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Abnormal chondrocyte apoptosis in the cartilage growth plate is influenced by genetic background and deletion of CHOP in a targeted mouse model of pseudoachondroplasia.

Piróg KA, Irman A, Young S, Halai P, Bell PA, Boot-Handford RP, Briggs MD - PLoS ONE (2014)

Bottom Line: Although mutant COMP is not retained in significant quantities within the ER of chondrocytes, both BiP and the pro-apoptotic ER stress-related transcription factor CHOP are mildly elevated, whilst bcl-2 levels are decreased, resulting in increased and spatially dysregulated chondrocyte apoptosis.Although abnormal apoptosis was alleviated in the resting zone following CHOP deletion, the mutant growth plates were generally more disorganised.Furthermore, the bone lengths of COMP mutant CHOP mice were significantly shorter at 9 weeks of age when compared to the COMP mutant mice, including a significant difference in the skull length.

View Article: PubMed Central - PubMed

Affiliation: Institute of Genetic Medicine, Newcastle University, Newcastle Upon Tyne, United Kingdom.

ABSTRACT
Pseudoachondroplasia (PSACH) is an autosomal dominant skeletal dysplasia caused by mutations in cartilage oligomeric matrix protein (COMP) and characterised by short limbed dwarfism and early onset osteoarthritis. Mouse models of PSACH show variable retention of mutant COMP in the ER of chondrocytes, however, in each case a different stress pathway is activated and the underlying disease mechanisms remain largely unknown. T585M COMP mutant mice are a model of moderate PSACH and demonstrate a mild ER stress response. Although mutant COMP is not retained in significant quantities within the ER of chondrocytes, both BiP and the pro-apoptotic ER stress-related transcription factor CHOP are mildly elevated, whilst bcl-2 levels are decreased, resulting in increased and spatially dysregulated chondrocyte apoptosis. To determine whether the abnormal chondrocyte apoptosis observed in the growth plate of mutant mice is CHOP-mediated, we bred T585M COMP mutant mice with CHOP- mice to homozygosity, and analysed the resulting phenotype. Although abnormal apoptosis was alleviated in the resting zone following CHOP deletion, the mutant growth plates were generally more disorganised. Furthermore, the bone lengths of COMP mutant CHOP mice were significantly shorter at 9 weeks of age when compared to the COMP mutant mice, including a significant difference in the skull length. Overall, these data demonstrate that CHOP-mediated apoptosis is an early event in the pathobiology of PSACH and suggest that the lack of CHOP, in conjunction with a COMP mutation, may lead to aggravation of the skeletal phenotype via a potentially synergistic effect on endochondral ossification.

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Bone measurements in mice lacking CHOP.A) Long bone measurements (cm) of wild type and CHOP  mice at 3, 6 and 9 weeks of age confirming that deletion of CHOP had no effect on the long bone formation (n = 10). B) Head measurements (cm) in wild type and CHOP  mice demonstrating shorter skulls in CHOP  mice at 9 weeks of age (n = 10; One Way ANOVA). Key: ICD = inner canthal distance; CHOP+/+ = wild type, CHOP−/− = knock-out. Error bars show standard error of the mean (SEM); * P<0.05.
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pone-0085145-g001: Bone measurements in mice lacking CHOP.A) Long bone measurements (cm) of wild type and CHOP mice at 3, 6 and 9 weeks of age confirming that deletion of CHOP had no effect on the long bone formation (n = 10). B) Head measurements (cm) in wild type and CHOP mice demonstrating shorter skulls in CHOP mice at 9 weeks of age (n = 10; One Way ANOVA). Key: ICD = inner canthal distance; CHOP+/+ = wild type, CHOP−/− = knock-out. Error bars show standard error of the mean (SEM); * P<0.05.

Mentions: CHOP mice were previously described as skeletally normal based on X-ray analysis performed from 1 to 12 months of age [31]. We performed a detailed analysis of radiographs from CHOP mice at 3, 6 and 9 weeks of age and confirmed that there were no significant differences in the lengths of the tibia, pelvis and femur between wild type and CHOP mice (Figure 1A and Table S1). Intramembraneous ossification (assessed by measuring the inner canthal distance) was also not affected by the deletion of CHOP. In contrast, the length of the skull, which is formed through a combination of endochondral and intramembranous ossification, was 4.7% shorter in CHOP mice at 9 weeks of age when compared to the wild type controls (n = 10) (Figure 1B and Table S1). This unexpected finding suggests a role for CHOP in skull morphogenesis.


