Status and advances in the mechanism research on dento-maxillofacial skeletal abnormalities

doi:10.3969/j.issn.1674-8115.2024.06.001

Abstract

Abstract:

Dento-maxillofacial skeletal abnormalities exhibit high incidence rate, complex etiology, severe symptoms, difficult diagnosis and treatment, and lack of early intervention strategies, which is mainly due to insufficient exploration of mechanism research. These diseases are characterized by abnormal morphology, disordered mutual location and impaired function of bones and teeth, including skeletal abnormalities and malocclusion. Among them, maxillofacial bone and dento-periodontal complex are the two core structures, which respectively determine facial aesthetics and occlusal function. As for maxillofacial skeletal abnormalities, mechanism studies on skeletal development and pathogenesis are required for precise prevention and treatment. As for malocclusion, mechanism studies on homeostasis and stress remodeling are required from the perspective of orthodontics. Both mechanism studies can provide basic support for the diagnosis and treatment of dento-maxillofacial skeletal deformities. In this regard, previous studies usually focused on the expression maps of mutated genes and differential factors. In recent years, the development of conditional gene editing techniques, such as Cre-LoxP system, has enabled researchers to intuitively evaluate the function of key genes in a single cell lineage in vivo, helping to advance research on dento-maxillofacial skeletal abnormalities from phenotype level to molecular mechanism level. This review summarizes recent domestic and foreign researches on dento-maxillofacial skeletal abnormalities, as well as recent achievements of the author's team, and systematically proposes a research mode concluded as “One Centre, Two Motives”. The centre is dento-maxillofacial skeletal abnormalities. One motive is the development and pathogenic mechanisms of maxillofacial bone, and the other is the homeostasis and remodeling mechanisms of dento-periodontal complex. The research mode aims at systematical study of the pathogenesis and prognosis of diseases to explore potential therapies. Many advanced technologies have contributed to the exploration of “One Centre” through “Two Motives”: on the one hand, conditional gene editing models have provided a new strategy for studying the function of key factors in key cells in vivo; on the other hand, inducible conditional gene editing models have supported the precise control of the timeline for interventions after birth. Furthermore, with the help of single-cell sequencing and lineage tracing techniques, researchers have been focusing on tissue-specific stem cells, due to their in situ and characteristic functions. This situation is highly in line with the “One Centre, Two Motives” mode, and is benefit to shed a new insight on the theoretical researches and clinical applications of dento-maxillofacial skeletal abnormalities. The article reviews the “One Centre, Two Motives” mechanism research mode of dento-maxillofacial skeletal abnormalities.

Key words: dento-maxillofacial skeletal abnormality, dental and maxillofacial skeletal development, bone homeostasis, gene editing, tissue-specific stem cell

CLC Number:

JIANG Lingyong. Status and advances in the mechanism research on dento-maxillofacial skeletal abnormalities[J]. Journal of Shanghai Jiao Tong University (Medical Science), 2024, 44(6): 663-675.

