Severe Extracellular Matrix Abnormalities and Chondrodysplasia in Mice Lacking Collagen Prolyl 4-Hydroxylase Isoenzyme II in Combination with a Reduced Amount of Isoenzyme I

Aro, Ellinoora; Salo, Antti M.; Khatri, Richa; Finnilä, Mikko A. J.; Miinalainen, Ilkka; Sormunen, Raija; Pakkanen, Outi; Holster, Tiina; Soininen, Raija; Prein, Carina; Clausen‐Schaumann, Hauke; Aszódi, Attila; Tuukkanen, Juha; Kivirikko, Kari I.; Schipani, Ernestina; Myllyharju, Johanna

doi:10.1074/jbc.m115.662635

Cited by 47 publications

(62 citation statements)

References 40 publications

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“…Notably, the chondrodysplasia observed in p4ha1 þ / À ;p4ha2 À / À double mutant mice is not secondary to uncompensated ER stress, but it is most likely due to severe matrix abnormalities. 38 Overall, these findings suggest that, differently from what has been recently suggested by others 16 and from what our own in vitro data imply, 15 C-P4Hs have a minor role downstream of HIF-1a in the developing growth plate. Similarly, C-P4Hs do not mediate HIF1a function as an early differentiation factor in limb bud mesenchyme.…”

Section: Hif-1a and The Fetal Growth Plate: Facts And Challengescontrasting

confidence: 71%

“…The global knockout of C-P4H-I is embryonic lethal, whereas mutant mice universally lacking C-P4H-II are alive and well with no obvious phenotypic abnormalities. 38 Consistent with our hypothesis, whereas heterozygous inactivation of both C-P4H-I and C-P4H-II (p4ha1 þ / À ;p4ha2 þ / À ) or homozygous inactivation of C-P4H-II only (p4ha2 À / À ) leads to the formation of virtually normal cartilage, growth plates from mice carrying heterozygous inactivation of C-P4H-I combined to homozygous inactivation of C-P4H-II (p4ha1 þ / À ; p4ha2 À / À ) display an inner cell death phenotype that is reminiscent of what we observed in HIF-1a null growth plates. However, despite an almost 70% decrease of C-P4H enzymatic activity, the inner cell death phenotype observed in the growth plates of p4ha1 þ / À ; p4ha2 À / À double mutant mice is extremely mild and transient; moreover, it virtually disappears postnatally, and it does not affect mouse survival.…”

Section: Hif-1a and The Fetal Growth Plate: Facts And Challengesmentioning

confidence: 99%

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HIF-1α and growth plate development: what we really know

2015

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Adaptation to low oxygen tension or hypoxia is a critical event in development and tissue homeostasis. Studies by us and others have shown that the fetal growth plate is an avascular tissue with a gradient of oxygenation, and the transcription factor hypoxia-inducible factor-1a (HIF-1a) is essential for its development. In this brief review, we will summarize our current understanding of the role of HIF-1a in fetal growth plate development, and we will discuss yet unanswered questions in the field of hypoxia and endochondral bone formation.

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Section: Hif-1a and The Fetal Growth Plate: Facts And Challengescontrasting

confidence: 71%

Section: Hif-1a and The Fetal Growth Plate: Facts And Challengesmentioning

confidence: 99%

HIF-1α and growth plate development: what we really know

2015

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“…These findings are important since collagens are primary components of the extracellular matrix of the sclera and the reduced hydroxylation of their fibrils likely lead to the typical deformation of the myopic eye . The importance of P4HA2 in the pathogenesis of myopia is further supported by evidence that its expression is very intense in the mouse eye as demonstrated by our experimental data, while it is almost undetectable in other tissues of both in human and mouse . We first performed expression and localization studies of P4HA2 in mammalian eye where this molecule co‐localizes with collagens.…”