Abnormal chondrocyte apoptosis in the cartilage growth plate is influenced by genetic background and deletion of CHOP in a targeted mouse model of pseudoachondroplasia.

Piróg KA, Irman A, Young S, Halai P, Bell PA, Boot-Handford RP, Briggs MD - PLoS ONE (2014)

Bone measurements in mice lacking CHOP.A) Long bone measurements (cm) of wild type and CHOP  mice at 3, 6 and 9 weeks of age confirming that deletion of CHOP had no effect on the long bone formation (n = 10). B) Head measurements (cm) in wild type and CHOP  mice demonstrating shorter skulls in CHOP  mice at 9 weeks of age (n = 10; One Way ANOVA). Key: ICD = inner canthal distance; CHOP+/+ = wild type, CHOP−/− = knock-out. Error bars show standard error of the mean (SEM); * P<0.05.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3928032&req=5

pone-0085145-g001: Bone measurements in mice lacking CHOP.A) Long bone measurements (cm) of wild type and CHOP mice at 3, 6 and 9 weeks of age confirming that deletion of CHOP had no effect on the long bone formation (n = 10). B) Head measurements (cm) in wild type and CHOP mice demonstrating shorter skulls in CHOP mice at 9 weeks of age (n = 10; One Way ANOVA). Key: ICD = inner canthal distance; CHOP+/+ = wild type, CHOP−/− = knock-out. Error bars show standard error of the mean (SEM); * P<0.05.
Mentions: CHOP mice were previously described as skeletally normal based on X-ray analysis performed from 1 to 12 months of age [31]. We performed a detailed analysis of radiographs from CHOP mice at 3, 6 and 9 weeks of age and confirmed that there were no significant differences in the lengths of the tibia, pelvis and femur between wild type and CHOP mice (Figure 1A and Table S1). Intramembraneous ossification (assessed by measuring the inner canthal distance) was also not affected by the deletion of CHOP. In contrast, the length of the skull, which is formed through a combination of endochondral and intramembranous ossification, was 4.7% shorter in CHOP mice at 9 weeks of age when compared to the wild type controls (n = 10) (Figure 1B and Table S1). This unexpected finding suggests a role for CHOP in skull morphogenesis.

Bottom Line: Although mutant COMP is not retained in significant quantities within the ER of chondrocytes, both BiP and the pro-apoptotic ER stress-related transcription factor CHOP are mildly elevated, whilst bcl-2 levels are decreased, resulting in increased and spatially dysregulated chondrocyte apoptosis.Although abnormal apoptosis was alleviated in the resting zone following CHOP deletion, the mutant growth plates were generally more disorganised.Furthermore, the bone lengths of COMP mutant CHOP mice were significantly shorter at 9 weeks of age when compared to the COMP mutant mice, including a significant difference in the skull length.

View Article: PubMed Central - PubMed

Affiliation: Institute of Genetic Medicine, Newcastle University, Newcastle Upon Tyne, United Kingdom.

ABSTRACT
Pseudoachondroplasia (PSACH) is an autosomal dominant skeletal dysplasia caused by mutations in cartilage oligomeric matrix protein (COMP) and characterised by short limbed dwarfism and early onset osteoarthritis. Mouse models of PSACH show variable retention of mutant COMP in the ER of chondrocytes, however, in each case a different stress pathway is activated and the underlying disease mechanisms remain largely unknown. T585M COMP mutant mice are a model of moderate PSACH and demonstrate a mild ER stress response. Although mutant COMP is not retained in significant quantities within the ER of chondrocytes, both BiP and the pro-apoptotic ER stress-related transcription factor CHOP are mildly elevated, whilst bcl-2 levels are decreased, resulting in increased and spatially dysregulated chondrocyte apoptosis. To determine whether the abnormal chondrocyte apoptosis observed in the growth plate of mutant mice is CHOP-mediated, we bred T585M COMP mutant mice with CHOP- mice to homozygosity, and analysed the resulting phenotype. Although abnormal apoptosis was alleviated in the resting zone following CHOP deletion, the mutant growth plates were generally more disorganised. Furthermore, the bone lengths of COMP mutant CHOP mice were significantly shorter at 9 weeks of age when compared to the COMP mutant mice, including a significant difference in the skull length. Overall, these data demonstrate that CHOP-mediated apoptosis is an early event in the pathobiology of PSACH and suggest that the lack of CHOP, in conjunction with a COMP mutation, may lead to aggravation of the skeletal phenotype via a potentially synergistic effect on endochondral ossification.

Show MeSH
Related in: MedlinePlus