Disproportionate micromelia (Dmm) in mice caused by a mutation in the C-propeptide coding region ofCol2a1

Pace, James M.; Li, Yefu; Seegmiller, Robert E.; Teuscher, Cory; Taylor, Benjamin A.; Olsen, Bjørn R.

doi:10.1002/(sici)1097-0177(199701)208:1<25::aid-aja3>3.0.co;2-3

Cited by 48 publications

(6 citation statements)

References 53 publications

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“…However, Ddr2-deficient mice showed a non-homogenous staining pattern, predominantly in pericellular space adjacent to chondrocytes. Interestingly, similar results were observed in Dmm/Dmm mice harboring a mutation in the C-propeptide globular domain of type II collagen ( Col2a1 ) 45 as well as in mice containing an R992C mutation associated with spondyloepiphyseal dysplasia. 37 These mutations cause defects in the assembly and folding of type II collagen and alter collagen distribution in cartilage ECM.…”

Section: Discussionsupporting

confidence: 69%

“…Fibrillar type II collagen, the predominant collagen species of cartilage matrix and one of ligands for DDR2, is important for normal chondrocyte proliferation as well as maintenance of the structural integrity and cellular organization of developing tissues. [44][45][46][47][48] In this study, we evaluated type II collagen distribution in synchondroses using immunofluorescence and showed uniform staining throughout the cartilage matrix of wild type mice. However, Ddr2-deficient mice showed a non-homogenous staining pattern, predominantly in pericellular space adjacent to chondrocytes.…”

Section: Discussionmentioning

confidence: 99%

“…37 These mutations cause defects in the assembly and folding of type II collagen and alter collagen distribution in cartilage ECM. 37,44,45 Mutant mice are dwarf, have a shortened vertebral column and small rib cage as well as craniofacial defects characterized by skull dysmorphogenesis, reduced skull length, reduced cranial base length, cleft palate, and short mandible. These phenotypes are similar to those seen in Ddr2 -deficient mice.…”

Section: Discussionmentioning

confidence: 99%

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Control of Craniofacial Development by the Collagen Receptor, Discoidin Domain Receptor 2

Mohamed

Cowling

et al. 2022

Preprint

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Development of the craniofacial skeleton requires interactions between progenitor cells and the collagen-rich extracellular matrix (ECM). The mediators of these interactions are not well-defined. Mutations in discoidin domain receptor 2 (DDR2), a non-integrin collagen receptor, are associated with craniofacial abnormalities, such as midface hypoplasia and open fontanels. However, the exact role of DDR2 in craniofacial morphogenesis is not known. As will be shown, Ddr2-deficient mice exhibit defects in craniofacial bones including impaired calvarial growth and frontal suture formation, cranial base hypoplasia due to aberrant chondrogenesis and delayed ossification at growth plate synchondroses. As established by localization and lineage tracing studies, Ddr2 is expressed in progenitor cell-enriched craniofacial regions including sutures and synchondrosis resting zone cartilage, overlapping with Gli1+ cells, and contributing to chondrogenic and osteogenic lineages during skull growth. Tissue-specific knockouts further established the requirement for Ddr2 in Gli1+ skeletal progenitors and chondrocytes and suggest important functions in chondrocyte proliferation and orientation as well as ECM organization. These studies establish a cellular basis for regulation of craniofacial morphogenesis by this understudied collagen receptor.

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Section: Discussionsupporting

confidence: 69%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Control of Craniofacial Development by the Collagen Receptor, Discoidin Domain Receptor 2

Mohamed

Cowling

et al. 2022

Preprint

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“…The Dmm mouse is characterized by a three-nucleotide mutation in the C-propeptide domain of COL2A1 [30,31]. Unlike the cho/+ mouse, the heterozygote Dmm/+ mouse does exhibit mild dwarfism at birth; however, both develop OA, beginning at three months of age.…”

Section: Individuals With Chondrodystrophies Frequently Develop Eamentioning

confidence: 99%

Endoplasmic Reticulum Stress and Unfolded Protein Response in Cartilage Pathophysiology; Contributing Factors to Apoptosis and Osteoarthritis

Hughes

Oxford

Tawara

et al. 2017

IJMS

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Chondrocytes of the growth plate undergo apoptosis during the process of endochondral ossification, as well as during the progression of osteoarthritis. Although the regulation of this process is not completely understood, alterations in the precisely orchestrated programmed cell death during development can have catastrophic results, as exemplified by several chondrodystrophies which are frequently accompanied by early onset osteoarthritis. Understanding the mechanisms that underlie chondrocyte apoptosis during endochondral ossification in the growth plate has the potential to impact the development of therapeutic applications for chondrodystrophies and associated early onset osteoarthritis. In recent years, several chondrodysplasias and collagenopathies have been recognized as protein-folding diseases that lead to endoplasmic reticulum stress, endoplasmic reticulum associated degradation, and the unfolded protein response. Under conditions of prolonged endoplasmic reticulum stress in which the protein folding load outweighs the folding capacity of the endoplasmic reticulum, cellular dysfunction and death often occur. However, unfolded protein response (UPR) signaling is also required for the normal maturation of chondrocytes and osteoblasts. Understanding how UPR signaling may contribute to cartilage pathophysiology is an essential step toward therapeutic modulation of skeletal disorders that lead to osteoarthritis.

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“…In this mouse model, heterozygotes were smaller than their WT siblings and showed disproportionately short limbs and slightly hypoplastic vertebral bodies, while homozygotes died at birth and exhibited severe dwarfism with shortened limbs and snout. Other mouse models of GSDs have also been established, including for SEDC, osteoarthritis, and disproportionate micromelia (Esapa et al, 2012b;Helminen et al, 1993;Pace et al, 1997).…”

Section: Discussionmentioning

confidence: 99%

A CRISPR-engineered swine model of COL2A1 deficiency recapitulates altered early skeletal developmental defects in humans

et al.

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Loss-of-function mutations in the COL2A1 gene were recently described as a cause of type II collagenopathy, a major subgroup of genetic skeletal diseases. However, the pathogenic mechanisms associated with COL2A1 mutations remain unclear, and there are few large-mammal models of these diseases. In this study, we established a swine model carrying COL2A1 mutations using CRISPR/Cas9 and somatic cell nuclear transfer technologies. Animals mutant for COL2A1 exhibited severe skeletal dysplasia characterized by shortened long bones, abnormal vertebrae, depressed nasal bridge, and cleft palate. Importantly, COL2A1 mutant piglets suffered tracheal collapse, which was almost certainly the cause of their death shortly after birth. In conclusion, we have demonstrated for the first time that overt and striking skeletal dysplasia occurring in human patients can be recapitulated in large transgenic mammals. This model underscores the importance of employing large animals as models to investigate the pathogenesis and potential therapeutics of skeletal diseases.

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Disproportionate micromelia (Dmm) in mice caused by a mutation in the C-propeptide coding region ofCol2a1

Cited by 48 publications

References 53 publications

Control of Craniofacial Development by the Collagen Receptor, Discoidin Domain Receptor 2

Control of Craniofacial Development by the Collagen Receptor, Discoidin Domain Receptor 2

Endoplasmic Reticulum Stress and Unfolded Protein Response in Cartilage Pathophysiology; Contributing Factors to Apoptosis and Osteoarthritis

A CRISPR-engineered swine model of COL2A1 deficiency recapitulates altered early skeletal developmental defects in humans

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