Figures/Tables 6

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References 120

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Key cell lineage (marker-Cre)	Gene	Pathway	Characteristic of abnormalities	Related phenotype, syndrome or disease	Reference
NCC (Wnt1-Cre)	Med23	WNT signaling	③④	Pierre Robin syndrome, micrognathia, cleft palate	[35]
NCC (Wnt1-Cre)	Fgf18	WNT signaling	①③④	Micrognathia, cleft palate, hypoplastic craniofacial bones	[36]
NCC (Wnt1-Cre)	Six1	WNT signaling, BMP signaling	③④	Branchio-oto-renal syndrome, micrognathia, cleft palate with ankyloglossia	[37]
NCC (Wnt1-Cre)	Bmp2	BMP signaling	③④	Pierre Robin syndrome	[38]
NCC (Wnt1-Cre)	Bmp4	BMP signaling	②③④	Severe deformation of molar buds, palate, and maxilla-mandibular bony structures; defected Meckel's cartilage	[32]
NCC (Wnt1-Cre)	Foxf2	SHH signaling	④	Cleft palate	[39]
NCC (Wnt1-Cre)	Setdb1	BMP signaling, WNT signaling	④	Cleft palate	[40]
NCC (Wnt1-Cre)	Ift20	WNT signaling	①③④	Death shortly after birth due to difficulties in feeding and breathing, severe craniofacial malformation, loss of craniofacial bones, frontonasal dysplasia, micrognathia, cleft palate	[41-42]
NCC (Wnt1-Cre, Sox9-Cre)	G9a	SHH signaling	Wnt1: ①③; Sox9: ①②	Wnt1: death shortly after birth, shortened maxilla, restricted airway, frontonasal dysplasia Sox9: death shortly after birth, cranial skeletal dysplasia, smaller tooth germ, impaired tooth inner enamel epithelium	[43-45]
NCC (Wnt1-Cre)	Tak1	FGF signaling	③④	Pierre Robin syndrome, micrognathia, abnormal tongue, cleft palate	[46]
NCC (Wnt1-Cre)	Tgfbr2	FGF signaling	‒	Abnormal tongue	[47]
NCC (Wnt1-Cre)	Nell1	WNT signaling	①	Craniosynostosis	[48]
NCC (Wnt1-Cre)	Dlx3	WNT signaling	①③	Tricho-dento-osseous syndrome, defected frontal bone and mandible	[49]
NCC (Wnt1-Cre)	Yap/Taz	WNT signaling	①③	Neural tube malformation, craniofacial vascular malformation, mandibular abnormalities	[50]
NCC (Wnt1-Cre)	Tfap2	WNT signaling, RA signaling	①③④	Branchio-oto-renal syndrome, midface cleft, defected craniofacial bone	[51]
NCC (Wnt1-Cre)	Twist1	FGF signaling	①	Defected craniofacial bone	[52]
NCC (Wnt1-Cre)	Brca1/2	P53 signaling	①④	Craniostenosis, cleft palate, defected craniofacial bone	[53]
NCC (Wnt1-Cre)	Smo	SHH signaling	①	Defected craniofacial bone	[54]
NCC (Wnt1-Cre)	Ldb1	WNT signaling	④	Cleft palate	[55]
NCC (Wnt1-Cre)	Osx	FGF signaling	①③	Micrognathia, defected craniofacial bone	[28]
First branchial arch mesenchymal cell (Pax2-Cre)	Bmp4	BMP signaling	‒	Bilateral hyperplastic tissues	[32]
First branchial arch mesenchymal cell (Hand2-Cre)	Twist1	FGF signaling	③④	Micrognathia, cleft palate	[56]
