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Deletion of IFT80 Impairs Epiphyseal and Articular Cartilage Formation Due to Disruption of Chondrocyte Differentiation.

Yuan X, Yang S - PLoS ONE (2015)

Bottom Line: Intraflagellar transport proteins (IFT) play important roles in cilia formation and organ development.Loss of IFT80 in the embryonic stage resulted in short limbs at birth.These findings demonstrate that loss of IFT80 blocks chondrocyte differentiation by disruption of ciliogenesis and alteration of Hh and Wnt signaling transduction, which in turn alters epiphyseal and articular cartilage formation.

View Article: PubMed Central - PubMed

Affiliation: Department of Oral Biology, School of Dental Medicine, University of Buffalo, State University of New York, Buffalo, NY, United States of America.

ABSTRACT
Intraflagellar transport proteins (IFT) play important roles in cilia formation and organ development. Partial loss of IFT80 function leads Jeune asphyxiating thoracic dystrophy (JATD) or short-rib polydactyly (SRP) syndrome type III, displaying narrow thoracic cavity and multiple cartilage anomalies. However, it is unknown how IFT80 regulates cartilage formation. To define the role and mechanism of IFT80 in chondrocyte function and cartilage formation, we generated a Col2α1; IFT80f/f mouse model by crossing IFT80f/f mice with inducible Col2α1-CreER mice, and deleted IFT80 in chondrocyte lineage by injection of tamoxifen into the mice in embryonic or postnatal stage. Loss of IFT80 in the embryonic stage resulted in short limbs at birth. Histological studies showed that IFT80-deficient mice have shortened cartilage with marked changes in cellular morphology and organization in the resting, proliferative, pre-hypertrophic, and hypertrophic zones. Moreover, deletion of IFT80 in the postnatal stage led to mouse stunted growth with shortened growth plate but thickened articular cartilage. Defects of ciliogenesis were found in the cartilage of IFT80-deficient mice and primary IFT80-deficient chondrocytes. Further study showed that chondrogenic differentiation was significantly inhibited in IFT80-deficient mice due to reduced hedgehog (Hh) signaling and increased Wnt signaling activities. These findings demonstrate that loss of IFT80 blocks chondrocyte differentiation by disruption of ciliogenesis and alteration of Hh and Wnt signaling transduction, which in turn alters epiphyseal and articular cartilage formation.

No MeSH data available.


Related in: MedlinePlus

Histological examination of tibial growth plates of P30 mice.Mice were administered tamoxifen at P4-7 and P14-17. (A-B and A’-B’) H&E staining of tibial growth plates of P30 IFT80f/f mice (A—B) and Col2α1; IFT80f/f mice (A’—B’). (C) Quantitative analysis of the length of the proliferation zone and the hypertrophic zone. The length of the proliferation zone in Col2α1; IFT80f/f mice was significantly reduced compared to IFT80f/f mice (n = 3). (D and D’) Safranin O stained tibial growth plates of P30 IFT80f/f mice (D) and Col2α1; IFT80f/f mice (D’). (E and E’) H&E staining of articular cartilage of P30 IFT80f/f mice (E) and Col2α1; IFT80f/f mice (E’). The green arrows indicate the ossified bone, and the blue double-ended arrows measure the distance between the tidemark and the surface of the articular cartilage. (F and F’) Safranin O stained articular cartilage of P30 IFT80f/f mice (F) and Col2α1; IFT80f/f mice (F’). (G) Quantification of the distance between the articular surface and the tidemark in the tibias of IFT80f/f and Col2α1; IFT80f/f mice (n = 3). (H) Quantification of the number of chondrocytes in the articular cartilage between the articular surface and tidemark (40× magnification fields) (n = 3).
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pone.0130618.g005: Histological examination of tibial growth plates of P30 mice.Mice were administered tamoxifen at P4-7 and P14-17. (A-B and A’-B’) H&E staining of tibial growth plates of P30 IFT80f/f mice (A—B) and Col2α1; IFT80f/f mice (A’—B’). (C) Quantitative analysis of the length of the proliferation zone and the hypertrophic zone. The length of the proliferation zone in Col2α1; IFT80f/f mice was significantly reduced compared to IFT80f/f mice (n = 3). (D and D’) Safranin O stained tibial growth plates of P30 IFT80f/f mice (D) and Col2α1; IFT80f/f mice (D’). (E and E’) H&E staining of articular cartilage of P30 IFT80f/f mice (E) and Col2α1; IFT80f/f mice (E’). The green arrows indicate the ossified bone, and the blue double-ended arrows measure the distance between the tidemark and the surface of the articular cartilage. (F and F’) Safranin O stained articular cartilage of P30 IFT80f/f mice (F) and Col2α1; IFT80f/f mice (F’). (G) Quantification of the distance between the articular surface and the tidemark in the tibias of IFT80f/f and Col2α1; IFT80f/f mice (n = 3). (H) Quantification of the number of chondrocytes in the articular cartilage between the articular surface and tidemark (40× magnification fields) (n = 3).

Mentions: To further investigate how IFT80 regulates growth plate development, we examined the structure of tibia growth plates by histological analysis. Consistent with the dwarfish phenotype, Col2α1; IFT80f/f mice displayed a significantly shorter proliferation zone and a slightly shorter hypertrophic zone compared to IFT80f/f mice (Fig 5A, 5A’, 5B, 5B’ and 5C). Safranin O staining showed the disorganized growth plate structure and reduced proteoglycan production (Fig 5D and 5D’).


