A human <i>COL2A1</i> gene with an Arg519Cys mutation causes osteochondrodysplasia in transgenic mice

Sahlman, Johanna; Pitkänen, Minna; Prockop, Darwin J.; Arita, Machiko; Li, Shiwu; Helminen, Heikki J.; Långsjö, Teemu K.; Puustjärvi, Kaija; Lammi, Mikko J.

doi:10.1002/art.20552

Cited by 18 publications

(12 citation statements)

References 33 publications

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“…Defects in type II collagen have frequently been associated with the occurrence of impairments in cartilage and as a consequence bone development in humans and mice [25–36]. In support of our results, disruption of cartilage growth and development in LJD has been reported by previous studies.…”

Section: Discussionsupporting

confidence: 92%

Multigenic Delineation of Lower Jaw Deformity in Triploid Atlantic Salmon (Salmo salar L.)

et al. 2016

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Lower jaw deformity (LJD) is a skeletal anomaly affecting farmed triploid Atlantic salmon (Salmo salar L.) which leads to considerable economic losses for industry and has animal welfare implications. The present study employed transcriptome analysis in parallel with real-time qPCR techniques to characterise for the first time the LJD condition in triploid Atlantic salmon juveniles using two independent sample sets: experimentally-sourced salmon (60 g) and commercially produced salmon (100 g). A total of eleven genes, some detected/identified through the transcriptome analysis (fbn2, gal and gphb5) and others previously determined to be related to skeletal physiology (alp, bmp4, col1a1, col2a1, fgf23, igf1, mmp13, ocn), were tested in the two independent sample sets. Gphb5, a recently discovered hormone, was significantly (P < 0.05) down-regulated in LJD affected fish in both sample sets, suggesting a possible hormonal involvement. In-situ hybridization detected gphb5 expression in oral epithelium, teeth and skin of the lower jaw. Col2a1 showed the same consistent significant (P < 0.05) down-regulation in LJD suggesting a possible cartilaginous impairment as a distinctive feature of the condition. Significant (P < 0.05) differential expression of other genes found in either one or the other sample set highlighted the possible effect of stage of development or condition progression on transcription and showed that anomalous bone development, likely driven by cartilage impairment, is more evident at larger fish sizes. The present study improved our understanding of LJD suggesting that a cartilage impairment likely underlies the condition and col2a1 may be a marker. In addition, the involvement of gphb5 urges further investigation of a hormonal role in LJD and skeletal physiology in general.

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Section: Discussionsupporting

confidence: 92%

Multigenic Delineation of Lower Jaw Deformity in Triploid Atlantic Salmon (Salmo salar L.)

et al. 2016

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“…The Col2a1 sedc mouse harbours a homozygous missense mutation in Col2a1 resulting in a number of defects including osteoarthritis 111,112 . A transgenic mouse with an arginine-to-cysteine substitution at position 519 of the human COL2A1 gene has also been generated resulting in generalized OA with mild chondrodysplasia 113 . The Del1 transgenic mouse contains 6 copies of a deletion mutation in the Col2a1 gene, resulting in generalized OA lesions 114 .…”

Section: Animal Models Of Oamentioning

confidence: 99%

Modulating hedgehog signaling can attenuate the severity of osteoarthritis

Lin

Seeto

Bartoszko

et al. 2009

Nat Med

299

340

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Osteoarthritis is associated with the irreversible degeneration of articular cartilage. Notably, in this condition, articular cartilage chondrocytes undergo phenotypic and gene expression changes that are reminiscent of their end-stage differentiation in the growth plate during skeletal development. Hedgehog (Hh) signaling regulates normal chondrocyte growth and differentiation; however, the role of Hh signaling in chondrocytes in osteoarthritis is unknown. Here I examined human osteoarthritic samples and mice in which osteoarthritis was surgically induced and find that Hh signaling is activated in osteoarthritis. Using several genetically modified mice, I found that higher levels of Hh signaling in chondrocytes cause a more severe osteoarthritic phenotype. Furthermore, Ishow in mice and in human cartilage explants that pharmacological or genetic inhibition of Hh signaling reduces the severity of osteoarthritis and that runtrelated transcription factor-2 (Runx2) potentially mediates this process by regulating a disintegrin and metalloproteinase with thrombospondin type 1 motif-5 (Adamts5) expression. Together, these findings raise the possibility that Hh blockade can be used as a therapeutic approach to inhibit articular cartilage degeneration.iii ACKNOWLEDGEMENTS