Section: Discussionmentioning

confidence: 59%

Autosomal‐dominant myopia associated to a novel P4HA2 missense variant and defective collagen hydroxylation

et al. 2018

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We recently described a complex multisystem syndrome in which mild-moderate myopia segregated as an independent trait. A plethora of genes has been related to sporadic and familial myopia. More recently, in Chinese patients severe myopia (MYP25, OMIM:617238) has been linked to mutations in P4HA2 gene. Seven family members complaining of reduced distance vision especially at dusk underwent complete ophthalmological examination. Whole-exome sequencing was performed to identify the gene responsible for myopia in the pedigree. Moderate myopia was diagnosed in the family which was associated to the novel missense variant c.1147A > G p.(Lys383Glu) in the prolyl 4-hydroxylase,alpha-polypeptide 2 (P4HA2) gene, which catalyzes the formation of 4-hydroxyproline residues in the collagen strands. In vitro studies demonstrated P4HA2 mRNA and protein reduced expression level as well as decreased collagen hydroxylation and deposition in mutated fibroblast primary cultures compared to healthy cell lines. This study suggests that P4HA2 mutations may lead to myopic axial elongation of eyeball as a consequence of quantitative and structural alterations of collagen. This is the first confirmatory study which associates a novel dominant missense variant in P4HA2 with myopia in Caucasian patients. Further studies in larger cohorts are advisable to fully clarify genotype-phenotype correlations.

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“…Although the prolyl 4‐hydroxylase inhibitor DHB showed a similar effect in both WM239 and SKMEL‐28 cell lines, P4HA1 silencing only resulted in minor changes in the cellular behavior of the SKMEL‐28 cells. This may be due to a compensatory effect of the other common prolyl 4‐hydroxylase alpha subunit, P4HA2, which was expressed at a higher level in SKMEL‐28 cells than in WM239 cells, although previous studies have suggested that P4HA1 may largely compensate for the lack of P4HA2 but not vice versa (Aro et al , ; Holster et al , ). Further, in primary melanoma tumor samples (from http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE98349 dataset), P4HA2 was expressed at a lower level than P4HA1, and its mRNA expression was not significantly associated with survival (as analyzed by us), in concert with our data.…”

Section: Discussionmentioning

confidence: 97%

Prolyl 4‐hydroxylase subunit alpha 1 (P4HA1) is a biomarker of poor prognosis in primary melanomas, and its depletion inhibits melanoma cell invasion and disrupts tumor blood vessel walls

et al. 2020

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Melanoma is an unpredictable, highly metastatic malignancy, and treatment of advanced melanoma remains challenging. Novel molecular markers based on the alterations in gene expression and the molecular pathways activated or deactivated during melanoma progression are needed for predicting the course of the disease already in primary tumors and for providing new targets for therapy. Here, we sought to identify genes whose expression in primary melanomas correlate with patient disease‐specific survival using global gene expression profiling. Many of the identified potential markers of poor prognosis were associated with the epithelial–mesenchymal transition, extracellular matrix formation, and angiogenesis. We studied further the significance of one of the genes, prolyl 4‐hydroxylase subunit alpha 1 (P4HA1), in melanoma progression. P4HA1 depletion in melanoma cells reduced cell adhesion, invasion, and viability in vitro. In melanoma xenograft assays, we found that P4HA1 knockdown reduced melanoma tumor invasion as well as the deposition of collagens, particularly type IV collagen, in the interstitial extracellular matrix and in the basement membranes of tumor blood vessels, leading to vessel wall rupture and hemorrhages. Further, P4HA1 knockdown reduced the secretion of collagen triple helix repeat containing 1 (CTHRC1), an important mediator of melanoma cell migration and invasion, in vitro and its deposition around tumor blood vessels in vivo. Taken together, P4HA1 is an interesting potential prognostic marker and therapeutic target in primary melanomas, influencing many aspects of melanoma tumor progression.

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Severe Extracellular Matrix Abnormalities and Chondrodysplasia in Mice Lacking Collagen Prolyl 4-Hydroxylase Isoenzyme II in Combination with a Reduced Amount of Isoenzyme I

Cited by 47 publications

References 40 publications

HIF-1α and growth plate development: what we really know

HIF-1α and growth plate development: what we really know

Autosomal‐dominant myopia associated to a novel P4HA2 missense variant and defective collagen hydroxylation

Prolyl 4‐hydroxylase subunit alpha 1 (P4HA1) is a biomarker of poor prognosis in primary melanomas, and its depletion inhibits melanoma cell invasion and disrupts tumor blood vessel walls

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