Mesenchymal cell (Twist2-Cre)	Fgf18	WNT signaling	①③	Micrognathia, defected craniofacial bone	[36]
Mesenchymal cell (Twist1-Cre)	Twist1	FGF signaling	②	Defected dentin and enamel, tooth abnormalities	[57]
Osteoblast (Prx1-Cre)	Ift20	WNT signaling	①	Craniostenosis	[58]
Osteoblast (Osx-Cre, Col1-Cre)	Fgfr3	WNT signaling	①	Osx: CATSHL syndrome, frontonasal dysplasia Col1: CATSHL syndrome	[59-60]
Osteoblast (Osx-Cre)	Rar	RA signaling	①③	Vitamin A deficiency, micrognathia, frontonasal dysplasia	[61]
Osteoblast (Prx1-Cre, Osx-Cre)	Ror2	BMP signaling, STAT signaling	①②③	Robinow syndrome, brachyrhinia	[62]
Osteoblast (Prx1-Cre, Osx-Cre)	Stat3	STAT signaling	①③	AD-HIES syndrome, defected craniofacial bone	[3,63]
Osteoblast/chondroblast (Dermo1-Cre, Col2a1-Cre, Prx1-Cre, Osx-Cre)	Cbfb	WNT signaling	①②③	Dermo1 & Col2a1: Cleidocranial dysostosis, hypomineralized craniofacial bones, clavicle dysplasia Prx1: Cleidocranial dysostosis, hypomineralized parietal bones, clavicle missing Osx: Cleidocranial dysostosis, hypomineralized parietal bones, tooth deformities	[30,64-65]
Osteoblast/chondroblast (Prx1-Cre, Col2-Cre)	Recql4	P53 signaling	①②	Rothmund-Thomson syndrome, Baller-Gerold syndrome	[66]
Chondroblast (Col2-Cre)	Yap/Taz	WNT signaling	①④	Defected craniofacial bone, cleft palate	[67]
Osteoblast (Ocn-Cre)	Wls	WNT signaling	①③	Defected craniofacial bone, molar deformity	[68]
Osteoblast (Ocn-Cre)	Ift20	WNT signaling	①	Osteopenia-like phenotypes in skulls	[42]
Osteoblast (Osx-Cre)	Notch2	Notch signaling	①②③	Hajdu-Cheney syndrome	[69-70]
Osteoblast (Osx-Cre)	Fgfr2	FGF signaling	①②③	Crouzon syndrome	[71-72]
Osteoblast (Prrx1-Cre)	Gα	RANKL signaling	①	Fibrous dysplasia	[73]
Osteoblast (Osx-Cre)	Efnb1	Unclear	①③	Larger cranial height, larger interorbital and nasal widths, smaller maxillary width	[74]
Osteoblast (Osx-Cre)	Atg5	MMP signaling	①	Defected craniofacial bone	[75]
Osteoblast (Osx-Cre)	Fip200	MMP signaling	①	Defected craniofacial bone	[75]
Epithelial cell (Krt14-Cre、Eiia-Cre)	Wnt10a	WNT signaling	②	Taurodontism	[76]
Epithelial cell (Krt14-Cre)	Tgfbr2	WNT signaling	④	Soft palate cleft	[77]
Epithelial cell (Krt14-Cre)	Dlx3	WNT signaling	②	Hypomineralized enamel	[78]
Epithelial cell (Krt14-Cre)	Fgfr2	FGF signaling	②	Retarded tooth formation, cleft palate	[79]
Epithelial cell (Shh-Cre)	Wls	WNT signaling	②	Defective ameloblast and odontoblast differentiation	[76]
CNC-derived cell subset in the developing palatal mesenchyme (Osr2-Cre)	β-catenin	WNT signaling	④	Cleft palate	[80]
CNC-derived cell subset in the developing palatal mesenchyme (Osr2-Cre)	Runx2	RA signaling	④	Cleft palate	[33]
Pharyngeal endoderm cell (Foxg1-Cre)	Tbx1	Unclear	①③	Velo-cardio-facial syndrome	[81]

