Abnormal growth plate function in pigs carrying a dominant mutation in type X collagen

Nielsen, V. H.; Berthou, Christian; Arnbjerg, J.; Sørensen, Charlotte Mehlin; Jensen, Henrik Elvang; Shukri, Naseer M.; Thomsen, Bo

doi:10.1007/s003350010212

Cited by 31 publications

(18 citation statements)

References 38 publications

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“…In spontaneously occurring forms of MCDS in man [13] and pig [28], an expansion of the collagen X-expressing hypertrophic zone of the growth plate is associated with the decreased rates of longitudinal bone growth. In wt/m mice, a decrease in bone length accompanied by a growth plate hypertrophic zone expansion was apparent at 3 weeks of age compared to controls (Table 1; Figure 3).…”

Section: Discussionmentioning

confidence: 99%

Targeted Induction of Endoplasmic Reticulum Stress Induces Cartilage Pathology

et al. 2009

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Pathologies caused by mutations in extracellular matrix proteins are generally considered to result from the synthesis of extracellular matrices that are defective. Mutations in type X collagen cause metaphyseal chondrodysplasia type Schmid (MCDS), a disorder characterised by dwarfism and an expanded growth plate hypertrophic zone. We generated a knock-in mouse model of an MCDS–causing mutation (COL10A1 p.Asn617Lys) to investigate pathogenic mechanisms linking genotype and phenotype. Mice expressing the collagen X mutation had shortened limbs and an expanded hypertrophic zone. Chondrocytes in the hypertrophic zone exhibited endoplasmic reticulum (ER) stress and a robust unfolded protein response (UPR) due to intracellular retention of mutant protein. Hypertrophic chondrocyte differentiation and osteoclast recruitment were significantly reduced indicating that the hypertrophic zone was expanded due to a decreased rate of VEGF–mediated vascular invasion of the growth plate. To test directly the role of ER stress and UPR in generating the MCDS phenotype, we produced transgenic mouse lines that used the collagen X promoter to drive expression of an ER stress–inducing protein (the cog mutant of thyroglobulin) in hypertrophic chondrocytes. The hypertrophic chondrocytes in this mouse exhibited ER stress with a characteristic UPR response. In addition, the hypertrophic zone was expanded, gene expression patterns were disrupted, osteoclast recruitment to the vascular invasion front was reduced, and long bone growth decreased. Our data demonstrate that triggering ER stress per se in hypertrophic chondrocytes is sufficient to induce the essential features of the cartilage pathology associated with MCDS and confirm that ER stress is a central pathogenic factor in the disease mechanism. These findings support the contention that ER stress may play a direct role in the pathogenesis of many connective tissue disorders associated with the expression of mutant extracellular matrix proteins.

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Section: Discussionmentioning

confidence: 99%

Targeted Induction of Endoplasmic Reticulum Stress Induces Cartilage Pathology

et al. 2009

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“…Mutations in the human COL10A1 gene interfere with collagen X trimer assembly and secretion, with retention of mutant chains in the ER [21–23], resulting in metaphyseal chondrodysplasia type Schmid (MCDS) (reviewed in [24,25]). Abnormal organization of chondrocytes and an expanded hypertrophic zone (HZ) have been observed in the growth plate of a swine model for MCDS [26]. …”

Section: Introductionmentioning

confidence: 99%

Surviving Endoplasmic Reticulum Stress Is Coupled to Altered Chondrocyte Differentiation and Function

et al. 2007

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In protein folding and secretion disorders, activation of endoplasmic reticulum (ER) stress signaling (ERSS) protects cells, alleviating stress that would otherwise trigger apoptosis. Whether the stress-surviving cells resume normal function is not known. We studied the in vivo impact of ER stress in terminally differentiating hypertrophic chondrocytes (HCs) during endochondral bone formation. In transgenic mice expressing mutant collagen X as a consequence of a 13-base pair deletion in Col10a1 (13del), misfolded α1(X) chains accumulate in HCs and elicit ERSS. Histological and gene expression analyses showed that these chondrocytes survived ER stress, but terminal differentiation is interrupted, and endochondral bone formation is delayed, producing a chondrodysplasia phenotype. This altered differentiation involves cell-cycle re-entry, the re-expression of genes characteristic of a prehypertrophic-like state, and is cell-autonomous. Concomitantly, expression of Col10a1 and 13del mRNAs are reduced, and ER stress is alleviated. ERSS, abnormal chondrocyte differentiation, and altered growth plate architecture also occur in mice expressing mutant collagen II and aggrecan. Alteration of the differentiation program in chondrocytes expressing unfolded or misfolded proteins may be part of an adaptive response that facilitates survival and recovery from the ensuing ER stress. However, the altered differentiation disrupts the highly coordinated events of endochondral ossification culminating in chondrodysplasia.

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“…Unfortunately, at the time of writing, this sequence is not yet defined in the dog genome. A similar dwarfism in pigs has been found to be caused by a defect in collagen type X (Nielsen and others 2000).…”

Section: Discussionmentioning

confidence: 62%

X‐linked spondylo‐epiphyseal dysplasia tarda in the Danish‐Swedish farm hound

Arnbjerg¹,

Jensen²,

Olesen³

2006

J of Small Animal Practice

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In two litters from the same parents, three out of four males had an abnormally short leg and body length. Affected dogs showed signs of pain when moving, which could be eliminated by analgesia. On radiography, these animals had widened, radiolucent, irregularly bordered intervertebral disc spaces. When examined at seven months of age, the epiphyses appeared widened and irregular in shape and outline. General bone opacity in the vertebral column was lower in the affected male dogs than in the normal littermate. The affected dogs developed spondylosis and arthrosis of the larger limb joints. All affected dogs were euthanased on humane grounds, the eldest at the age of two years nine months. Based on the clinical and radiographic evidence, the condition seen in the male dogs described here resembles X-linked spondylo-epiphyseal dysplasia tarda caused by a collagenopathy due to malformation of COL2A1 as seen in human beings.

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Abnormal growth plate function in pigs carrying a dominant mutation in type X collagen

Cited by 31 publications

References 38 publications

Targeted Induction of Endoplasmic Reticulum Stress Induces Cartilage Pathology

Targeted Induction of Endoplasmic Reticulum Stress Induces Cartilage Pathology

Surviving Endoplasmic Reticulum Stress Is Coupled to Altered Chondrocyte Differentiation and Function

X‐linked spondylo‐epiphyseal dysplasia tarda in the Danish‐Swedish farm hound

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