][A/G]
ATF4/ATF3	+	+	+	+	+	+	+	+	+	+	+	Promote CC proliferation and PHC differentiation
ATF2 and CREB	+	+	+	+	+	+	+	+	+	+	+	Promote CC proliferation
ATF6			+	+	+	+						Promotes HC differentiation
BBF2H7			+	+	+							Promotes CC proliferation and PHC differentiation
4.2.2. AP1 family													TA	(TGA[G/C]TCA) or TGACGTCA
cJUN					+	+	+	+	+		+	Represses the chondrogenic fate in JPs; may promote GPC maturation
FOS								+			+	Delays HC differentiation
FOSL2					+	+	+	+			+	Promotes HC differentiation
4.2.3. MAF family
c-MAF and MAF-B		+				+	+	+				Promote endochondral ossification		Multicentric carpotarsal osteolysis syndrome (MAFB)
4.2.4. CCAAT-enhancer-binding protein family
C/EBPβ and C/EBPδ	+	+	+	+	+	+	+	+	+	+	+	Promote PHC/HC differentiation
4.3. Basic leucine-zipper (bZIP) transcription factors
4.3.1. AP2 family														GTCGGTG
AP2α, β, and γ	+		+	+	+			+				SSC survival and proliferation; delay GPC maturation
AP2ε						+				+	+	Repress Col2a1 expression in HC
5. Transcription factors with a β-hairpin exposed by a α/β-scaffold
NFIC/X	+	+	+	+	+	+	+	+	+	+	+	Promote endochondral ossification	TA/TR	TTGGC(N5)GCCAA	Marshall-Smith and Sotos syndromes
SMAD1 to 9	+	+	+	+	+	+	+	+	+	+	+	Promote chondrogenesis at virtually every step	TA/TR	GC-rich motifs (CTGGAGCC)

Abbreviations: ACC, articular chondrocyte; CC, columnar chondrocyte; EC, early chondrocyte; EO, endochondral ossification; GP, growth plate; GPC, growth plate chondrocyte; HC, hypertrophic chondrocyte; JP, joint progenitor cells; OB, osteoblast; PeriC, perichondrium cell; PC, prechondrocyte; PHC, prehypertrophic chondrocyte; SSC, skeletal progenitor/stem cell; TC, terminal chondrocyte; TA, trancriptional activator; TR, transcriptional repressor