Key cell lineage (marker-Cre)	Gene	Pathway	Characteristic of abnormalities	Related phenotype, syndrome or disease	Reference
NCC (Wnt1-Cre)	Med23	WNT signaling	③④	Pierre Robin syndrome, micrognathia, cleft palate	[35]
NCC (Wnt1-Cre)	Fgf18	WNT signaling	①③④	Micrognathia, cleft palate, hypoplastic craniofacial bones	[36]
NCC (Wnt1-Cre)	Six1	WNT signaling, BMP signaling	③④	Branchio-oto-renal syndrome, micrognathia, cleft palate with ankyloglossia	[37]
NCC (Wnt1-Cre)	Bmp2	BMP signaling	③④	Pierre Robin syndrome	[38]
NCC (Wnt1-Cre)	Bmp4	BMP signaling	②③④	Severe deformation of molar buds, palate, and maxilla-mandibular bony structures; defected Meckel's cartilage	[32]
NCC (Wnt1-Cre)	Foxf2	SHH signaling	④	Cleft palate	[39]
NCC (Wnt1-Cre)	Setdb1	BMP signaling, WNT signaling	④	Cleft palate	[40]
NCC (Wnt1-Cre)	Ift20	WNT signaling	①③④	Death shortly after birth due to difficulties in feeding and breathing, severe craniofacial malformation, loss of craniofacial bones, frontonasal dysplasia, micrognathia, cleft palate	[41-42]
NCC (Wnt1-Cre, Sox9-Cre)	G9a	SHH signaling	Wnt1: ①③; Sox9: ①②	Wnt1: death shortly after birth, shortened maxilla, restricted airway, frontonasal dysplasia Sox9: death shortly after birth, cranial skeletal dysplasia, smaller tooth germ, impaired tooth inner enamel epithelium	[43-45]
NCC (Wnt1-Cre)	Tak1	FGF signaling	③④	Pierre Robin syndrome, micrognathia, abnormal tongue, cleft palate	[46]
NCC (Wnt1-Cre)	Tgfbr2	FGF signaling	‒	Abnormal tongue	[47]
NCC (Wnt1-Cre)	Nell1	WNT signaling	①	Craniosynostosis	[48]
NCC (Wnt1-Cre)	Dlx3	WNT signaling	①③	Tricho-dento-osseous syndrome, defected frontal bone and mandible	[49]
NCC (Wnt1-Cre)	Yap/Taz	WNT signaling	①③	Neural tube malformation, craniofacial vascular malformation, mandibular abnormalities	[50]
NCC (Wnt1-Cre)	Tfap2	WNT signaling, RA signaling	①③④	Branchio-oto-renal syndrome, midface cleft, defected craniofacial bone	[51]
NCC (Wnt1-Cre)	Twist1	FGF signaling	①	Defected craniofacial bone	[52]
NCC (Wnt1-Cre)	Brca1/2	P53 signaling	①④	Craniostenosis, cleft palate, defected craniofacial bone	[53]
NCC (Wnt1-Cre)	Smo	SHH signaling	①	Defected craniofacial bone	[54]
NCC (Wnt1-Cre)	Ldb1	WNT signaling	④	Cleft palate	[55]
NCC (Wnt1-Cre)	Osx	FGF signaling	①③	Micrognathia, defected craniofacial bone	[28]
First branchial arch mesenchymal cell (Pax2-Cre)	Bmp4	BMP signaling	‒	Bilateral hyperplastic tissues	[32]
First branchial arch mesenchymal cell (Hand2-Cre)	Twist1	FGF signaling	③④	Micrognathia, cleft palate	[56]
Mesenchymal cell (Twist2-Cre)	Fgf18	WNT signaling	①③	Micrognathia, defected craniofacial bone	[36]
Mesenchymal cell (Twist1-Cre)	Twist1	FGF signaling	②	Defected dentin and enamel, tooth abnormalities	[57]
Osteoblast (Prx1-Cre)	Ift20	WNT signaling	①	Craniostenosis	[58]
Osteoblast (Osx-Cre, Col1-Cre)	Fgfr3	WNT signaling	①	Osx: CATSHL syndrome, frontonasal dysplasia Col1: CATSHL syndrome	[59-60]
Osteoblast (Osx-Cre)	Rar	RA signaling	①③	Vitamin A deficiency, micrognathia, frontonasal dysplasia	[61]
Osteoblast (Prx1-Cre, Osx-Cre)	Ror2	BMP signaling, STAT signaling	①②③	Robinow syndrome, brachyrhinia	[62]
Osteoblast (Prx1-Cre, Osx-Cre)	Stat3	STAT signaling	①③	AD-HIES syndrome, defected craniofacial bone	[3,63]
Osteoblast/chondroblast (Dermo1-Cre, Col2a1-Cre, Prx1-Cre, Osx-Cre)	Cbfb	WNT signaling	①②③	Dermo1 & Col2a1: Cleidocranial dysostosis, hypomineralized craniofacial bones, clavicle dysplasia Prx1: Cleidocranial dysostosis, hypomineralized parietal bones, clavicle missing Osx: Cleidocranial dysostosis, hypomineralized parietal bones, tooth deformities	[30,64-65]
Osteoblast/chondroblast (Prx1-Cre, Col2-Cre)	Recql4	P53 signaling	①②	Rothmund-Thomson syndrome, Baller-Gerold syndrome	[66]
Chondroblast (Col2-Cre)	Yap/Taz	WNT signaling	①④	Defected craniofacial bone, cleft palate	[67]
Osteoblast (Ocn-Cre)	Wls	WNT signaling	①③	Defected craniofacial bone, molar deformity	[68]
Osteoblast (Ocn-Cre)	Ift20	WNT signaling	①	Osteopenia-like phenotypes in skulls	[42]
Osteoblast (Osx-Cre)	Notch2	Notch signaling	①②③	Hajdu-Cheney syndrome	[69-70]
Osteoblast (Osx-Cre)	Fgfr2	FGF signaling	①②③	Crouzon syndrome	[71-72]
Osteoblast (Prrx1-Cre)	Gα	RANKL signaling	①	Fibrous dysplasia	[73]
Osteoblast (Osx-Cre)	Efnb1	Unclear	①③	Larger cranial height, larger interorbital and nasal widths, smaller maxillary width	[74]
Osteoblast (Osx-Cre)	Atg5	MMP signaling	①	Defected craniofacial bone	[75]
Osteoblast (Osx-Cre)	Fip200	MMP signaling	①	Defected craniofacial bone	[75]
Epithelial cell (Krt14-Cre、Eiia-Cre)	Wnt10a	WNT signaling	②	Taurodontism	[76]
Epithelial cell (Krt14-Cre)	Tgfbr2	WNT signaling	④	Soft palate cleft	[77]
Epithelial cell (Krt14-Cre)	Dlx3	WNT signaling	②	Hypomineralized enamel	[78]
Epithelial cell (Krt14-Cre)	Fgfr2	FGF signaling	②	Retarded tooth formation, cleft palate	[79]
Epithelial cell (Shh-Cre)	Wls	WNT signaling	②	Defective ameloblast and odontoblast differentiation	[76]
CNC-derived cell subset in the developing palatal mesenchyme (Osr2-Cre)	β-catenin	WNT signaling	④	Cleft palate	[80]
CNC-derived cell subset in the developing palatal mesenchyme (Osr2-Cre)	Runx2	RA signaling	④	Cleft palate	[33]
Pharyngeal endoderm cell (Foxg1-Cre)	Tbx1	Unclear	①③	Velo-cardio-facial syndrome	[81]

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