Primary cilia in hard tissue development and diseases

doi:10.1007/s11684-021-0829-6

Frontiers of Medicine

2021, Vol. 15

Issue (5): 657-678 https://doi.org/10.1007/s11684-021-0829-6

本期目录

Primary cilia in hard tissue development and diseases

Sijin Li¹, Han Zhang², Yao Sun²(

)

¹. Department of Orthodontics, School & Hospital of Stomatology, Tongji University, Shanghai Engineering Research Center of Tooth Restoration and Regeneration, Shanghai 200072, China
². Department of Implantology, School & Hospital of Stomatology, Tongji University, Shanghai Engineering Research Center of Tooth Restoration and Regeneration, Shanghai 200072, China

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Abstract：

Bone and teeth are hard tissues. Hard tissue diseases have a serious effect on human survival and quality of life. Primary cilia are protrusions on the surfaces of cells. As antennas, they are distributed on the membrane surfaces of almost all mammalian cell types and participate in the development of organs and the maintenance of homeostasis. Mutations in cilium-related genes result in a variety of developmental and even lethal diseases. Patients with multiple ciliary gene mutations present overt changes in the skeletal system, suggesting that primary cilia are involved in hard tissue development and reconstruction. Furthermore, primary cilia act as sensors of external stimuli and regulate bone homeostasis. Specifically, substances are trafficked through primary cilia by intraflagellar transport, which affects key signaling pathways during hard tissue development. In this review, we summarize the roles of primary cilia in long bone development and remodeling from two perspectives: primary cilia signaling and sensory mechanisms. In addition, the cilium-related diseases of hard tissue and the manifestations of mutant cilia in the skeleton and teeth are described. We believe that all the findings will help with the intervention and treatment of related hard tissue genetic diseases.

Key words： primary cilia bone mechanical sensing hard tissue cilium-related bone disease tooth

收稿日期: 2020-06-14 出版日期: 2021-11-01

Corresponding Author(s): Yao Sun

引用本文:

. [J]. Frontiers of Medicine, 2021, 15(5): 657-678.
Sijin Li, Han Zhang, Yao Sun. Primary cilia in hard tissue development and diseases. Front. Med., 2021, 15(5): 657-678.

链接本文:

https://academic.hep.com.cn/fmd/CN/10.1007/s11684-021-0829-6
https://academic.hep.com.cn/fmd/CN/Y2021/V15/I5/657

Fig.1

Fig.2

Fig.3

Diseases	Mutant genes	Clinical manifestation
Diseases	Mutant genes	Craniofacial deformity	Skeletal deformity
MZSDS	IFT140, IFT172	No reports found	Cone-shaped epiphyses of phalanges
OFD
?OFDI	CXORF5	Lobed tongue; tongue nodules; ?median pseudoclefting of the upper ?lip; clefts of the palate and tongue; ?micrognathia; abnormal dentition; ?telecanthus; hypoplasia of the alae ?nasi	Syndactyly; branchydactyly
?OFDVI	C5ORF42	Cleft or hamartoma of the tongue; ?micrognathia; additional frenula; ?cleft lip/palate	Polydactyly; skeletal dysplasia
Sensenbrenner syndrome/CED	WDR19, IFT122, WDR35, ?SPAGE17, IFT43	Dolichocephaly; high forehead; full ?cheeks; telecanthus; hypodontia ?and/or microdontia	Narrow thorax; brachydactyly; short ?limbs
Weyers acrofacial dysostosis	IFT80, EVC, EVC2	Median cleft; conical teeth; fused ?teeth; abnormal shape and number ?of lower and upper incisors; ?hypodontia; enamel hypoplasia	Postaxial polydactyly; mild shortness ?of stature with short limbs
SRPs^a
?SRPI	Unknown	Cleft lip/palate; lobed tongue	Postaxial polydactyly (++); severely ?shortened and flipper-like limbs; ?striking metaphyseal dysplasia of ?tubular bones; defective ossification in ?the calvaria, vertebrae, pelvis, and ?bones of the hands and feet
?SRPII	DYNC2H1, NEK1	Cleft lip/palate	Pre- and postaxial polysyndactyly ?(+++); short and narrow thorax with ?horizontally oriented ribs; short ?tubular bones with smooth ends; tibial ?agenesis or ovoid tibiae shorter than ?fibulae
?SRP III	IFT80, DYNC2H1	Cleft lip/palate	Polydactyly (++); extreme narrowness ?of the thorax; severely shortened ?tubular bones with round metaphyseal ?ends and lateral spikes
?SRP IV	Unknown	Flat face; hamartoma of the ?tongue; lobed tongue; cleft ?lip/palate; natal tooth	Polydactyly (+); short and narrow ?thorax with horizontally oriented ribs; ?small iliac bones; short tubular bones ?with smooth metaphyseal margins; ?bowed radii and ulna
EVC	EVC, EVC2	Dysplastic teeth; natal tooth; ?labiogingival adhesions	Polydactyly (+++); short ribs; short ?limbs
ATD	WDR34, IFT80, DYNC2H1, ?TTC21B, WDR19	Dental abnormalities	Inconstant polydactyly; short ribs and ?limbs; short stature; trident acetabular ?roof
?SRP type V	WDR35	Facial abnormalities	Polydactyly (+); acromesomelic ?hypomineralization; and campomelia
BBS	BBSome1–19	Brachycephaly/macrocephaly; ?bitemporal narrowing; male ?frontal balding; short and narrow ?palpebral fissures; long shallow ?philtrum; nasal anomalies; dental ?crowding; midfacial hypoplasia; ?mild retrognathia	Postaxial polydactyly
JS	INPP5E, ARL13B, CC2D2A, ?RPGRIP1L, TMEM67, NPHP1, ?AHI1, CEP290, CXORF5, ?TMEM216…	Large head and frontal prominence; ?arched eyebrows; drooping upper ?eyelids; widened eyes; low ears; ?triangular mouths; cleft lip/palate	Polydactyly (10%–15%); scoliosis