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“…This result is rather well in line with those of this study. Mice with two active COL2A1 genes with Arg519Cys mutation and no active murine Col2a1 genes at the age of 2 months had distinctly thinner collagen fibrils when these were qualitatively estimated compared with fibrils from their wt littermates [Sahlman et al, 2004].…”

Section: Discussionmentioning

confidence: 99%

“…The stereological collagen fibril estimates were compared with those obtained from wt littermates. Tibial growth cartilages of the following mouse lines and the wt mice were investigated: (i) wt FVB/ N mice with two active murine Col2a1 genes (M +/+ ) (n = 8); (ii) mice with one active murine Col2a1 gene and one allele of the human COL2A1 transgene with Arg519Cys mutation (M +/-H) (n = 6) [Arita et al, 2002]; (iii) mice with no active murine Col2a1 gene alleles and one allele of the human COL2A1 transgene with Arg519Cys mutation (M -/-H) (n = 10) [Arita et al, 2002], and (iv) mice with no active murine Col2a1 gene alleles and two alleles of the human COL2A1 transgene with Arg519Cys mutation (M -/-HH) (n = 13) [Sahlman et al, 2004].…”

Section: Transgenic Micementioning

confidence: 99%

“…For example, embryos of transgenic mice made by random insertion technique of two alleles of the mutated human COL2A1 with active normal murine Col2a1 genes display a small body size, cleft palate, and disorganized growth plate with a possibly decreased density of collagen II fibrils in articular cartilage when examined qualitatively [Arita et al, 2002]. Another transgenic mouse line harboring the same mutated human COL2A1 gene construct but with no active normal murine Col2a1 genes, generated animals with dysplastic changes in their long bones, OA changes in their joints, and the mice seem to have decreased collagen fibril diameter in the growth plate cartilage at the age of 2 months when examined qualitatively [Sahlman et al, 2004]. Procollagen N -proteinase (ADAMTS-2), a zinc metalloproteinase, has been shown to cleave off the N -propeptides from both type I and II procollagens.…”

Section: Introductionmentioning

confidence: 99%

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Cartilage Collagen Fibril Network in Newborn Transgenic Mice Analyzed by Electron Microscopic Stereology

Långsjö¹,

Arita

Helminen³

2009

Cells Tissues Organs

Self Cite

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The objective was to investigate by electron microscopic stereology the properties of the cartilage collagen fibril network in newborn transgenic mice. The mice harbored transgenes targeted to affect the structure or assembly of the collagen fibrils. The mouse lines investigated here harbored either (i) one or (ii) two human COL2A1 genes with Arg519Cys mutation in addition to one or (iii) no active allele(s) of the murine Col2a1 gene, (iv) two inactive alleles of the procollagen N-proteinase genes, or (v) a human COL2A1 gene with deleted exons 16–27. In all newborn mice carrying the COL2A1 transgene with Arg519Cys mutation, the growth plate collagen fibrils were thinner than in the wild-type (wt) mice and showed clearly reduced volume fraction of the fibril network. In mice with the inactive procollagen N-proteinase genes, the fibril thickness and the volume fraction of collagen did not differ from the wt mice. In mice harboring the transgene of human COL2A1 gene with internally deleted exons 16–27, the collagen fibril diameter remained the same, but the volume density of collagen network was reduced. Using the indirect stereology, the differences in the collagen fibril stereological estimates could be reliably detected in newborn mice harboring mutations that affect the structure and assembly of collagen fibrils. The EM stereology permitted early detection of altered phenotype of the collagen fibril network in newborn transgenic mice. It is recommended that the indirect model-based stereological technique is utilized instead of the direct design-based technique for the estimation of collagen volume, surface, and length densities.

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A human COL2A1 gene with an Arg519Cys mutation causes osteochondrodysplasia in transgenic mice

Cited by 18 publications

References 33 publications

Multigenic Delineation of Lower Jaw Deformity in Triploid Atlantic Salmon (Salmo salar L.)

Multigenic Delineation of Lower Jaw Deformity in Triploid Atlantic Salmon (Salmo salar L.)

Modulating hedgehog signaling can attenuate the severity of osteoarthritis

Cartilage Collagen Fibril Network in Newborn Transgenic Mice Analyzed by Electron Microscopic Stereology

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