Deletion of IFT80 Impairs Epiphyseal and Articular Cartilage Formation Due to Disruption of Chondrocyte Differentiation.

Yuan X, Yang S - PLoS ONE (2015)

Histological examination of tibial growth plates of P30 mice.Mice were administered tamoxifen at P4-7 and P14-17. (A-B and A’-B’) H&E staining of tibial growth plates of P30 IFT80f/f mice (A—B) and Col2α1; IFT80f/f mice (A’—B’). (C) Quantitative analysis of the length of the proliferation zone and the hypertrophic zone. The length of the proliferation zone in Col2α1; IFT80f/f mice was significantly reduced compared to IFT80f/f mice (n = 3). (D and D’) Safranin O stained tibial growth plates of P30 IFT80f/f mice (D) and Col2α1; IFT80f/f mice (D’). (E and E’) H&E staining of articular cartilage of P30 IFT80f/f mice (E) and Col2α1; IFT80f/f mice (E’). The green arrows indicate the ossified bone, and the blue double-ended arrows measure the distance between the tidemark and the surface of the articular cartilage. (F and F’) Safranin O stained articular cartilage of P30 IFT80f/f mice (F) and Col2α1; IFT80f/f mice (F’). (G) Quantification of the distance between the articular surface and the tidemark in the tibias of IFT80f/f and Col2α1; IFT80f/f mice (n = 3). (H) Quantification of the number of chondrocytes in the articular cartilage between the articular surface and tidemark (40× magnification fields) (n = 3).
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pone.0130618.g005: Histological examination of tibial growth plates of P30 mice.Mice were administered tamoxifen at P4-7 and P14-17. (A-B and A’-B’) H&E staining of tibial growth plates of P30 IFT80f/f mice (A—B) and Col2α1; IFT80f/f mice (A’—B’). (C) Quantitative analysis of the length of the proliferation zone and the hypertrophic zone. The length of the proliferation zone in Col2α1; IFT80f/f mice was significantly reduced compared to IFT80f/f mice (n = 3). (D and D’) Safranin O stained tibial growth plates of P30 IFT80f/f mice (D) and Col2α1; IFT80f/f mice (D’). (E and E’) H&E staining of articular cartilage of P30 IFT80f/f mice (E) and Col2α1; IFT80f/f mice (E’). The green arrows indicate the ossified bone, and the blue double-ended arrows measure the distance between the tidemark and the surface of the articular cartilage. (F and F’) Safranin O stained articular cartilage of P30 IFT80f/f mice (F) and Col2α1; IFT80f/f mice (F’). (G) Quantification of the distance between the articular surface and the tidemark in the tibias of IFT80f/f and Col2α1; IFT80f/f mice (n = 3). (H) Quantification of the number of chondrocytes in the articular cartilage between the articular surface and tidemark (40× magnification fields) (n = 3).
Mentions: To further investigate how IFT80 regulates growth plate development, we examined the structure of tibia growth plates by histological analysis. Consistent with the dwarfish phenotype, Col2α1; IFT80f/f mice displayed a significantly shorter proliferation zone and a slightly shorter hypertrophic zone compared to IFT80f/f mice (Fig 5A, 5A’, 5B, 5B’ and 5C). Safranin O staining showed the disorganized growth plate structure and reduced proteoglycan production (Fig 5D and 5D’).

Bottom Line: Intraflagellar transport proteins (IFT) play important roles in cilia formation and organ development.Loss of IFT80 in the embryonic stage resulted in short limbs at birth.These findings demonstrate that loss of IFT80 blocks chondrocyte differentiation by disruption of ciliogenesis and alteration of Hh and Wnt signaling transduction, which in turn alters epiphyseal and articular cartilage formation.

View Article: PubMed Central - PubMed

Affiliation: Department of Oral Biology, School of Dental Medicine, University of Buffalo, State University of New York, Buffalo, NY, United States of America.

ABSTRACT
Intraflagellar transport proteins (IFT) play important roles in cilia formation and organ development. Partial loss of IFT80 function leads Jeune asphyxiating thoracic dystrophy (JATD) or short-rib polydactyly (SRP) syndrome type III, displaying narrow thoracic cavity and multiple cartilage anomalies. However, it is unknown how IFT80 regulates cartilage formation. To define the role and mechanism of IFT80 in chondrocyte function and cartilage formation, we generated a Col2α1; IFT80f/f mouse model by crossing IFT80f/f mice with inducible Col2α1-CreER mice, and deleted IFT80 in chondrocyte lineage by injection of tamoxifen into the mice in embryonic or postnatal stage. Loss of IFT80 in the embryonic stage resulted in short limbs at birth. Histological studies showed that IFT80-deficient mice have shortened cartilage with marked changes in cellular morphology and organization in the resting, proliferative, pre-hypertrophic, and hypertrophic zones. Moreover, deletion of IFT80 in the postnatal stage led to mouse stunted growth with shortened growth plate but thickened articular cartilage. Defects of ciliogenesis were found in the cartilage of IFT80-deficient mice and primary IFT80-deficient chondrocytes. Further study showed that chondrogenic differentiation was significantly inhibited in IFT80-deficient mice due to reduced hedgehog (Hh) signaling and increased Wnt signaling activities. These findings demonstrate that loss of IFT80 blocks chondrocyte differentiation by disruption of ciliogenesis and alteration of Hh and Wnt signaling transduction, which in turn alters epiphyseal and articular cartilage formation.

No MeSH data available.


Related in: MedlinePlus