Tab.1

Tab.2

Fig.4

Genes	Encode protein	Function	Mutant model	Deformity
Basal body
?BBSome1–21	BBS1–21	BBS1, BBS2, BBS4, BBS5, ?BBS7, BBS8, and BBS9 along ?with an interacting protein BBIP?10 form a complex called the ?BBSome, which is involved in ?ciliary membrane biogenesis	Knockdown of bbs1 in zebrafish	Disruption of Kupffer’s vesicle ?formation, heart laterality defects ?(jogging and looping), and delay in ?melanosome retrograde transport
			Mouse BBS model (Bbs7 and ?Ift88^orpk double mutants)	Embryonic lethality
		BBS4, BBS6, and BBS8 are ?expressed in ciliated epithelia ?and localize to the centrosome ?and basal bodies	Mouse BBS models (Bbs4^−/−and ?Bbs6^−/−)	Increased face width, upward nasal ?displacement, midfacial flattening, ?and retrognathia
			bbs4, bbs6, and bbs8 zebrafish ?morphants	Shortened anterior neurocranium, ?reduced mandibles, and few ?hypoplastic branchial arches
?EVC	Evc and Evc2	Evc and Evc2 are mutually ?required for localizing to primary ?cilia and for maintaining ?their normal protein levels	Mouse BBS model (Evc^−/−)	Decreased Ptch1 and Gli1 ?expression, delayed bone collar ?formation, and advanced ?chondrocyte maturation in the ?growth plate
?EVC2	Evc and Evc2	Evc and Evc2 are mutually ?required for localizing to primary ?cilia and for maintaining ?their normal protein levels	Mouse BBS model (Evc2^−/−)	Reduced Ptch1, Gli1, and Pthrp ?expression; distalward shortening ?of the limbs and short ribs; delayed ?perichondrial osteoblast ?differentiation in the mutant growth ?plate
?CXORF5	OFD1	Maintaining the microtubule ?length stability of centrioles	OFD1-mutated human (formerly ?named “Cxorf5/71-7a”)	Craniofacial anomalies (facial skin ?milia and broadened nasal ridge), ?facial asymmetry and oral ?anomalies (hamartomas, clefts of ?the lip and palate, and dental ?abnormalities)
Transition zone
?CEP290 (also ?known as NPHP6 ?and MKS4)	CEP290	CEP290 controls ciliary protein ?composition and signaling	CEP290 nonsense mutations in ?fibroblast cells	Cilial elongation, impaired ?ciliogenesis, and ciliary ?composition defects
Motors
?DYNC2H1	DYNC2H1	DYNC2H1 plays a role in ?retrograde transport in the cilia. ?The loss of DYNC2H1 function can ?affect the movement of organelles ?and the transport of critical cargo ?necessary for signal transduction ?and skeletal development	DYNC2H1-mutated human	Perinatal lethality, skeletal disorders, ?polydactyly and multisystem organ ?abnormalities; shortened cilia and ?abnormal cytoskeletal microtubule ?architecture in chondrocytes
?WDR34	WDR34	WDR34 is a dynein intermediate ?chain that is associated with the ?retrograde IFT motor	WDR34-mutated human	Protruding abdomen, narrow thorax, ?short horizontal ribs, acetabular ?spurs, shortened femora, and ?handlebar clavicles
IFT
?IFT122	IFT122	Part of IFT-A	Loss of ift122 in zebrafish	Shortened body axis and curvature, ?cardiac edema, and small eyes
?IFT140	IFT140	Part of IFT-A	Mouse model (Ift140 mutant ?or knockout)	Perinatal lethality, slowed embryo ?development, exencephaly, ?polydactyly, severe rib defects, ?calvarial development failure, and ?cervical vertebral fusion
?TTC21B/IFT139	IFT139	Part of IFT-A	ttc21b tb-MO in zebrafish	Shortening of the embryonic axis, ?widening and kinking of the ?notochord, broadening and thinning ?of the somites
?WDR19	IFT144	Part of IFT-A	WDR19-mutated human	Skeletal anomalies, chronic renal ?failure, and retinitis pigmentosa
?IFT172	IFT172	Part of IFT-B	Knockdown of ift172 in ?zebrafish	Ventral body axis curvature, kidney ?cysts, otolith defects, retinal ?degeneration, hydrocephaly, and ?ciliogenesis defects
?IFT80	IFT80	Part of IFT-B	Mouse model (Ift80^gt/gt)	Embryonic lethality, growth ?retardation, constricted thoracic ?cages, shortened long bones, and ?characteristic bilateral preaxial ?polydactyly

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