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Post-weaning epiphysiolysis causes distal femur dysplasia and foreshortened hindlimbs in fetuin-A-deficient mice.

ABSTRACT: Fetuin-A / ?2-Heremans-Schmid-glycoprotein (gene name Ahsg) is a systemic inhibitor of ectopic calcification. Due to its high affinity for calcium phosphate, fetuin-A is highly abundant in mineralized bone matrix. Foreshortened femora in fetuin-A-deficient Ahsg-/- mice indicated a role for fetuin-A in bone formation. We studied early postnatal bone development in fetuin-A-deficient mice and discovered that femora from Ahsg-/- mice exhibited severely displaced distal epiphyses and deformed growth plates, similar to the human disease slipped capital femoral epiphysis (SCFE). The growth plate slippage occurred in 70% of Ahsg-/- mice of both sexes around three weeks postnatal. At this time point, mice weaned and rapidly gained weight and mobility. Epiphysis slippage never occurred in wildtype and heterozygous Ahsg+/- mice. Homozygous fetuin-A-deficient Ahsg-/- mice and, to a lesser degree, heterozygous Ahsg+/- mice showed lesions separating the proliferative zone from the hypertrophic zone of the growth plate. The hypertrophic growth plate cartilage in long bones from Ahsg-/- mice was significantly elongated and V-shaped until three weeks of age and thus prior to the slippage. Genome-wide transcriptome analysis of laser-dissected distal femoral growth plates from 13-day-old Ahsg-/- mice revealed a JAK-STAT-mediated inflammatory response including a 550-fold induction of the chemokine Cxcl9. At this stage, vascularization of the elongated growth plates was impaired, which was visualized by immunofluorescence staining. Thus, fetuin-A-deficient mice may serve as a rodent model of growth plate pathologies including SCFE and inflammatory cartilage degradation.

SUBMITTER: Brylka LJ

PROVIDER: S-EPMC5663435 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature

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Post-weaning epiphysiolysis causes distal femur dysplasia and foreshortened hindlimbs in fetuin-A-deficient mice.

Brylka Laura J LJ Köppert Sina S Babler Anne A Kratz Beate B Denecke Bernd B Yorgan Timur A TA Etich Julia J Costa Ivan G IG Brachvogel Bent B Boor Peter P Schinke Thorsten T Jahnen-Dechent Willi W

PloS one 20171031 10

Fetuin-A / α2-Heremans-Schmid-glycoprotein (gene name Ahsg) is a systemic inhibitor of ectopic calcification. Due to its high affinity for calcium phosphate, fetuin-A is highly abundant in mineralized bone matrix. Foreshortened femora in fetuin-A-deficient Ahsg-/- mice indicated a role for fetuin-A in bone formation. We studied early postnatal bone development in fetuin-A-deficient mice and discovered that femora from Ahsg-/- mice exhibited severely displaced distal epiphyses and deformed growth ...[more]

PMID: 29088242

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Project description:BackgroundIn addition to external bone shape and cortical bone thickness and distribution, the distribution and orientation of internal trabecular bone across individuals and species has yielded important functional information on how bone adapts in response to load. In particular, trabecular bone analysis has played a key role in studies of human and nonhuman primate locomotion and has shown that species with different locomotor repertoires display distinct trabecular architecture in various regions of the skeleton. In this study, we analyse trabecular structure throughout the distal femur of extant hominoids and test for differences due to locomotor loading regime.MethodsMicro-computed tomography scans of Homo sapiens (n = 11), Pan troglodytes (n = 18), Gorilla gorilla (n = 14) and Pongo sp. (n = 7) were used to investigate trabecular structure throughout the distal epiphysis of the femur. We predicted that bone volume fraction (BV/TV) in the medial and lateral condyles in Homo would be distally concentrated and more anisotropic due to a habitual extended knee posture at the point of peak ground reaction force during bipedal locomotion, whereas great apes would show more posteriorly concentrated BV/TV and greater isotropy due to a flexed knee posture and more variable hindlimb use during locomotion.ResultsResults indicate some significant differences between taxa, with the most prominent being higher BV/TV in the posterosuperior region of the condyles in Pan and higher BV/TV and anisotropy in the posteroinferior region in Homo. Furthermore, trabecular number, spacing and thickness differ significantly, mainly separating Gorilla from the other apes.DiscussionThe trabecular architecture of the distal femur holds a functional signal linked to habitual behaviour; however, there was more similarity across taxa and greater intraspecific variability than expected. Specifically, there was a large degree of overlap in trabecular structure across the sample, and Homo was not as distinct as predicted. Nonetheless, this study offers a comparative sample of trabecular structure in the hominoid distal femur and can contribute to future studies of locomotion in extinct taxa.

Project description:Na+/H+ exchanger 3 (NHE3) provides a major route for intestinal Na+ absorption. NHE3 has been considered a target of proinflammatory cytokines and enteropathogenic bacteria, and impaired NHE3 expression and/or activity may be responsible for inflammation-associated diarrhea. However, the possibility of loss of NHE3 function reciprocally affecting gut immune homeostasis has not been investigated. In this report, we describe that NHE3-deficient mice spontaneously develop colitis restricted to distal colonic mucosa. NHE3(-/-) mice housed in a conventional facility exhibited phenotypic features such as mild diarrhea, occasional rectal prolapse, and reduced body weight. Genomewide microarray analysis identified not only a large group of transport genes that potentially represent an adaptive response, but also a considerable number of genes consistent with an inflammatory response. Histological examination demonstrated changes in the distal colon consistent with active inflammation, including crypt hyperplasia with an increased number of 5-bromo-2'-deoxyuridine-positive cells, diffuse neutrophilic infiltrate with concomitant 15-fold increase in matrix metalloproteinase 8 expression, an increased number of pSer276-RelA-positive cells, and a significant decrease in periodic acid-Schiff-positive goblet cells. Real-time PCR demonstrated elevated expression of inducible nitric oxide synthase (38-fold), TNF-alpha (6-fold), macrophage inflammatory protein-2 (48-fold), and IL-18 (3-fold) in the distal colon of NHE3(-/-) mice. NHE3(-/-) mice showed enhanced bacterial adhesion and translocation in the distal colon. Colitis was ameliorated by oral administration of broad-spectrum antibiotics. In conclusion, NHE3 deficiency leads to an exacerbated innate immune response, an observation suggesting a potentially novel role of NHE3 as a modifier gene, which when downregulated during infectious or chronic colitis may modulate the extent and severity of colonic inflammation.

Dataset Information

Post-weaning epiphysiolysis causes distal femur dysplasia and foreshortened hindlimbs in fetuin-A-deficient mice.

Publications

Post-weaning epiphysiolysis causes distal femur dysplasia and foreshortened hindlimbs in fetuin-A-deficient mice.

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