Restoration of normal bone development by human homologue of collagen type II (COL2A1) gene in Col2a1 null mice

Rani, Pyapalli; Stringa, E.; Dharmavaram, Rita M.; Chatterjee, Devjani; Tuan, Rocky S.; Khillan, Jaspal S.

doi:10.1002/(sici)1097-0177(199901)214:1<26::aid-dvdy3>3.0.co;2-v

Cited by 18 publications

(3 citation statements)

References 26 publications

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“…The observed severely disrupted ECM architecture in central foetal growth plates following hypoglycaemia throughout gestation may have resulted, at least in part, from decreased expression of the ECM protein MATN-3, essential to structural integrity of the chondrocyte scaffold 7 . In contrast, expression of COMP, collagen IX, and collagen II were unaffected, although similarly important for growth plate structural integrity through the formation of interconnected complexes with MATN-3 7,8 . In murine growth plates, ablation of any one of these proteins causes a longitudinal, central disruption of the columnar chondrocyte organisation and decreased cell numbers, occasionally accompanied by hypertrophic chondrocytes with pyknotic nuclei 9-13 .…”

Section: Discussionmentioning

confidence: 91%

Inner histopathologic changes and disproportionate zone volumes in foetal growth plates following gestational hypoglycaemia in rats

Jensen

Mølck

Bøgh

et al. 2020

Sci Rep

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Maternal hypoglycaemia throughout gestation until gestation day (GD)20 delays foetal growth and skeletal development. While partially prevented by return to normoglycaemia after completed organogenesis (GD17), underlying mechanisms are not fully understood. Here, we investigated the pathogenesis of these changes and significance of maternal hypoglycaemia extending beyond organogenesis in non-diabetic rats. Pregnant rats received insulin-infusion until GD20 or GD17, with sacrifice on GD20. Hypoglycaemia throughout gestation increased maternal corticosterone levels, which correlated with foetal levels. Growth plates displayed central histopathologic changes comprising disrupted cellular organisation, hypertrophic chondrocytes, and decreased cellular density; expression of pro-angiogenic factors, HIF-1α and VEGF-A increased in surrounding areas. Disproportionately decreased growth plate zone volumes and lower expression of the structural protein MATN-3 were seen, while bone ossification parameters were normal. Ending maternal/foetal hypoglycaemia on GD17 reduced incidence and severity of histopathologic changes and with normal growth plate volume. Compromised foetal skeletal development following maternal hypoglycaemia throughout gestation is hypothesised to result from corticosterone-induced hypoxia in growth plates, where hypoxia disrupts chondrocyte maturation and growth plate structure and volume, decreasing long bone growth. Maternal/foetal hypoglycaemia lasting only until GD17 attenuated these changes, suggesting a pivotal role of glucose in growth plate development.

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Section: Discussionmentioning

confidence: 91%

Inner histopathologic changes and disproportionate zone volumes in foetal growth plates following gestational hypoglycaemia in rats

Jensen

Mølck

Bøgh

et al. 2020

Sci Rep

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“…Such a change in morphology results in less demarcation between the resting and proliferating zones. Restoration of type II collagen in the Col2a1 null mice rescues the animals from the lethal phenotype and from the chondrocyte disorganization (36). Overexpression of normal type II collagen in the cartilage is also responsible for embryonic dwarfism (13).…”

Section: Discussionmentioning

confidence: 99%

Bone growth retardation in mouse embryos expressing human collagenase 1

Imai¹,

Dalal²,

Hambor

et al. 2007

American Journal of Physiology-Cell Physiology

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Cellular growth and differentiation are readouts of multiple signaling pathways from the intercellular and/or extracellular milieu. The extracellular matrix through the activation of cellular receptors transmits these signals. Therefore, extracellular matrix proteolysis could affect cell fate in a variety of biological events. However, the biological consequence of inadequate extracellular matrix degradation in vivo is not clear. We developed a mouse model expressing human collagenase (matrix metalloproteinase-1, MMP-1) under the control of Col2a1 promoter. The mice showed significant growth retardation during embryogenesis and a loss of the demarcation of zonal structure and columnar array of the cartilage. Immunological examination revealed increased degradation of type II collagen and upregulation of fibronectin and alpha(5)-integrin subunit in the transgenic cartilage. The resting zone and proliferating zone of the growth plate cartilage exhibited a simultaneous increase in bromodeoxyuridine (BrdU)-incorporated proliferating cells and terminal deoxynucleotidyl transferase-mediated X-dUTP nick-end labeling-positive apoptotic cells, respectively. Chondrocyte differentiation was not disturbed in the transgenic mice as evidenced by normal expression of the Ihh and type X collagen expression. These data demonstrate that type II collagen proteolysis is an important determinant for the skeletal outgrowth through modulation of chondrocyte survival and cartilagenous growth.

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“…[59] With respect to COL1A2 gene, Spotila et al [60] demonstrated a Gly661Ser mutation in a woman with features suggestive of postmenopausal osteoporosis. Recently, Rani et al [61] expressed human COL2A1 gene in COL2A1-null mice by crossing with transgenic mice in which the human COL2A1 gene was integrated. The collagen type II expressed from the human gene rescued the lethal phenotype in the knockout mice.…”

Section: Cartilage Matrix Metabolismmentioning

confidence: 99%

Candidate Genes for Osteoporosis

Niu

2001

American Journal of PharmacoGenomics

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Osteoporosis, which afflicts 10 million Americans, is a complex disease characterized by decreased bone mass, microarchitectural deterioration of bone tissue, and an increase in fracture risk. Family and twin studies have established a genetic contribution to the etiology of osteoporosis. The biological candidate genes of osteoporosis can be ordered into 5 categories: (i) calcium homeostasis; (ii) hormonal dysfunction; (iii) osteoblast and osteoclast development and regulation; (vi) cartilage matrix metabolism; and (v) lipoprotein metabolism. In addition, genome-wide scans have identified a number of chromosomal regions harboring genes that influence bone mineral density. Moreover, the drug responses to various treatments of osteoporosis are reported to be modulated by DNA polymorphisms of the vitamin D receptor gene, the estrogen receptor 1 gene, and the transforming growth factor beta 1 gene. With the rapid advancement of the Human Genome Project and biotechnology, it will be possible to carry out parallel analyses of large numbers of candidate genes for osteoporosis and to calculate a patient's individual fracture risk in the context of specific environmental influences. This will eventually lead to more advanced diagnostic methods and more efficacious drugs targeting osteoporosis.

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Restoration of normal bone development by human homologue of collagen type II (COL2A1) gene in Col2a1 null mice

Cited by 18 publications

References 26 publications

Inner histopathologic changes and disproportionate zone volumes in foetal growth plates following gestational hypoglycaemia in rats

Inner histopathologic changes and disproportionate zone volumes in foetal growth plates following gestational hypoglycaemia in rats

Bone growth retardation in mouse embryos expressing human collagenase 1

Candidate Genes for Osteoporosis

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